clinical research organization fees

The Ultimate Guide to Clinical Trial Costs

• by Kunal Sampat
• January 29, 2022
• in Clinical Project Management

Have you been tasked to develop a clinical trial budget? Well, you’re in luck because I’m going to share everything you need to know about clinical trial costs.

Clinical trial budgets are often put together in haste. The focus is on getting the product to market as quickly as possible. Or revenues and profits.

Developing a clinical trial budget can be a confusing exercise for sponsors and CROs. There are too many cost variables to account for.  

This post covers the key cost drivers for medical device clinical trials. If you are a researcher or financial analyst working in clinical research space or simply curious about clinical trial costs, this post will serve you well.

So let’s get started.

1. Patient Grant Costs

Patient grant costs are broken down into screening, baseline and follow-up visits and medical imaging costs.

a. Screen Failures

Clinical trial protocols have inclusion and exclusion criteria to qualify patients. Strict inclusions and exclusion criteria reduce the available patient pool for trial enrollment. Clinical sites spend physician and site coordinator time to screen for potential patients.

During the budgeting process, map out the complete patient screening workflow. Speak with a few clinical sites to understand how many patients they would have to see in order to find one qualified patient.

For example, a site may need to screen four patients to find one qualified patient. Understand how many hours the site is spending on screening activities and reimburse accordingly. Therefore it’s not unusual to reimburse sites anywhere between $50 to $250+ per screen failure.

b. Baseline/index Procedure and Follow-up Visits

Depending on the clinical trial design, data is collected at baseline or index procedures and follow-up visits. The site coordinator is generally responsible for entering the data in the case report form. Sites are reimbursed for the time spent to collect clinical trial data.

Based on number and type data fields you are collecting, you’ll want to estimate the site coordinator time needed to collect and input trial data. Then multiply the estimated coordinator time by the hourly bill rate to obtain the fair market value for each patient visit.

In some cases, sponsors may choose to reimburse patients. Reimbursement for patients can include paying for their participation, reimbursement for travel, meals or overnight hotel stays.

c. Non-standard of Care Tests

A clinical trial may require non-standard of care tests such as medical imaging scans. Insurance companies or medical care agencies generally do not reimburse non-standard of care costs. Therefore you should include them in your clinical trial budget.

d. Procedure Costs

Medical payor such as Medicare or private insurance may reimburse clinical trial procedure costs. If procedure reimbursement is available, you don’t need to budget for the procedure cost. In case a brand new procedure where no reimbursement available, budget for the procedure costs.

2. Site costs

A. site start-up fees.

Clinical sites spend significant time to initiate a new clinical trial. Sites are responsible for site-specific informed consent development, Ethics Committee (EC)/ Investigational Review Board (IRB) submissions, staff training including participation in investigator/ site coordinator meetings and site initiation visits and execute a clinical trial contract. It is typical for a sponsor to pay anywhere between $3500 – $7500+ in site start-up fees.

b. Ethics Committee (EC)/ Institutional Review Board (IRB) Fees

EC/IRB fees are in addition to site start-up fees. These fees cover the time spent by EC/IRB to plan and conduct a review of the clinical trial protocol and other associated materials. Many EC/IRBs update and publish their rates annually.

c. Close-out fees

Close-out fees include time spent by site staff to reconcile clinical trial data, finances, and regulatory documents during study closure. Not all sites require this payment but, in recent years,  this cost has become a more common line item in the study budget.

d. Storage Fees

Government regulations require that clinical trial data be stored after study close-out. The duration for storage can range from 2-years to permanent storage. Thus it’s not uncommon for sites to have boxes of regulatory paperwork that need to be stored once a clinical trial ends. The storage fees vary by country and site.  

Some sponsors make arrangements for the site to send trial documents to an offsite storage location. Due to country-specific regulations, a site might be unable to move documents outside their country.

e. Administrative Overhead

Clinical sites may require as much as 30% administrative overhead in addition to per patient grant amount. This cost covers management and legal resources needed to provide clinical research oversight and legal review of clinical contracts respectively.

f. Site Management Organization (SMO)

In certain countries such as Japan, data entry and collection tasks are outsourced to SMOs. For post-approval studies, sites do not research coordinator support. Thus sponsors are expected to hire SMOs to support the site or pay the sites to hire their preferred SMOs.

3. Non-patient costs

A. clinical evaluation committee (cec).

Adverse event and endpoint data is adjudicated by a non-biased, independent CEC. CEC is generally composed of 3 or more physicians. CEC members review adverse events and trial endpoints in a team setting or independently.

A sponsor can hire physicians to serve as the CEC and reimburse them at fair market value rates. It is more cost effective for the sponsor to contract with physicians directly. But the sponsor has to assign its own resources to manage the CEC.

The other option is for the sponsor to outsource management and conduct of CEC activities. However, this option is more expensive because you are hiring professionals to manage the CEC.

CEC is a very important component of medical device clinical trial. Adjudicated adverse event data is highly regarded by regulatory agencies and the physician community. In many cases, it is a requirement to have adjudicated adverse event data in order to get the product on the market.

b. Data Safety Monitoring Board (DSMB)

DSMB is sometimes known as the Data Monitoring Committee (DMC). According to IMARC research , the purpose of the DMC is to advise the sponsor on continuing safety of the trial subjects and those yet to be recruited and provide continuing validity and scientific merit of the study.

For budgeting purposes, it is important to know that DSMB is required during the trial enrollment phase. In some cases, DSMB meetings occur until all patients have reached their primary endpoint. The decision of whether or not to conduct DSMB meetings after the primary endpoint is reached is up to the sponsor.

c. Physician consulting

Physicians are consulted during all phases of a clinical trial. Physician guidance is needed to develop clinical trial strategy, enrollment plan, final data analysis, and publication plans.

Physician consulting costs can be anywhere between $150 – $600+ per hour. The billable rate varies based on the physician’s medical expertise and geographical location. If a clinical trial is interesting to the physician, he or she may be willing to provide consulting services at little or no cost.

d. Independent core lab analysis

Many medical device trials collect imaging data such as angiograms, CT scans, and X-Rays. Since this data comes from multiple sites, variability is expected. An independent core lab standardizes the collection and analysis of imaging data.

Corelab costs can add up quickly. Costs depend upon the number of images analyzed per patient, the time it takes for the core lab to analyze the data, and the duration of the trial.

Corelabs usually hire analysts to collect and calibrate data from different sites. The final analysis is usually done by a physician. Given the complexity of imaging data collection and analysis combined with the importance of core lab data to regulatory agencies, it is important that adequate and accurate budget is allocated for independent core lab analysis.

e. Medical product cost

Once you are ready to enroll patients in the clinical trial, you’ll need to ship the medical product to the sites. Most sites will expect to receive the medical product for free. The only exception is when conducting post-approval trials for commercially available medical product.

Medical device and biologics manufacturers may conduct a trial for clinical indication expansion. For example, a stent company may conduct a trial to get their heart stent approved for use in different anatomy. For such expansion trials, sponsors may need to provide commercially available medical product to sites at no cost.  

Whether or not you want to provide the medical product at no cost is a business decision.  When investigational medical product is provided at no cost, sites can enroll faster and have a much stronger, collaborative relationship with the Sponsor.

4. Labor Costs

In order to conduct a clinical trial, you need to hire people that have expertise in clinical research and clinical trial management. Depending on the size of the trial and the number of trials conducted, resource allocations vary. Therefore the amount of labor needed to run a study also varies.

a. Clinical Research Assistants or Associates (CRAs)

CRAs are primarily responsible for monitoring clinical trial data that is collected during the course of the study. They visit clinical research sites to ensure data is collected in a compliant manner.

b. Project Manager (also known as Clinical Trial Manager or Study Manager)

A project manager’s responsibilities can vary from one organization to another. Project managers are like “general contractors.” A project manager is responsible for managing the clinical trial budget, resources, and timelines. The core function of a project manager is to resolve or escalate issues that come up during the course of a clinical study.

c. Clinical Data Manager

A data manager’s job is to address data discrepancy issues by generating queries to sites. Data managers may also be responsible for implementing an electronic data capture system or paper case report forms needed to collect trial data.

d. Clinical Research Scientist

The scientist is primarily responsible for developing the clinical strategy for a trial. Individuals with Ph.D. or M.D. degrees are usually the right fit for this role. In some organizations, the project manager also plays the role of the scientist.

e. Biostatistician

A biostatistician is responsible for developing a statistical analysis plan (SAP). The SAP documents on the data will be analyzed during the course of the study. A statistician or statistical programmer is also responsible for programming data tables that are incorporated in the final clinical study reports.

Clinical research is a regulated industry. Quality plays an important role in ensuring sponsors, CROs, and clinical sites are conducting the trial in a compliant manner. Thus a quality associate or manager helps an organization create and implement standard operating procedures (SOPs).

Salaries for these roles can vary by geography and experience. The above list is not comprehensive. However, it should give you an idea of the core resources needed to conduct a medical device clinical trial.

5. Site Management

A. pre-study visits.

Prior to inviting any site to participate in a clinical trial, you want to conduct a pre-study visit, also known as the site assessment visit. This visit becomes even more important if you don’t have any prior experience working with the site in a clinical or commercial setting.

Although sites don’t charge for this visit, the sponsor will need to pay for travel and CRA labor costs.

b. Site Initiation Visits (SIV)

Once the site has received Institutional Review Board (IRB) or Ethics Committee (EC) approval and the trial contract has been signed, it’s time to activate the site for patient enrollment.

A SIV is conducted when you are ready to activate the site. SIV involves training the site on the clinical protocol and any other study-specific requirements.

Similar to the pre-study visit, the sponsor will need to pay for travel and CRA labor costs.

c. Monitoring – Remote, Virtual, In-person

Once patients are enrolled in the study, it is critical to collect data in compliance with regulations and the clinical study protocol. This is when monitoring comes into play.

A CRA, sometimes known as the site monitor, visits clinical sites at regular intervals to ensure compliance.

In recent years, due to the push for a reduction in clinical trial costs, several sponsors have started to monitor remotely rather than conducting an in-person monitoring trip.

d. Close-out

Once all patients at a site have completed their follow-up visits, it’s time to conduct a close-out visit. Any open items related to study conduct are addressed during the close-out visit.

Although it’s always nice to have in-person close-out visits, it’s acceptable to close trials via remote close-out calls.

6. Miscellaneous

A. investigator meetings.

Investigator Meetings serve to kick-off a new clinical trial. Site investigators and research coordinators are invited to participate in a 1-2 day meeting. These meetings serve to educate site personnel on the clinical trial protocol and any other trial specific requirements.

These meetings can be quite expensive and the sponsor pays for attendee airfare, hotel, and meals. 

Plan and budget for ad hoc travel. Clinical research is highly regulated. You’ll need to visit a site to address a compliance issue or help them prepare for an audit. In other cases, you want to visit a site to motivate them to enroll patients. Whatever the case may be, it’s always good to have a bit of money set aside for travel.

c. Document Translations

Document translations cost increase significantly depending on the countries in which the clinical trial is conducted. Sites where English is not the primary language, you may receive a request for translation of key documents such as the protocol and site-specific informed consent in the local language.

Also if the adverse event source documents from non-English speaking sites are in their native language, additional costs will incur to translate documents into English for event adjudication purposes.

d. Technology solutions

To conduct clinical trials, you need systems such as Clinical Trial Management System (CTMS),  Electronic Data Capture (EDC), Electronic Trial Master File (eTMF), Interactive Voice/Web Response System (IxRS). These systems manage site contact information, collect clinical data and maintain clinical trial records. Budget monthly or annual license fees associated with these systems. Additionally, you need staff to manage and maintain these systems.

e. Regulatory filing fees

Don’t overlook regulatory filing fees. These fees can run into thousands of dollars. Depending on the class of medical device, different applications are filed with regulatory agencies, competent authorities and notified bodies.

7. Other Clinical Trial Cost Factors

A. protocol amendments.

Due to unforeseen circumstances, a clinical protocol amendment may be necessary. A protocol amendment has many downstream effects that can increase the cost of a clinical trial.

A protocol amendment usually leads to additional IRB/EC fees, site costs, regulatory re-submissions and more.

b. Inflation, Value Added Tax (VAT) and Foreign Exchange 

Don’t forget to factor inflation for multi-year clinical trials. Generally speaking, plan for a minimum of 3% inflation rate.

For sites in countries such as Australia and Europe, add VAT for the research services. The VAT can be upwards of 12% on all research services.

For trials conducted in multiple countries, pay attention to foreign exchange rates. At a minimum, an annual review of exchange rates is advised. Adjust clinical trial cost projections based on exchange rates.

c. Trial enrollment delays

Enrolling in trials is a tricky business. It takes longer to complete enrollment and initial projections are overly optimistic. Therefore account for these delays when you develop your clinical trial budget.

Conclusion:

We’ve covered a lot of ground in this Ultimate Guide to Clinical Trial Costs. To summarize, you should now have a solid understanding of these factors that impact clinical trial costs:

• Patient grant amounts such as screen failure costs, data entry costs, and travel reimbursement
• Site costs such as site start-up fees, EC/IRB fees, close-out and storage fees
• Non-patient costs such as core laboratory fees, clinical events committee and data safety monitoring board
• Labor costs such as clinical research employee salaries or contractor payments
• Site management costs such as pre-study, site initiation, monitoring, and close-out visits
• Miscellaneous costs such as travel, technology solutions, and regulatory filing costs
• Other factors such as value-added tax, inflation, protocol amendment and delays in enrollment

What’s your best tip to planning a clinical trial budget? Leave in the comment section below. 

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Tidor Morgan

Kunal, thanks for summarising this so concisely…. a really useful read and reference point for future discussion.

Hi Tidor, I’m so glad to hear you found this post useful. This should severe as a useful guide to the clinical community when it comes to planning trial budgets. Thanks again for taking the time to read and comment.

Nice summary Kunal. The overview is very concise and you touched on all the important aspects to consider when budgeting for a clinical trial.

Hey Chris, Thanks for the positive feedback 🙂 It’s good to hear from industry professionals such as yourself who developed hundreds of budget models and scenarios. If you have any other insights or suggestions, please do let me know.

Thank you for writing the article and sharing the excel file. These are great!

Kunal Sampat

Thanks Ehsan! Let me know if you have any follow-up questions. Happy to help!

Thank you, Ehsan!

Hi Kunal, what a tremendous resource you’ve provided here, thank you! I’m looking for someone to consult on a budget for a medical device trial. Do you know anyone offering these services?

Excellent, thank you.

Thank you, Laura. Glad to hear your feedback.

Thank you, Laura

Vladimir Shnaydman

Hi Kunal, Several questions. 1. How budgeting is coordinated with site selection? 2. How did you included risk in budgeting process? 3. What are major cost drivers for a clinical trial budget? Thank you, Vladimir

Hi Vladimir,

1. budgeting in most cases would not be coordinated with site selection 2. many of the clinical trial costs are tried to patient recruitment. patient recruitment is a dynamic process. you will likely need to re-forecast your budget on a regular basis depending on how fast or slow you enroll 3. Major cost drives are generally patient grant costs, labor costs, and monitoring. Every study is different and there may be other high ticket items.

This post should be renamed Clinical Trial Budgeting for dummies, as it gives an informative yet easy to understand breakdown of the whole process. Thank you Kunal.

Hi Ivy, Thank you 🙂 Kunal

Thanks Kunal , this is helpful. I may also add that it might also be required to include the product’s manufacturing costs in a study budget, especially in budgets of small Biotech companies.

Hi Uri, Yes, I agree. Product manufacturing costs should be part of the study budget. I’ve mentioned “device costs” in this article. Will update it to include “biologics costs” as well. Thanks for the input.

Francis Akenami

Hi Kunal – thank you for the comprehensive presentation. Where do you include costs for Medical Writing Services such content development for Protocols, Clinical Study Reports, Clinical Evaluation Reports, New Drug Applications and publications in peer-reviewed journals? Can they be added to the overall cost of Clinical Trials? I should think so since a Clinical Trial cannot be considered complete if those are missing.

Gerard Abate

What is the average cost per patient for a CRO for an interventional trial?

It depends on the study design.

Really got a good understanding of the basics especially when I am in a project involving a major player in the clinical trials domain. Thanks a lot!

Kenneth Quintana

What is the average time a cro spends on final data analysis? Thank You

This average time a CRO spends time on data analysis can vary based on study design (ex: how complex are your statistics), quality of the data collected (ex: lot of missing data = more time needed), and resources (ex: do you have a team to do the work). I would say plan for 3-months but it can take more or less time based on the above factors

raveena aher

thank you for sharing your blogs

Thankyou for sharing Clinical Trial Costs with us.

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• UB Directory
• Research and Economic Development >
• Research Services >
• Clinical Research >
• Set Up Study >
• Clinical Research Initiation and Maintenance Costs

Research Start-up and Maintenance Costs

There are several start-up fees when you initiate a clinical trial. These vary depending on the design of the study. Below, we have defined the fees and identifed the responsible parties.

In creating your budget, log into the rates page for up-to-date fees. 

On this page:

Administrative start-up fee.

The sponsor pays the institution a non-refundable administrative start-up fee. This covers the cost of preparing and submitting regulatory documents / required documentation to the IRB. This fee is not contingent upon receiving IRB approval and is due upon receipt of an invoice.  

Clinical Research Center (CRC) fee

This fee includes review of protocol and staff assignment for all research studies conducted at the CRC. It includes space and access to fax/copier internet for all monitoring visits.

Pharmacy fees

*The CRC pharmacy study fees shall be determined before final budgets are agreed upon.

**A separate fee will be assessed if sponsor alters protocol that increases pharmacist involvement after the final budget.                                

The sponsor pays for local IRB review of all regulatory documents. This is payable upon review and not contingent upon approval. It includes an initial review fee and any subsequent continuing review fees.

Affiliate fees

If the study is conducted in locations outside UB practice and institutional facilities, additional fees may be added on study initiation. These include standard fees charged by Erie County Medical Center and the Kaleida Health system.

Coverage Analysis / Clinical Trial Management System (CTMS) fee

The sponsor pays for the billing grid, which helps determine the party responsible for paying the clinical services costs provided to human participants enrolled in the studies.

This fee also covers the cost of setting up and maintaining the trial in the CTMS. 

Lab set-up fee

The institution pays a one-time lab set-up fee upon receipt of a correct and itemized invoice.

The sponsor covers additional training costs for the study coordinator and principal investigator if the sponsor requires training beyond that included in the site initiation visit and investigator meeting. The additional costs are based on an hourly rate and include time spent at webinars or in training on devices or equipment.

IND safety reports

The sponsor pays the institution per IND Safety report received from sponsor and acknowledged by principal investigator. This fee also includes submitting documents to local IRB if applicable.  

SAE reporting

Sponsor pays the institution for each completed SAE report. This reimburses the coordinator for his / her time spent gathering all SAE information. This fee may be adjusted depending on the complexity of the study.

Administrative IRB submission fees

The sponsor pays the institution for each annual review and/or amendment to the protocol or investigator brochure including revisions to the informed consent.

Site monitor visits and remote monitoring

• Institution receives fees for site monitor visits.  
• Sponsor pays for preparation of scheduled sessions. This includes copying, faxing, emails, conference calls and addressing outstanding items that originate from the session. 

FDA regulatory and sponsor audits

• The institution receives a fee for the FDA not-for-cause regulatory audit.
• The institution receives a fee for sponsor audit.
• These are based on hourly rates upon receipt of correct and itemized invoices from the institution .

The sponsor reimburses the institution for dry ice upon receipt of a correct and itemized invoice, not to exceed $1,000.

Unscheduled visits

CRO defines an unscheduled visit as a subject visit which is not expressly set forth in the protocol, but is otherwise required for the study. Unscheduled visits are reimbursed on a per procedure basis in accordance with the rates set forth in the budget. 

In the event a medically necessary procedure is not included in the budget, the institution must receive prior written approval before procedure is performed. Amount of compensation for a procedure not included in budget will be approved at the time written approval is provided. 

Mid-study change of monitor and/or of clinical research organization

• Institution receives a fee for each mid-study change of monitor.
• Institution receives a fee for each mid-study change of CRO. Payment is due within 30 days upon receipt of correct and itemized invoice from institution.

Close-out fee

The sponsor pays a close-out fee upon completion of all study related procedures, including resolution of all queries and notification from the IRB of study closure.

Storage fees

The sponsor pays storage fees for study documents for the duration of required storage as stated in the contract. These fees are inclusive of all items charged to the study site for preparation and storage of study documents.

Once the study has ended and the IRB has been notified of study closure, the sponsor is billed for all documents to be sent to storage. If in the future, the sponsor requests documents from storage, such as for an audit, sponsor will pay the incurred fees.

For industry sponsored studies, the start-up costs are added to the Clinical Trial Agreement. Please contact the CRO if you have any questions pka2buffalo.edu or [email protected]

Top 17 Clinical Research Organizations (CRO) in 2023

In clinical research and treatment development, clinical research organizations (CROs) are frequently a sponsor’s most important partner and ally.

Depending on the nature of the clinical trial, and your existing capabilities as a sponsor to run the trial, the CRO company of your choice will typically be responsible for facilitating most of the micro and macro processes that go into designing and running a successful clinical trial.

When contracting a CRO to help you with your trial, you are transferring over a large portion of responsibility into the hands of your clinical research partner. The CRO of your choice will have the responsibility to control a variety of factors and processes of a clinical trial, and depending on their expertise, team structures, service offerings, internal resources and many other capabilities.

Your ability to find and contract a top CRO company that is the right fit for your unique trial will be a determinant of whether or not you will be able to operate a high-quality clinical trial that meets your expected timelines, budget and delivers a top-notch patient experience.

At ClaraHealth (a patient-centric recruitment acceleration platform) , we have put together an extensive list of the top CRO companies in the US and around the world.

This is not a cro rankings list, but rather a compiled list of some of the top clinical research organizations around the world. We have highlighted their strengths and core service offerings to make it easier for you to find the right fit clinical research partner.

In addition, we’ve put together a list of 9 fundamental questions to ask the prospective clinical research organization , which will help you to save time and ensure a right fit in picking the CRO.

Formerly known as Quintiles and IMS Health, IQVIA is one of the largest CROs in the world, with a large range of service offerings to help advance clinical research.

The company was founded in North Carolina in 1982, and has since grown to over 88,000 employees in more than 100 countries.

Some clinical trial solutions offered by IQVIA include:

• Assistance with protocol design
• Design of phase 1 clinical trials
• Assessment and improvement of phase 2 and 3 clinical trials
• Site identification & selection
• Patient recruitment
• Access to global laboratories via their wholly owned subsidiary Q2 Solutions

Parexel is a global clinical research organization that was founded in 1982, and specializes in conducting clinical studies on behalf of its pharmaceutical partners in order to accelerate and ensure the drug approval process of up-and-coming potential treatments. It currently operates in more than 50 countries, and is run by more than 18,000 employees around the world.

The company has a wide range of service offerings, covering nearly every type of clinical trial service to assist sponsors in running successful clinical studies.

Some clinical trial solutions offered by Parexel include:

• Clinical trial design and development for early phase, phase 2 & 3, and late phase clinical trials
• Clinical data management
• Decentralized clinical trials
• Clinical supply chain management
• Medical writing
• Regulatory affairs consulting
• Pharmacovigilance

3. PRA Health Sciences

PRA Health Sciences is one of the largest contract research organizations in the world. Founded in 1976 under the name “Anti-Inflammatory Drug Study Group”, the company was renamed to PRA in 1982. PRA Health Sciences employees more than 17,000 people, and provides coverage to more than 90 countries.

In 2021, PRA Health Sciences was acquired by the Ireland-headquartered global CRO leader ICON, which is also reviewed in this list.

Some clinical trial solutions offered by PRA Health Sciences include:

• Decentralized Clinical Trials Platform
• Protocol Consultation & Study Design
• Onsite Support services
• Customized Solutions for Biotech (such as asset valuation, regulatory strategy, engagement and support, drug development strategy and funding solutions)
• Clinical Diagnostics
• Site Commercial Solutions
• PRA’s Laboratories for Drug Development

Headquartered in Ireland, ICON was founded in 1990 in Dublin by co-founders John Climax and Ronan Lambre. The company has since grown to be one of the largest CROs in the world. As of September 2020, the company employs more than 15,000 people in 94 locations and across 40 countries.

ICON offers clinical research services which include consulting, clinical development and commercialization across a wide range of therapeutic areas.

In 2021, ICON acquired PRA Health Sciences, which is another CRO and global leader in clinical research services.

Some clinical trial solutions offered by ICON:

• Commercial Positioning
• Early Phase
• Functional Services Provision
• Laboratories
• Language Services
• Medical Imaging
• Real World Intelligence
• Site & Patient Solutions
• COVID-19 Clinical Operations

5. Syneos Health

Formerly known as InVentiv Health Incorporated and INC Research, Syneos Health is a publicly listed and global contract research organization. The company is based in Morrisville, North Carolina, and specializes in assisting companies with late-stage clinical trials. Syneos Health currently employs more than 25,000 people, and has offices across 91 locations.

In early 2018, INC Research was acquired inVentiv Health, and the merged company was named Syneos Health.

Some clinical trial solutions offered by Syneos Health include:

• Decentralized Clinical Trials Solutions
• Bioanalytical Solutions
• Phase II-III/Phase IIIb-IIIV
• Medical Device Diagnostics
• Clinical Data Management
• Clinical Project Management
• Clinical Monitoring
• Drug Safety & Pharmacovigilance
• Site and Patient Access

6. Labcorp Drug Development (Formerly Covance)

Formerly known as Covance and renamed to Labcorp Drug Development in early 2021, this CRO is one of the largest contract research organizations in the world. The company claims to provide the world’s largest central laboratory network, and has been rated as one of the best places to work for LGBTQ+ equality by the Human Rights Campaign organization in 2018 to 2021. Currently, Labcorp employs over 70,000 people and is able to support clinical research efforts in almost 100 countries around the world.

Some clinical trial solutions offered by Labcorp Drug Development include:

• Preclinical Services
• Clinical Trials
• Clinical Trial Laboratory Services
• Post-Marketing Solutions
• Medical Devices
• Data & Technology

Also known as Pharmaceutical Product Development, PPD is a large global contract research organization headquartered in Wilmington, North Carolina. Started as a one-person consulting firm in 1985, PPD has grown to over 27,000 employees worldwide, and provides a wide range of clinical research services to pharmaceutical and biotech companies.

Some clinical trial solutions offered by PPD include:

• Clinical Development
• Early Development
• Peri- and Post-Approval
• PPD Biotech
• PPD Laboratories
• Product Development and Consulting
• Site and Patient Centric Solutions

8. Fisher Clinical Services

Part of Thermo Fisher Scientific, Fisher Clinical Services is a global clinical research organization with headquarters in Center Valley, Philadelphia.

The company has been in the business of clinical supply chain management for over 20 years, and is focused exclusively on working with the packaging and distribution requirements of clinical trials across the globe.

Some clinical trial solutions offered by Fisher Clinical Services include:

• Biologistics Management
• Cell & Gene Therapy
• Clinical Ancillary Management
• Clinical Label Services
• Clinical Trial Packaging & Storage
• Clinical Supply Optimization Services
• Cold Chain Management & Expertise
• Direct-to-Patient
• Distribution & Logistics
• Strategic Comparator Sourcing
• Public Health Research

Established in 1997 under the name Kiecana Clinical Research, KCR is a full-service contract research organization that provides a variety of services for clinical monitoring, safety & pharmacovigilance, clinical project management, quality assurance and regulatory affairs.

KCR operates globally, and has offices in North America, Western Europe, Central Europe and Eartern Europe. The company currently employs more than 700 staff.

Some clinical trial solutions offered by KCR include:

• Trial Execution

10. Medpace

Founded in 1992 and based in Cincinnati, Ohio, Medpace is a midsize clinical contract research organization. The company has operations in over 45 countries, and employs over 2,800 people. Medpace provides support services for Phase I-IV clinical trials for pharmaceutical and biotechnology companies, which include central laboratory services and regulatory services.

Some clinical trial solutions offered by Medpace include:

• Biostatistics and Data Sciences
• Clinical Trial Management
• Drug Safety and Pharmacovigilance
• Medical Writing
• Quality Assurance
• Regulatory Affairs
• Risk-Based Monitoring
• Medpace Laboratories

11. Clintec

Now in business for over 22 years, Clintec is a medium-sized global contract research organization for pharmaceutical, biotech and medical device industries, with large expertise in oncology and rare diseases.

The company provides the flexibility and agility of a smaller-sized CRO, while also having a wide global coverage that large CRO companies are known for. Clintec is based in more than 50 countries, and was acquired by the leading global CRO IQVIA in late 2018.

Some clinical trial solutions offered by Clintec include:

• Project Management
• Data Management
• Biostatistics
• Global Feasibilities
• Patient Recruitment & Retention

12. Worldwide Clinical Trials

Bringing over 30 years of experience to the clinical research market, Worldwide Clinical Trials is a leading medium-sized global contract research organization. Founded by physicians with a dedication and commitment to advancing medical research, Worldwide Clinical Trials was the first customer-centric CRO.

Currently the company has coverage in more than 60 countries, and has extensive experience in a wide range of therapeutic areas, including central nervous system, metabolic, cardiovascular, oncology, rare diseases and general medicine.

Some clinical trial solutions offered by Worldwide Clinical Trials include:

• Bioanalytical Lab
• Early Phase Development
• Clinical Phase IIB-II Clinical Trials
• Phase IIIB-IV Clinical Trials
• Trial Management Technologies

Named #1 CRO in the world for operational excellence at the 2021 CRO Leadership Awards, CTI Clinical Trial And Consulting Services is a medium-sized global contract research organization that has been serving pharmaceutical companies since 1999.

Based in Covington, Kentucky, CTI has offices around the world in more than 60 countries, with coverage in North America, Europe, Latin America, Middle-East, Africa, and Asia-Pacific regions.

Some clinical trial solutions offered by CTI include:

• Feasibility
• Regulatory Affairs Study Start-Up
• Medical Monitoring
• Safety & Pharmacovigilance
• Clinical Services

14. Wuxi AppTec

Founded in 2000 as WuXi PharmaTech in the city of Wuxi, China, Wuxi AppTec has grown from a single laboratory into a leading global contract research organization with more than 28,000 employees, including 23,000 scientists and more than 30 research & development and manufacturing sites around the world.

With offices in Asia, U.S, Europe and the Middle East, the company is able to provide coverage to more than 30 countries around the world.

Some clinical trial solutions offered by Wuxi AppTec include:

• Small Molecule Drug R&D and Manufacturing
• Cell Therapy and Gene Therapy
• Drug R&D and Medical Device Testing
• Clinical Services (Phase I-IV)

15. Advanced Clinical

Founded in 1994 and based out of Deerfield, Illinois, Advanced Clinical is a midsize and full-service CRO that helps sponsors with running clinical trials. The company employs more than 700 staff, and offers a wide variety of services across many therapeutic areas. Advanced Clinical has global representation in over 50 countries around the world.

Some clinical trial solutions offered by Advanced Clinical include:

• eTMF & Document Management
• Global Medical Services
• Quality & Validation

16. Pharm-Olam

Pharm-Olam is a leading midsize CRO with global headquarters located in Houston, Texas and its European headquarters in Bracknell, United Kingdom. The company employs more than 800 staff, and has 25 offices around the world, with a global coverage in more than 60 countries.

The company has therapeutic expertise in 5 areas, including Rare & Orphan Disease, Infectious Disease & Vaccine, Oncology-Hematology, Allergy and Autoimmune.

Some clinical trial solutions offered by Pharm-Olam include:

• Study Feasibility
• Site Activation
• Patient Recruitment
• Medical Affairs
• Compliance & Training
• Clinical Monitoring & Operations

17. Clinipace

Founded in 2003 and based out of Morrisville, North Carolina, Clinipace is a global midsize full-service CRO with a focus on solution customization for clinical trials. The company has a large global coverage in more than 50 countries, and has offices in North America, South America, Europe and Asia-Pacific regions.

Clinipace’s therapeutic focus areas include Oncology, Nephrology and Urology, Rare Disease, Gastroenterology and Women’s Health. The company also has complete therapeutic expertise in Infectious Disease & Vaccines, Cardiology, CNS, Immunology, and Respiratory.

Some clinical trial solutions offered by Clinipace include:

• Clinical Analytics
• Clinical Technology and Ecosystem
• Functional Service Partnership (FSP)
• Regulatory & Strategic Product Development

9 Fundamental Questions To Ask A Top CRO Company Before Signing The Contract

1. which services does the cro provide.

CROs offload a lot of operational tasks from trial sponsors, which can touch any component of clinical trial operations. From formulating an overall study strategy and implementing technologies to support the operational processes of the trial, to picking and identifying sites, and supporting patients during the trial, the range of clinical services offered by a CRO tends to be vast and inclusive of all the typical services and support you will require for running a successful clinical trial.

However, not all CROs are the same in their service offerings, or are able to offer the same depth of capability within a seemingly same clinical trial support process. For this reason it is important to understand exactly which kind of clinical services and support you are looking to receive from the prospective CRO when running your clinical trial.

While services such as clinical monitoring and clinical trial management are offered by the majority of CROs, the specific needs of each trial are unique, and for this reason it is important to first identify what will be the unique services your trial requires. Completing this internal analysis first will help you to understand the extent to which a potential CRO partner will be able to provide all of these services.

Some CROs specialize in specific clinical trial functions which the company may label as a “core services”, in which case this is a sign the company will have more expertise, experience, and will be set up in a way to maximize their capabilities in providing support for these services compared to other services that the CRO offers.

For example, a CRO may include patient recruitment as part of its “core services”, which implies that they are highly skilled in and have the necessary infrastructure to design and implement a high-quality patient recruitment strategy.

Clara Health CRO Support Services: At Clara Health our specialty services include technology-augmented digital and patient advocacy recruitment, as well as patient support via our signature patient recruitment platform, which we use to upgrade clinical trials and deliver results sponsors look for in their recruitment and retention campaigns.

At Clara, we work alongside CROs to supplement and support clinical trials with modern and personalized capabilities that CROs do not typically have the bandwidth, corporate structure or infrastructure to support.

If you would like to learn more about exactly how our platform can upgrade your unique trial, feel free to book a Free 30 Minute Consultation Session Here with one of our in-house experts.

2. What Related Experience Does The CRO Have?

It is helpful to ask the prospective CRO company if they have any relevant experience in running clinical trials that would be an asset in designing and running your study. Previous experience in a related therapeutic area or in running a trial with a similar design allows CROs to have a deeper understanding into potential opportunities and challenges, increasing the likelihood of your clinical study being successful.

For example, if a sponsor is planning to run a trial in oncology, for the purpose of site identification and selection it would be valuable to partner with a CRO vendor that has expertise in this area, as they likely already have a good understanding of which sites will lead to optimal results.

However, it is also important to consider all factors when selecting a CRO vendor and not to rely on therapeutic experience as the sole qualifier for whether or not a potential CRO is a fit for your trial. While previous experience is beneficial, some sponsors close themselves off from working with vendors that have not worked in their therapeutic area, which significantly limits options when choosing a CRO partner that is truly a good fit for their clinical study.

This can impact the end result of your clinical study, as sponsors that are not successful in choosing a CRO vendor that is the right overall fit may face difficulties if the needs of their clinical study aren’t being properly met.

Clara Health: We have worked to provide support for clinical trials across a wide range of therapeutic areas and trial designs. Our specialty is filling in the gaps that CROs traditionally did not have to think about, which include digital patient recruitment, patient advocacy recruitment, and technology-augmented patient support.

Additionally, we are constantly building our proprietary data and running tests in a variety of therapeutic areas. These research efforts allow us to have a detailed understanding of the expected level of difficulty when recruiting particular patient populations, as well as allow us to predict with accuracy which segments of the targeted population will be likely to qualify in a particular study.

3. What Are The Communication Workflows & Expectations For Performing And Delivering Contracted Services?

It is important that you clarify what the expectations for communication will be between your prospective CRO vendor and your internal teams, as you will most likely be working with the CRO of your choice for the entire duration of your clinical trial.

There are a vast variety of factors and success determinants for a clinical trial, which are continuously undergoing change as the study unfolds. For this reason, it is recommended that you work with a CRO that is proactive in their communication, so that you are kept up to date with information about important changes as your clinical trial progresses.

A vendor that is proactive rather than reactive in their communication and approach to dealing with arising issues is one of the most important qualities in CRO. Challenging situations will naturally arise, and the promptness with which they are taken care of will significantly impact your clinical trial’s degree of success. Therefore, seeking a vendor that is able to match the standard of communication that you as a sponsor would like to experience throughout the duration of your partnership is one of the most critical steps in determining which CRO is the right fit for your clinical trial.

We’ve included a few additional questions pertaining to the communication structure and reporting expectations that you can ask a prospective CRO vendor to determine the degree of fit in this particular category:

Communication Expectations:

• If we were to move forward with you, which of your team members will be our main point of contact?
• How available will you be outside of the scheduled meetings to address any of our concerns or additional requests?
• What will be the frequency at which update meetings will be conducted, and who will be present at those meetings?
• Which clinical study processes will be reported on, and what will be the workflow for how we will receive this information?
• What will be the cadence at which we will receive progress reports?
• Would we be able to access metrics electronically via an interactive dashboard, or will you send us formal reports?

Clara Health: At Clara Health, we directly interact and actively work with several key stakeholders involved in running a clinical trial, which includes sponsors, CROs, sites, and patients. This unique position allows us to have a centralized perspective which helps us to see all the moving parts of a clinical trial at the same time, which helps to identify issues and relay this vital information and insight back to the sponsor (or other appropriate stakeholders) in the shortest time possible.

The ability to access this perspective allows us to gather the most accurate, complete, and up-to-date information about how the clinical trial is unfolding, and quickly becomes very valuable to sponsors for their clinical trial.

As an example, we may receive feedback from patients about having an unsatisfactory experience with a particular study site. We are able to aggregate and analyze this information, and relay our findings back to the sponsor and the study site to improve the experience for other patients.

4. What Is The CRO’s Client Satisfaction Record?

It is a good practice to request information or metrics from the prospective CRO vendor that can point to the degree of satisfaction of their past clients. Prior to signing the contract, vendors will naturally do their best to uplift their image and future value to you during their sales conversations with you and your team. It can be tricky to get an objective understanding of what the partnership experience will actually entail, especially when there are multiple vendors fighting for your commitment.

We recommend that you ask the prospective vendor to provide success metrics regarding areas of clinical trial operations that are going to be important for your trial.

For example, you may be interested in learning about the vendor’s relationship to finances, in which case it will be useful to ask them about situations in which they went over the planned budget, and investigate into the reasons behind that. Alternatively you may be concerned about potential delays in timelines, in which case it would be helpful to learn about metrics regarding the CRO’s ability to meet timeline expectations.

You may also request to talk to the prospective CRO’s past clients, which will help you to gain insight into what the relationship was like and give you the opportunity to examine if the way in which the particular CRO manages its relationships and performs its services meets the expectations that you would have for your potential relationship and for your clinical trial.

Clara Health: At Clara Health, our relationships with our partners and with our patients are most important to us. In the unique position where we fit in the clinical trial process, we have the opportunity to directly co-create the clinical trial patient experience with a variety of stakeholders, including sponsors, sites, CROs, and patients.

Our company’s values and culture have been directed and developed to be such that the client and patient experience is at the top of priority for all of our internal teams, and we work to provide the best quality of care to all stakeholders.

We have many testimonials from every type of partner we’ve worked with which we can happily share with you.

5. How Do You Adapt When Encountering Challenges With Running A Clinical Trial?

It is inevitable that challenges and unforeseen changes will arise throughout the operational clinical trial process, and for this reason it is important to work with a CRO vendor that can provide you with evidence of their flexibility and ability to adapt to sudden changes.

The ideal CRO partner is one that is highly consultative throughout the entire process, and has an ability and the initiative to deal with challenges at their seed stage, prior to them turning into major obstacles for the success of your trial.

CROs naturally have a large reach, and there are a lot of different clinical trial mechanisms and processes that are under their control. They are able to monitor and respond to what is going on in every key link in the chain of the clinical trial operation.

It is reasonable to expect this level of oversight from a CRO, and additional questions that can help you gain insight into this include:

• What are some examples where the CRO was effective at monitoring the health of clinical trials they’ve helped operate in the past?
• How quickly does the CRO respond to challenges or opportunities for improving the clinical trial experience?
• How well does the CRO gather & process information from study sites, study teams, patients & the sponsor, and what are their typical data analysis workflows?

It is also recommended to speak to the prospective CROs past clients to help you gain insight into how well they respond and adapt to the naturally arising challenges in clinical trials.

Clara Health: While CROs do have a large reach within the clinical trial, no CRO has complete visibility into every clinical process. They are not typically set up to support full visibility, which can manifest as a potential threat to your clinical trial as it unfolds. This is especially true for parts of the clinical trial processes that CROs naturally do not specialize and often subcontract, such as clinical trial recruitment.

At Clara, we are in a unique position in relation to other key partners involved in operating the clinical trial. We are in direct and frequent contact with patients, CROs, study sites, study teams, and the sponsor, and have a very deep understanding of the patient pipeline. This allows us the unique ability to go very deep into specific parts of the recruitment chain and investigate what is working and what is not working.

In addition, Clara functions as a resource for all partners in the clinical trial. For example, we work directly with site teams to ensure that they have access to a 3rd party that they can relay their needs to and receive fast support in case there is anything they require that can improve the patient recruitment process.

6. Which Parts Of Operating The Clinical Trial Will You Be Outsourcing?

Since there are so many processes and mechanisms that go into operating a clinical trial, CROs will always outsource some parts of running and managing the study. While you can expect that the prospective CRO will subcontract some of the work, it is important to find out which exact parts the clinical study will be outsourced.

There are certain basic and key clinical processes (such as site selection) that CROs almost always help with, and if you find that these parts of your trial are going to be subcontracted to another company, it is recommended to find out why the CROs operations are set up this way and how this would impact the service you will receive.

Ultimately what matters to you as a partner and client is that the quality of service and care that you will receive will be up to standard, and meet what was promised and what you are expecting. While this trust is important after you have signed the contract, it is recommended that prior to entering into such a significant commitment that you have evidence and the conviction that the CRO of your choice is truly the right fit and will deliver the quality of service that was being discussed.

Since it is impossible to predict exactly what the quality of this relationship and services performed will actually be like in practice, it is recommended that you understand the details of what will be done for your trial and how. Investigating how the CRO outsources and subcontracts services for a clinical trial will help you to gain necessary insight that you would need to make the correct vendor selection decision.

Clara Health: At Clara, we maximize the effectiveness of the digital component across the entire digital & recruitment spectrum, which is added on top of the existing capabilities of the CROs and other vendors involved in operating your clinical trial. In addition, we offer services that augment the CROs efforts, which has the potential to significantly improve the patient experience, operations flows, recruitment and retention performance, which is so important in ensuring the success of a clinical trial.

For example, if a CRO wants to have a great site relationship, we are able to come in as a third party on behalf of the sponsor and CRO and act as a resource and additional support for sites.

In another example, If a sponsor wants to have great relationships with the patient community, Clara is able to come in on behalf of the sponsor and develop these relationships while being perceived more neutrally by the patient community.

7. Do You Have Experience Running International Trials?

If you are planning on operating an international clinical trial, it is recommended to work with a CRO that has extensive experience in this area. While many CROs will offer near-global coverage, the level of experience with specific geographic locations can significantly vary from one vendor to another.

It is important to work with a CRO that has experience running clinical trials in the specific countries and regions you are planning to conduct your research in. Being compliant with the local rules and regulations for clinical testing is a very complex process that requires existing understanding and familiarity in order to ensure logistical smoothness and to mitigate legal risks. In operating a clinical trial, there are a multitude of clinical services and processes, which can greatly vary across the many regions in which you can conduct clinical testing.

A CRO that is lacking experience in operating international trials or operating in particular regions where you plan on conducting research may not be able to meet your desired quality and agility expectations, and therefore may not be the right fit for your international clinical trial.

Clara Health: In the past, we have provided international patient recruitment and digitally-augmented trial support services for clinical trials in the EU, Canada, UK, Australia and South America.

Clara Health is fully compliant to operate international studies everywhere in the world, with the exception of Russia and China.

8. What Is Your Relationship With Patients?

Patient-centric approach to designing and operating a clinical trial is becoming more and more crucial in the clinical research space. The ability of a sponsor and their CRO partner to understand the needs and characteristics of their target patient community is a significant determinant of whether or not the study will be a success.

A sponsor that has close and authentic relationships with the patient community tends to have a deeper understanding of how to create the best clinical trial experience that will attract patients and keep their interest throughout the clinical trial.

In addition, strong relationships with patients allow sponsors and CROs to forecast recruitment and patient retention pipeline with much higher accuracy. This ability is critical for ensuring the success of the trial and mitigating the risk of low enrollment. After an understanding of the patient population is acquired, sponsors gain the necessary insight to design a clinical trial that is not only favorable to their research results, but is also practical and will result in the enrollment numbers they are looking for.

While many CROs have already recognized the importance of patient-centricity and evolved the ways in which they design and operate clinical trials, other CROs have not yet made such a pivot in their values. It is important to understand the degree of importance the prospective CRO places on creating a favorable patient experience, and what kind of infrastructure the company has to support it.

At Clara, we recommend choosing a CRO partner that is adapting to the patient-centric model which is becoming more and more important for running a successful clinical trial.

Clara Health: Since early stages of our development, we’ve had a dedicated patient advocacy team that has been integral in shaping our company’s vision and operations. We have built our entire platform and recruitment infrastructure around creating the best experience for patients. Our teams, corporate values, service offerings and company infrastructure all work in the service of the patient.

In addition, over the many years of being in business we have heavily invested in building authentic patient community relationships that span across a variety of therapeutic areas. This has given us a unique ability to receive feedback directly from patients that is genuine and authentic around marketing materials, strategy for patient recruitment, and other services that we build for specific trials.

This ability to build partnerships with the patient community in an authentic way gives us a very unique ability to engage with the patient community on behalf of a pharmaceutical company, allowing our sponsor & CRO partners the opportunity to start conversations with patients through our in-house patient advocacy team.

If you would like to learn how Clara can help you to build a strong & authentic relationship with your target patient community, get in touch with us and we’d be happy to share our capabilities and previous results with you as they relate to your current or upcoming clinical trial.

9. How Is The CRO Going To Utilize Patient Input For Developing The Trial?

In the initial stages of clinical trial design, sponsors often determine the ideal patient profiles that would help them to drive the most favorable research outcomes for their study. While it is important for the success of your trial to determine who your ideal patients are, very often these projections do not match up with what is viable in practice.

At Clara, we often encounter study protocols that are not set up realistically for successful recruitment to be possible.

Common mistakes that are made when determining trial eligibility criteria and trial design include:

• Overestimating the interest in the clinical trial from the target patient population
• A lack of patient focus in the trial design
• A lack of convenience for patients in their participation
• Complicated and/or inefficient study experience flows
• Crafting the eligibility criteria around the patient population that is most likely to lead to favorable study outcomes, without conducting sufficient research to more accurately estimate the recruitment and retention difficulty of the group for a particular study

It is natural for there to be a “push & pull” between the research ideal and the real world practicality. It is important to determine the correct balance between these two sides for your trial, as going too far in either direction will decrease the chance of your clinical study’s success.

The nature of the industry as it is right now is such that there is excess research idealization and not enough emphasis on patient centricity. This distorted orientation has resulted in many clinical trials being unsuccessful, negatively impacting sponsors, patients and the entire clinical trials industry.

The ideal CRO partner should help you make sure that your protocol design sets your study up for success. The CRO should be able to help you determine the proper balance between the research ideal and the real world practicality, and back up their findings with sufficient research and patient data that can project your trial being a success.

Clara Health: When formulating a recruitment and retention plan for our clients, we begin with conducting thorough research into the target trial patient population. This allows us to get a clear understanding of which recruitment channels will yield the best results and what kind of marketing materials will resonate with the prospective study participants.

To ensure accuracy and real-world applicability of our research, we consult and collaborate with our internal patient advocacy and patient support teams, as well as with our clients and patients representing the target trial patient profiles. We then tie our findings back with any existing proprietary data that we have in connection with the therapeutic area or the prospective target patient group.

Our unique position within the clinical recruitment chain gives us the presence and deep-rooted access needed to effectively tap into any of the three patient traffic sources: digital recruitment, offline recruitment, or patient advocacy recruitment.

Once a recruitment campaign has gone live, we constantly monitor, analyze and optimize our performance to make sure that the processes we have in place are as efficient as possible and drive the greatest results. In addition, we have the capability to layer in any traditional advertising (such as billboard ads) if requested by the study sponsor.

A Guide to Costs and Payments in Clinical Trials

• Posted on May 3, 2021
• By ciscrp_admin
• In Brochures , Resources

This brochure gives you the basic facts about costs and payments in clinical trials. It also suggests some questions to ask the doctors and staff of a specific trial.  

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Who Pays for Clinical Trials?

You may be wondering if clinical trials cost money and who pays for them.

Many clinical trial costs are covered by the sponsor of the study, a patient's insurance plan if one is available, and sometimes there are out-of-pocket costs. Before you join a study, ask the study coordinator which costs are covered and which are not.

Patient Care Costs in Clinical Trials

Paying for Clinical Trials

Learn about the different types of costs related to taking part in a clinical trial, and who is expected to pay for which costs.

Patient care costs are those costs that you would pay even if you weren’t in a trial. These costs are often covered by health insurance.

Types of patient care costs may include:

• doctor visits
• hospital stays
• standard cancer treatments
• treatments to improve symptoms of cancer or side effects from treatment
• x-rays and other imaging tests

If you need to travel to take part in a study, other costs might include travel, lodging, meals, parking, or child and elder care. Sometimes trials can help cover these extra costs, so ask the research team if the study offers financial help or know of support organizations that offer help.

Research Costs in Clinical Trials

Research costs are those costs that are related to taking part in the trial. Often these costs are not covered by health insurance. But they may be covered by the trial’s sponsor.

Examples of research costs include:

• the study drug
• lab tests performed purely for research purposes
• added x-rays and imaging tests performed solely for the trial
• extra doctor visits that you would not have with usual care

When you take part in a trial, you may have extra doctor visits that you would not have with usual care. During these visits, your doctor carefully watches for side effects and your safety in the study.

Health Insurance Coverage and Clinical Trials

Before you join a trial, learn as much as you can about which costs you or your health plan need to pay and those that will be covered by the study. Talk with your doctor, the research team, and your health plan. 

Ask your doctor if there is someone on staff who can help work with your health plan. This person might be a financial counselor or research coordinator. Or they might work in the hospital's patient finance department.

Ask the research coordinator or nurse if other people have had problems getting their health plans to cover routine patient care costs. If so, you might ask the research coordinator or nurse for help in sending information to your health plan that explains why this clinical trial might be a good fit for you. Items insurance companies may ask for include:

• medical journal articles that show possible patient benefits from the drug or procedure that is being tested
• a letter from your doctor that explains the trial or why it is a reasonable option for you
• support letters from patient advocacy groups

How to Work with Health Insurance Plans

Call your health insurance plan. If your doctor does not have a staff person to help work with health plans, call the customer service number on the back of your insurance card. Here are important questions to ask:

• Does the health plan cover routine patient care costs for people taking part in clinical trials?  
• If so, is a pre-authorization required? A pre-authorization means the health plan will review information about the clinical trial before deciding to cover the patient care costs.  
• If your health plan requires a pre-authorization, what information do you need to provide? Examples might include copies of your medical records, a letter from your doctor, and a copy of the informed consent form for the trial. If a pre-authorization is not required, you don't have to do anything else. But it is a good idea to request a letter from your health plan that states that a pre-authorization is not needed for you to take part in the clinical trial.  
• Understand all the costs related to the trial. Ask your doctor or the trial's contact person about the costs that must be covered by you or your health plan.  
• Work closely with your employer's benefits manager. This person may be able to help you work with your health plan.   
• Give your health plan a deadline. Ask your doctor or the trial’s contact person for a target date when you should start treatment. This can help to ensure that coverage decisions are made promptly.

What happens if my claim is denied?

If your claim is denied, contact your insurance plan's billing office for help. The billing manager may know how to appeal your health plan’s decision.

You can also read your health insurance policy to find out what steps you can follow to make an appeal. Ask your doctor to help you. It might help if they contact the medical director of your health plan.

Taking Part in a Clinical Trial When You Don’t Have Insurance

If you don’t have insurance or have other financial worries that you think may prevent you from taking part in a clinical trial, there are places to go for help. See Managing Cancer Costs and Medical Information for advice and a list of resources.

Some screening, prevention, and quality-of-life studies take place at sites that serve people with low incomes through the NCI Community Oncology Research Program (NCORP). If you receive health care at one of these sites, you may be able to take part in a clinical trial.  

People with cancer may be able to enroll in National Clinical Trials Network (NCTN)  clinical trials through NCORP, as well. Check with the clinic where you receive care about studies that you might be eligible for.

Federal Health Insurance and Programs for Clinical Trials

Some federal health insurance programs help pay the costs of care in clinical trials.

Medicaid is a US federal health insurance program for people who cannot afford regular medical care. Medicaid covers all routine patient care costs in a clinical trial. Each state has its own rules about who is eligible for Medicaid. Visit Medicaid.gov to learn more about your state’s Medicaid program.   

Medicare is a US federal health insurance program for people aged 65 years or older and people with certain disabilities. If you have Medicare, you may be reimbursed for some of the costs related to taking part in trials of new ways to diagnose or treat cancer. For more information, read the Centers for Medicare and Medicaid Services publication, Medicare and Clinical Research Studies or call Medicare at 1-800-MEDICARE (1-800-633-4227).

TRICARE is the Department of Defense’s health care program. If you are covered under TRICARE, you can be reimbursed for the medical costs related to taking part in NCI-sponsored trials for cancer prevention and treatment. Find more information on the  TRICARE's website .

The Department of Veterans Affairs  allows eligible veterans to take part in NCI-sponsored clinical trials at Veterans Affairs Medical Centers. All phases and types of NCI-sponsored trials are included. For more information, see Volunteering for a Clinical Trial  on the their website or talk with your doctor.

Budget Development

Budget development is an important piece of clinical trial management. There are different considerations if the budget will be federally funded, funded by industry or if the trial is investigator initiated.  

Federal Budgets

When requesting funding for a study, all study-related costs should be noted in the budget, including personnel, consultants, equipment, supplies, travel, and other expenses. NIH applications have special budget and justification forms that contain detailed instructions. Penn investigators must have their grant budgets approved by Office of Research Support Services (ORSS) . 

Industry Sponsored Budgets 

When considering an industry sponsored-study, all study related expenses should be determined and compared to the overall reimbursement offered by the sponsor to ensure the study is financially feasible. 

• The sponsor of a clinical trial generally sends a protocol and budget overview/template for the trial.
• After reviewing the protocol and events schedule, create an internal budget to reflect all costs, including time and effort of all personnel, in order to conduct the trial.
• Note : You may not bill insurance for a drug, test, device, or service paid for by the sponsor.
• Determine if the labs and testing procedures will be done in-house or at the sponsor’s site.
• Determine if there will be professional charges required for the technical tests performed.
• A study start-up fee must be included in order to cover the following costs: protocol review, staff training, budget preparation, regulatory documents, and administrative fees.
• There are one-time costs that should be included in the budget, if applicable: IRB fees, IRB continuing review fees, IRB amendment fees, investigational drug set-up fees, MCA preparation fee, archive fees, and advertising costs.
• PSOM has instituted a clinical trial indirect cost rate of 39%, which is an additional charge that must be applied to the total direct study costs. Only IRB fees are exempt. Indirect costs cover a small part of PSOM’s infrastructure costs for research.
• For multi-year clinical trials, consider adding an inflation rate of 5% to the per-completed-subject cost.
• Holdback on a trial should not exceed 10%.

Investigator Initiated Studies Budgets 

Penn sponsor-investigators should develop a budget based upon the expected expenses at each site. Billing rates for the same procedure will vary from place to place. 

To develop a budget work with your department BA and the Office of Clinical Research Finance group can also assist.  

Budget Preparation and Management FAQs 

Q: who should i contact to help me prepare a budget .

A: You should work with your department BA when developing a clinical research budget. The Office of Clinical Research (OCR) Finance Services can assist when needed.

Q: What resources are available to help create a clinical research budget? 

A: The Office of Clinical Research (OCR) has developed a template to help create clinical research budgets. In addition to the template, Costfinder can be used to look up hospital services by searching on CPT codes to find given research rates.  

In addition to the template, use the Cost Finder application (navigate to the Forms, Tools and Templates library) and search in categories 

Q: What is a prospective reimbursement analysis (PRA)? 

A: The PRA is a questionnaire designed to make a determination if a clinical trial is a qualifying clinical trial. A qualifying clinical trial means standard of care services can be charged to insurance if needed.  

Q: What is a Medicare coverage analysis (MCA)? 

A:   A Medicare Coverage Analysis (MCA) is a document that determines the appropriate payer (sponsor, Medicare, or third-party) for each item and service required by a clinical research trial. A MCA is required for all clinical trials in which tests, procedures, and interventions associated with a clinical trial are invoiced to third-party payers, and/or when research procedures are paid for by sponsors.  

Q: What are typical items that should be included in a budget? 

A: When requesting funding for a study, all study-related costs should be noted in the budget, including personnel, consultants, equipment, supplies, travel, and other expenses. Some common expenses are:

• Start-up costs
• Site Visit & Site Initiation Costs
• Institutional Review Board (IRB) fees
• Investigational Drug Service (IDS) fees
• Blood collection tubes, chemicals, dry ice
• Centrifuges, mass spectrometers, liquid simulation counters
• Technology (e.g. telephone, computer)
• Shipping/Packaging Supplies (e.g. dry ice)
• Advertising/Recruitment
• Archival fees
• Clinical Research Computing Unit (CRCU) fees
• Biostatistics and Epidemiology Consulting Center (BECC) fees
• External Institution or Contract Research Organization (CRO)
• Service Contracts (e.g. instrument maintenance)
• Training/Seminar/Conference (directly related to the research project) travel expenses
• Screen failures
• Travel Expenses
• Document Preparation
• Document Submission
• Medical Director
• Medical Record Retrieval
• Data Management
• Data Safety Monitoring Board
• Closeout Fees

Q: What is our current overhead rate? 

A: The current overhead rate can be found on the Office of Research Services (ORS) . 

Q: How do I pay for hospital services? 

A: The university uses the research billing application (RBA) to generate research billing numbers (RBN).  A research billing number (RBN) is a protocol-specific number used by the University of Pennsylvania Health System (UPHS) to bill research-only UPHS services/procedures to a School of Medicine fund set up for the protocol (e.g., research fund, departmental fund, etc.).  There can only be one RBN per IRB Protocol Number. All studies, regardless of payor, need to be registered in the Research Billing Application before they are loaded into Penn Chart (Epic) and enrollment can begin.   A User Guide for the RBA is available.   

Hospital fees are made up of either technical fees or professional fees. The definition for each is below: 

Technical Fees - A technical fee is the cost incurred for use of the mechanical equipment and processing. Tests/procedures that are study related and are not "standard of care" must be charged to the research budget. All costs should be based on the currently approved technical "research rate".

Professional Fees - The professional fee is the physician's charge for interpretation of diagnostic procedures/tests. It is important to note, if there is a professional fee associated with a test/procedure, you must include that charge in your expenses. A limited number of laboratory tests have professional fees associated with them. All radiology and cardiology procedures have an associated professional fee, as do various other procedures. All costs should be based on the currently approved professional "research rate".

Q: Is it allowable to supplement patient insurance costs with research funds? 

A: Only for hardship purposes can research funds be used to offset unpaid insurance claims, deductibles or co-pays. Medicare’s policy is referenced below:  

A research patient must, like all other patients, be responsible for deductibles and co-payments. Investigators may not induce patients to participate in clinical trials and fore go standard therapy by promising to waive these payments. Nor may the investigator offer as an enrollment incentive any free items or services to patients unless these items or services are customarily provided without charge to patients not enrolled in clinical research. (This does not prohibit, however, hardship discounts when applicable.)  

Medicare has no obligation to pay for items and services if a provider treats Medicare beneficiaries differently from non-Medicare patients or if other situations trigger Medicare exclusions. The provision sets out limited situations (such as patient indigency) when waiving charges for non-Medicare patients will not disturb Medicare coverage.   

The “No Legal Obligation to Pay” provision addresses scenarios such as billing Medicare for a service while not billing non-Medicare patients for the same service. This provision of the manual operates to prohibit billing Medicare for the same service that is provided free to non-Medicare beneficiaries. In such a case, Medicare has no legal obligation to pay for the service and the provider also cannot charge the Medicare beneficiary.  

Into this provision CMS inserted clinical research situations. The Special Edition Article advances the idea that if a provider does not charge a non-Medicare enrollee for a research study service, then the Medicare enrollee must also receive that same study service free. If the provider does not pursue collections against the research subject after the patient’s insurance denies coverage, CMS argues that the provider’s actions disallow billing for the same service for Medicare patients enrolled in the study.  

Q: What financial management requirements are needed? 

A: Each sponsor has their own regulations on all financial reporting and retention of documents. Review the contracts associated with each study to ensure financial requirements are being met. To ensure proper financial management, study expenditures should be reviewed on a regularly basis and should comply to the University’s policy 2106 which can be found here:  https://www.finance.upenn.edu/policy/2106-financial-responsibility/ .  

Q: I received an effort report, what do I need to do? 

A: The Effort Reporting System (ERS) is used to certify effort applied to research. Effort reporting is mandated by the federal government. If you receive an effort report, you should log into ERS, review the effort report, suggest changes if needed and certify the report. Effort Reporting System FAQs  

Q: How do I hire new staff? 

A: Penn uses Workday@Penn  for all its human resource needs. All new positions must be submitted in Workday for approval. Please consult with your Business Administrator (BA) and Human Resource Manager prior to posting a position.

For more information regarding hiring a staff member 

Q: How do I reimburse patient stipends? 

A: Penn’s preferred method for patient reimbursement is Greenphire. Greenphire is a reloadable prepaid clincard. More information about Greenphire click here:  https://www.finance.upenn.edu/payments-disbursing-funds/paying-program-participants-via-clincard .  

Q: What payment mechanisms does Penn accept from external funding sponsors?

A: Funding sponsors can pay via check or wire transfers. Click here for additional information   https://researchservices.upenn.edu/areas-of-service/research-operations-and-cash-management/

Sign in to your site’s geographic location:

Clinical research site reimbursement with crio.

Clinical research sites now get reimbursed for CRIO nearly half the time, at $2,000 per study

Many clients ask if sponsors will reimburse them for the use of CRIO on their studies. Not long ago the answer was that sponsors sometimes did, but often it was an uphill battle. Now, sponsor reimbursement is becoming commonplace and soon may be the default.

CRIO’s findings confirm that sites who seek reimbursement get it half the time

Across CRIO’s U.S. client base, 27% of all study budgets in the first quarter of 2023 had a specific invoiceable line item to reimburse the research site for their use of CRIO or a related site-adopted technology. When a reimbursement was provided, the average was $2,082.

However, this is not the complete picture. Some sites do not request reimbursement, and some sites require reimbursement, but in a different part of the budget, such as through a higher overhead percentage or a higher startup fee. To extrapolate the true “success rate” for sites that seek reimbursement, CRIO performed two separate analyses.

1. Site analysis

First, CRIO reviewed data for organizations that had a large number of study budgets in the data set to isolate the success of those who appear to be actively seeking reimbursement.

Among 18 organizations that had 10 or more study budgets, CRIO found the following:

• 6 were able to get reimbursed 60% or more of the time,
• 7 were able to get reimbursed roughly 10-40% of the time , and
• 5 had zero budgets with tech related line items.

Here’s a breakdown showing the % success rate by organization:

The five that had zero reimbursement rates were all large, sophisticated networks, on par in every respect with their peers who had positive rates of reimbursement. It’s unlikely that they lacked the negotiating leverage or skill of their peers.

Therefore, it’s reasonable to conclude that they either did not seek reimbursement for technology fees, or folded it somewhere else in the budget.

When this subset is excluded, the data shows:

• 47% of budgets have a line item reimbursing the organization for site technology.
• The average reimbursement amount is $2,012.

When factoring in the 53% of budgets that did not have technology reimbursement, the overall budget average becomes $947.

2. Study analysis

Second, CRIO reviewed data for studies that had multiple sites on it to see what percent of studies offered reimbursement for site technology to at least one site on the study. This is an indicator of the potential success rate for any site seeking reimbursement.

The following chart shows the results of the 22 studies that had 5 or more sites on the study. 

45% (10 out of 22) of the sites reimbursed at least one site for site technology fees – this percent is nearly identical to the 47% success rate the site-based analysis showed.

Across all sites, the overall success rate among this subset of studies is 26% – very close to the 27% overall success rate for the entire database.

Taken together, CRIO’s analysis suggests that up to half of sponsors are willing to reimburse sites for technology use, although not all sites seek reimbursement, and when they do, the average fee is a little over $2,000.

What’s behind this trend?

Sponsors are increasingly recognizing the benefits that site-technologies bring to their own studies. CRIO’s own research has shown – consistently – that sites who adopt eSource will have 40% fewer protocol deviations , 70% lower FDA audit risk , and 40% higher enrollment .

The benefits noted above do not even account for the direct benefits to the CRO from being able to perform remote monitoring as needed. For instance, one study team at a major CRO leveraged the remote monitoring capability enabled by their CRIO sites during the pandemic to post the highest monitoring productivity metrics within the CRO .

“Five years ago, we had CRAs telling us that we weren’t allowed to use CRIO,” said Luke Snedaker, CEO of West Clinical Research, and a long-time user of CRIO. “That all changed during the pandemic. Now, we are able to get reimbursed most of the time.”

“By using CRIO, we deliver significant value to our sponsor clients,” said Takoda Roland, Associate Director of Clinical Operations of Sitero, a CRO that distributes CRIO eSource to sites on an opt-in basis. “CRIO allows our monitoring team to review the data continuously, letting us prevent deviations from recurring and improving patient safety.”

This is great news for sites, and the industry as a whole

As protocols get more complicated and decentralized trials add more complexity to operations, it’s imperative for sites to become tech-enabled to manage this increasing inefficiency. When they do, all data shows that all stakeholders benefit. Sponsor subsidization is a clear signal to sites that they understand the benefits of site technology.

When doing a cost-benefit analysis, sites can now confidently underwrite partial offsets from sponsor reimbursement. For sites considering CRIO ’s technology (as our analysis is limited to CRIO site experience), they can assume they will be reimbursed, on average, $1000 per study. It’s also reasonable to assume that the rate and amount of this reimbursement will only increase in the years to come.

Methodology

CRIO downloaded every study-level invoiceable fee that was recorded in a budget associated with studies that had a start date in the first quarter of 2023 (U.S. sites only). There were 787 unique study budgets in total, after removing test, validation and other “non-real” studies.

Our staff reviewed each invoiceable fee and identified those that related to use of a site-adopted solution. We only included fees that unambiguously referred to a site-adopted technology.

Most of the fees described the technology very clearly as a variation of a “CTMS”, “eSource” or “eRegulatory”. Common fees included: “CTMS fee”, “CTMS Set up”, “CTMS Implementation”, “CTMS/eSource Technology Fee”, “E-Source Creation Fee”, “eSource/eRegulatory Fee” “eDocument Setup Fee”, or “eRegulatory Activation Fee”. Others simply used the generic moniker “Technology”, as in “Technology Start-Up”, or “Site Technology Fee”. A few characterized the fee in terms of remote monitoring benefits: “24/7 Monitor Access”, “EMR Access Fee”, “Remote Access Fee”.

If anything, CRIO’s analysis likely undercounts the degree of sponsor reimbursement success, as we are not able to capture those instances in which a site was able to get a higher overhead percent, or a higher startup figure, through inclusion of their technology costs. Our analysis is limited only to specific invoiceable line items explicitly tied to use of technology; these items are almost certainly incremental to any other budgetary line items.

JSCDM: Comparison of electronic health records and electronic source data in clinical research trials

The Journal of the Society for Clinical Data Management (JSCDM) recently published the original research article “Comparison of electronic health records and electronic source data in clinical research trials: a retrospective review” which was co-authored by Amelia Tian, CRIO Solutions Consultant, and Olivia Dennis, CRIO Analytics and Data Migration Manager, alongside Dr. Elena Christofides (Endocrinology...

The FDA’s Remote Regulatory Assessments: A Glimpse into the Future of Inspections

COVID-19 has fundamentally changed how clinical trials are conducted. In May 2021, FDA developed the ‘Resiliency Roadmap for FDA Inspectional Oversight’. In this document, FDA identified and embraced technological advancements by incorporating remote regulatory assessments (RRAs) into its inspection repertoire. During the pandemic, at a time where travel was restricted and personal contact heavily discouraged,...

CRIO President and COO authors new JSCDM Article

Congratulations to CRIO President and COO Jonathan Andrus on the publication of “Best Practice Recommendations for Electronic Clinical Outcome Assessment Data Changes” in the Journal of the Society of Clinical Data Management. This long awaited publication, a joint effort by industry thought leaders in the area of clinical data, summarizes the guidelines for eCOA data changes developed...

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Clinical Trials

• Contact Clinical Trials Staff
• Starting Point

Negotiation of Clinical Trial Agreements

Master clinical trial agreements.

• Budget Considerations

Confidential Disclosure Agreements

About clinical trials at uci.

A clinical trial is defined as the controlled, clinical testing in human subjects of investigational new drugs, devices, treatments or diagnostics, or comparisons of approved drugs, devices, treatments or diagnostics, to assess their safety, efficacy, benefits, costs, adverse reactions, and/or outcomes.

Clinical Trial Agreements (CTAs) can be categorized as follows:

• Sponsor Initiated – the protocol for the clinical trial has been written by the sponsor (e.g., a pharmaceutical or medical device company)
• PI Initiated – the protocol was written by an investigator

Sponsored Projects (SP) is responsible for reviewing, negotiating and legally executing agreements from external funding sources. In establishing a CTA, the resolution of many contractual issues requires coordination among the external sponsor, Investigator and SPA; the involvement of each party is essential to a successful contractual arrangement with mutually acceptable terms.

Clinical Trial Decision Tree

The  clinical trial decision tree  is a visual aid designed to help assess whether industry-funded studies qualify as clinical trials under the  UC definition .

The Starting Point

When participation in a Sponsored Clinical Trial appears likely , submit the documents listed below to Sponsored Projects in Kuali Research. These documents are required to begin contract negotiation.

• In Kuali Research, the clinical trial questions under the "Questions" tab, within the "Compliance" panel must be answered
• Form 700-U Financial Disclosure for Principal Investigator and Co-Principal Investigator, if applicable (original to be forwarded to Office of Research, Zot Code: 7600, 160 Aldrich Hall)-  as of 9/7/21, this form is no longer uploaded with the IRB Protocol Application
• Draft Budget
• Clinical Trial Protocol
• Draft Clinical Trial Agreement (CTA) or Draft contract, if provided by sponsor

Investigator-Initiated Trials (IITs) Toolkit

IITs require special consideration in the planning stages. UC Braid's IITs toolkit provides guidance on starting up an IIT to facilitate efficient contracting and move the trial forward as quickly as possible.

To trigger the review of the contract, send an email notification to the SPA CT team,  [email protected] , AND the Conflict of Interest team, [email protected] .  Use the "Link" function in KR PD to automatically generate a link to use when emailing both teams.  Please note that the COI review will not begin until the IRB protocol application for this clinical trial has been submitted.

While the contract or CTA negotiation process proceeds, the PI and study team should proceed with other required startup activities, including developing and negotiating the budget and submitting the IRB protocol application.

Investigators should notify their assigned Principal Contract Officer as soon as possible when initiating a clinical trial. The review of the proposal and negotiation of the clinical trial agreement requires time and cannot be left to the last minute.

Sponsored Projects can begin to negotiate a clinical trial agreement prior to IRB approval. However, the clinical trial cannot commence until the IRB approves the protocol and Sponsored Projects has signed the clinical trial agreement.

As a public, nonprofit educational institution, the University is bound by certain policies and regulations regarding what it can and cannot accept in a clinical trail contract. These policies are designed to protect the welfare of individuals participating as research subjects, foster the University's basic mission of teaching, research and public service, and minimize the various forms of liability associated with human research. For-profit private sponsors, such as pharmaceutical companies, are motivated by different forces than the University. As a result, they sometimes do not understand the ideals and principles behind our policies. Consequently, additional time may be required for contract negotiations while SP works with the sponsor to arrive at a mutually acceptable agreement.

When negotiating clinical trial contracts, the University primarily focuses on securing acceptable contract clauses regarding high-risk issues such as subject injury, indemnification, confidentiality, ownership of data, patent rights and publication rights.

The University's standard clinical trial agreement and the clauses proposed by the University during contract negotiations are based on the following assumptions:

• That the clinical investigation is conducted under a protocol that is a FDA Phase I, II, II, or IV drug study or a FDA regulated medical device study;
• That the sponsor provides its proprietary product and study protocol to the University for the purpose of conducting a clinical trial; and
• That the sponsor will fully fund the cost of the trial (i.e., no work will be supported in whole or in part with other funds, including Federal funds).

Principal Investigators should discuss all aspects of the clinical trial with their Contracts Officer prior to the start of negotiations. The involvement of UCI faculty in protocol development and/or study design creates additional issues that both parties must fully address. As a result, different or additional contract terms must be negotiated.

Investigators should provide SP with a copy of the draft clinical trial agreement (CTA), protocol, and a company contact person as early in the process as possible. If a Master Agreement between the Sponsor and the University of California exists already, the negotiation process will typically be expedited. IRB approval is not required in order to submit the proposal to SP and begin contract negotiations.

Although each document is reviewed on a case-by-case basis, there are a number of key issues that are common to most clinical trial agreements. These following items will be negotiated by SP with the sponsor:

Agreement Parties

All Clinical Trial Agreements should be only between The Regents of the University of California and the Sponsor. The Investigator is an employee of the institution and should not be a named party to the Agreement.

Financial Arrangements

Generally, the University negotiates a firm fixed-price per subject contract with a payment schedule. Such schedules usually provide for periodic payments at regular intervals or payments upon the completion of milestones (e.g., enrollment of a certain percentage of subjects, submission of a certain number of case report forms, etc.).

The University cannot underwrite expenses for the sponsor; therefore, the University requires a minimum advance payment of 10-20% of the total anticipated cost upon execution of the agreement. When a project involves significant start-up costs, the University may require a larger initial payment.

As a public-supported institution, UCI must recover the full cost of research conducted for outside sponsors, including all associated operating costs (overhead). To do otherwise would result in subsidizing for-profit research with public funds. Overhead costs are facilities and administrative (F&A) costs incurred in support of the University's research infrastructure. The University pools its overhead costs for ease of accounting because it is difficult to assign these costs with a relative degree of accuracy to a specific project or program. The federal government's Office of Management and Budget establishes the standards for calculating the indirect cost rate and UCI negotiates its rates with the United States Department of Health and Human Services audit agency on a periodic basis. The University derives its overhead rate for clinical studies from applicable components of the federally approved rate.

Our facilities and administrative (indirect) costs web page contains more information about F&A costs and current applicable F&A rates.

Indemnification

When conducting a sponsor designed clinical trial protocol, the University is following the sponsor's instructions. As a public, non-profit educational institution, UCI cannot bear the financial responsibility for any injury or damages resulting from the performance of the clinical trial. Consequently, UCI requests that the sponsor maintain a policy or program of insurance sufficient to support this obligation. The sponsor’s obligation to assume all financial responsibility does not apply to injury or damage to the extent caused by: 1) UCI's failure to adhere to the protocol; 2) UCI's failure to comply with FDA or other governmental requirements; or 3) the negligence of a faculty member or the University.

Confidentiality

UCI must maintain an open academic environment to fulfill its mission and meet its fiduciary responsibilities as a public educational institution. Clinical studies involving the use of a sponsor’s confidential information will be accepted if: (1) the extent of confidential information shared with the University is limited; (2) the information is clearly identified by the sponsor as confidential: and (3) the sponsor agrees that the University will not be financially liable for disclosure. The University cannot accept projects requiring overly broad access and use restrictions or elaborate data protection procedures.

Raw source data or documentation generated by the University during the conduct of a clinical study cannot be considered to be owned by the sponsor, nor can it be considered or treated as confidential information.

In addition, any agreements entered into by the University are subject to public disclosure under the State of California Public Records Act.

Publication

Timely publication and dissemination of research/study results are important principles behind the academic freedom afforded to each UCI faculty member. However, the sponsor may want to comment on the content of such publications, make arrangements for the protection of intellectual property, or ensure that sponsor confidential information is not improperly disseminated in such publications. These are legitimate business concerns and UCI is willing to work with sponsors to address these concerns. However, the resulting agreement cannot restrict UCI faculty from freely publishing research/study results.

UCI negotiates CTAs that address the needs of both parties by providing the sponsor with a pre-publication review and comment period. The sponsor may also request that their confidential information be removed from the proposed publication. UCI is also willing to delay dissemination of study results for a reasonable period of time to accommodate multi-site studies.

Intellectual Property

Sponsors of University research are usually granted patent rights in accordance with University policies. However, the University may grant greater rights to sponsors of studies that meet all of the following criteria:

• The clinical investigation is an FDA Phase I, II, III or IV drug study or an FDA regulated medical device study.
• The sponsor provides its proprietary product and study protocol to the University for the investigation.
• The cost of the clinical investigation conducted according to the sponsor's protocol is fully funded by the sponsor and is not supported in whole or in part with any other funds, including Federal funds, gift funds or foundation funds.
• There are no known third-party rights to intellectual property of The Regents that would be compromised by granting rights to the clinical trial sponsor.
• All University requirements regarding the administration of agreements with private sponsors for drug and device testing using human subjects have been satisfied.

If all of the above criteria are met, the University may grant to the sponsor a certain range of rights to inventions made in the direct performance of the clinical trial protocol. The terms contained in the standard clinical trial agreement are used for Phase III or IV trials meeting the above criteria and involving little or no investigator involvement in the conception or development of the protocol. However, the University reviews patent terms on a case-by-case basis and prefers to do so with a thorough understanding of the work contemplated.

Subject Injury

As a matter of University policy, in the case of subject injury resulting directly from study drug administration or study procedures carried out in accordance with the sponsor designed protocol, the University will provide reasonably necessary medical treatment. University policy specifically prohibits billing the subject or a third-party for the costs of treating such injuries. Therefore, the University requires reimbursement for the cost of such treatment from the sponsor. Human subject welfare is a primary concern for the University and exceptions to these terms cannot be accommodated.

To support the above indemnification obligations, the sponsor must maintain a sufficient level of insurance.

The University of California is self-insured and during the term of the agreement will maintain adequate insurance to cover its indemnification obligations.

Governing Law

The University of California is a constitutional corporation of the State of California and contracts accepted by the University also will be interpreted under California law. The University will also consider contractual silence regarding this issue, but cannot negotiate any other terms.

Termination

Generally, either party must have the ability to cancel the agreement by giving reasonable notice. In the event of premature termination, the University will seek reimbursement from the sponsor for all costs and uncancellable obligations incurred up to the termination date. In addition, untimely withdrawal from the protocol could jeopardize the welfare of human subjects. Therefore, the University requests that the sponsor cooperate with the University to safely withdraw subjects from the protocol should thirty days notice not be sufficient.

Use of Name

California Education Code Section 92000 prohibits the use of the University’s name to suggest that it endorses a product or service. A sponsor may use the University’s name to fulfill their obligations as required by law, or by otherwise requesting prior written approval from the University.

The Human Research Protections (HRP) unit in the Office of Research will charge Institutional Review Board (IRB) fees for new clinical research submissions that are partially or fully supported by industry sponsors, including chart review studies. If UCI defers review to an independent IRB (e.g., WCG, Advarra), HRP charges a fee for administrative review and oversight.

The IRB fee schedule has been simplified.

Effective September 1, 2021, NEW clinical research protocols partially or fully supported by industry sponsors will be charged a ONE-TIME fee at the time of UCI or sIRB approval.

• The ONE-TIME fee will be $1500.
• There will be no fee for renewals.
• There will be no fee for amendments.
• There will be no fee for unanticipated problems.
• Currently, approved protocols will no longer be charged.
• De-Novo review will go away; Kuali Research Protocols (KRP) allows for Researchers to maintain their protocols using up-to-date templates.

This fee will adjust annually to align with HRP expenses. The rate will adjust up or down based on actual expenditures for the current fiscal year, and projected expenses for the following fiscal year. For budgeting purposes, Researchers should assume that the future fee will be 3% higher than the current rate.

Note: IRB Review Fees are not charged for the following:

• Federally supported research
• Foundation supported research

For additional information, please see HRPP Policy# 6 and/ or the UCI IRB Review Fee Policy .

If you have questions, contact Beverley Alberola, Director of Human Research Protections, at 949-824-5746 or [email protected] .

Master Agreements are agreements that embody agreed upon terms and conditions of a basic relationship between the University and a sponsor. Once a Master Agreement is in place, an "addendum" or "study letter" is typically generated for each new study to be done under the Master Agreement. The Addendum sets forth the items particular to a certain study such as dollar amount, protocol name, and principal investigator. These Addenda are "attached" to the Master Agreement. This alleviates the need to negotiate the main terms of the agreement, as the majority of the terms are agreed upon and only the particulars need to be negotiated.

The following is an updated list of Master Clinical Trial Agreements.  When dealing with these sponsors, please inform them to use our Master Agreement:

Abbott Vascular (Abbott Device Subsidiaries)

Aimmune Therapeutics

Alpha Oncology

Arcus Biosciences

AstraZeneca

Atara Biotherapeutics (Template agreement)

Biogen – IDEC

Boehringer Ingelheim

Bioverativ Therapeutics

Bristol Meyers Squibb

Caris Science Inc

Edwards Lifesciences

GlaxoSmithKline (GSK)

GOG Foundation

Heron Therapeutics

Macrogenics

Opko Biologics

Pharmacyclics

Philips (Investigator-initiated studies)

Schering-Plough

Seattle Genetics

TG Therapeutics

UCB Biosciences

*As of 04/23/2024

The University of California has also adopted the Accelerated Clinical Trial Agreement (ACTA) .  The ACTA provides a standardized template for industry-sponsored, multi-center studies thus streamlining the contracting process.

Clinical Trial Budget Considerations

Generally, industry sponsors are concerned with the total cost of conducting a project rather than the classification of costs. As a consequence, the structure of most clinical trial budgets differs from that of grant proposal budgets. Sponsor-provided budget templates are typically separated into up front costs, per patient costs, and items to be invoiced on an as needed basis. Other budget issues for considerations are listed below:

Departmental Administrative Expenses

When preparing and negotiating the budget for an industry sponsored clinical trial (not investigator-initiated), be sure to cover all costs associated with conducting the trial. Due to the unique administrative nature of clinical trials and the reduced facilities and administrative rate currently being applied to clinical trials, charging administrative expenses is required and may be recovered as a direct charge and/or by assessment of an administrative fee.

Patient Care Costs and Coverage Analysis

To obtain a coverage analysis and current research rates for patient care costs, including Pharmacy services, contact the Research Revenue Integrity (RRI) unit at UCI Health.

Research Services

The Institute for Clinical Translational Science (ICTS) offers a variety of services to support clinical and translational studies.  For more information, see Institute for Clinical and Translational Science services.

Institutional Review Board (IRB) Fees

The Institutional Review Board (IRB) charges fees for the review of clinical trials from for-profit sponsors.  For a current listing of fees, please see the IRB Fees sheet.

Facilities & Administration Fees

Be sure to use the appropriate F&A rate for your study.  Further details and information is available at Facilities & Administration Fees and FAQ's about applying F&A for clinical trials .

Costs for travel to Investigator's Meetings or other study-related meetings may be managed in a variety of ways.  Be sure to clarify how such costs should be incorporated into your study budget, if appropriate.  See Special Travel Considerations for Trials for more information.

A company may want to send a protocol to the Principal Investigator (PI) so that he/she can decide whether to participate in the trial. The protocol may have confidential information that the company needs to safeguard. The mechanism to protect the confidential information is the execution of a Confidential Disclosure Agreement (CDA).  Please note that some sponsors do not require a CDA prior to releasing a protocol.

Once a sponsor or Contract Research Organization (CRO) has identified UCI as a potential site for a clinical trial, a CDA may be sent to the PI. In order to protect the University and the PI, all incoming CDA’s requiring University signature need to be reviewed, negotiated and executed by Sponsored Projects (SP).

CDAs are usually straightforward and require little negotiation; however, some CDAs can include requests that SP cannot honor. For example, as a State of California educational institution, the University cannot subject itself to the laws of other states.

To process the CDA:

• Send the CDA to [email protected]
• Include the name, address, telephone number and email address of the sponsor or CRO contact.
• If needed, include a note with any concerns about the CDA.

Once the terms of the CDA have been negotiated, SPA will execute the agreement and send the partially executed agreement to the sponsor or CRO for signature.

Once SPA receives a fully executed CDA, the agreement will be processed and a copy will be sent to the PI/study team.

Master CDAs

UC Office of the President and UC Irvine have master CDAs in place with several sponsors.

When dealing with the following entities, please inform them to use our master CDA:

Bristol-Myers Squibb Company

Pharmaceutical Research Associates

Sanofi US Services Inc

*As of 7/14/2020

• Conference Coverage
• CRO/Sponsor
• 2023 Salary Survey

• Publications
• Conferences

Key Cost Drivers in Clinical Research: Guide to Successful Budgeting

It's almost impossible to map out study budgets with absolute precision. Planning for the unexpected costs, such as those associated with slow enrollment, protocol amendments, and other contingencies—is vital.

Proper study budget is vital for a successful trial for both parties, contract research organizations (CRO) and pharma companies. Therefore, it is essential to take the time and prepare your financial plan by thoroughly thinking of all expenses.

So, what does a typical clinical trial budget consist of? First of all, the study budget can be broken into two main big parts: the cost of CRO services, and pass-through costs (PTC).

PTC, for their part, are all the expenses that are passed directly to the Sponsor at actual cost:

• Site and PI grant fees —grant fees paid to principal investigators and sites for the recruitment of patients; these costs often comprise the most significant part of the study budget;
• Vendors’ costs —Central Labs, IDMC, depots, ePRO, and any other vendors, if they are subcontracted by the CRO;
• Comparator and concomitant medication —depending on the study design, purchase, and logistics of these might add up to quite a significant sum that should be planned for in advance.
• Study supplies, equipment —complexity of study procedures may require specific equipment not usually used at site in routine practice, so there might be a need to purchase it for the study. Sometimes it can be expensive to procure, deliver, and then at the end of the study, collect it from the site.
• Travel costs, investigator meeting costs —keep in mind that travel costs may also form a substantial part of the budget, depending on the study design and needs (for example, frequency of on-site monitoring visits and site geography). Another important factor to be taken into consideration, especially when planning a multinational clinical study, are currency fluctuations that may influence the cost of travel, which is very hard to predict or plan for.
• Logistics and courier costs, depot services —these costs do not only depend on the study geography, but on the number of subjects (and, as a consequence—sites) as well. The larger the sample size is, the more medication and biosamples shipments, thus the more expensive the study is. And again, do not forget about currency fluctuations. So, it is imperative that logistics managers help plan the budget as precisely as possible.
• Regulatory authorities’ fees and patients’ insurance —make sure to include all local RA (as well as LECs—where applicable) fees and patients’ insurance that directly depends on the sample size and on the study phase and local country requirements.
• Questionnaire license fees —don’t forget about the licensing fees that can be both paid and free of charge. In certain cases, they can be accompanied by considerable costs.
• Taxes and bank commissions —local specific requirements for taxes and bank commissions vary among countries. So, your partner CRO should be responsible for double-checking that.

Taking a deeper dive into the structure of the CRO service costs we will see the following:

• Site management and monitoring —one of the highest in the overall structure of service fees, and it may account for the largest part of the clinical study budget. Amount of monitoring (including site initiation visits, interim monitoring visits, and closeout visits) will depend on both the sample size and Sponsor’s requirements towards SDV (Source Data Verification) percentage.
• EDC, data management and biostatistics —in general, data management costs strongly depend on the number of patients and sites. Another powerful cost driver for the cost of these services, is the complexity of CRF (which, in turn, depends on the amount of study procedures) as well as the duration of the study.
• Project management —the cost of project management (PM) depends on study duration and complexity (including number of sites, countries and specific vendors involved). And even though there is no direct connection between the number of subjects and cost of PM, if the increased number of subjects requires involvement of additional sites or even countries—this of course will add to the project management cost.
• RA support/CTA submission —geography definitely has an impact on the cost of regulatory support services, as the duration of clinical trial approval and the CTA process itself varies (sometimes significantly) from country to country. Different countries and regions may have their own requirements for submission packages and sometimes it can be a challenge to put everything together. For instance, in Russia, the package is relatively easy to collect as it is similar to what EMA and FDA require, but all documents should be translated into Russian language, which takes time and some additional costs. In Ukraine, the package is also simple, as they EU CTA for initial submission and EU requirements (for example, submission of complete IMPD for IMP), but the Ministry of Health requires a lot of documents from investigators, not only principal investigators. Accreditation and certification of each medical institution involved in the trial have to be collected and reviewed for validity. Of course, collection of such packages takes more time and costs are higher with respect to the services. Meanwhile, there is no need in full translation of study core documents into Ukrainian.
• Medical writing —even though the cost of services connected with medical writing, and CTA package preparation are normally lower than other project costs, it is hard to overestimate the importance of biostatisticians’ and medical writers’ work - both experts’ decisions regarding study approval and the efficiency of the clinical trial depend directly on properly and expertly prepared study design.
• Logistics —when we say “logistics” here, we are talking about CRO support in coordinating the import and shipments of investigational drugs, study supplies, concomitant or comparator medications, biosamples (while the cost of those shipments are pass-through costs, described above).
• Pharmacovigilance and quality assurance —quality assurance costs spent on maintenance of QA and QC systems, training and audit expenses, as well as PVG, even though highly important, usually comprise a smaller part of the overall study budget.

What if out-of-scope happens?

However, contingencies are hard to avoid in real life, therefore it is necessary to be ready to face the out-of-scope. So, how to find ways to effectively manage it? Indeed, with large-scale international studies, especially in the long term, it is almost impossible to map out study budgets with 100% precision. The majority of companies have all the responsibilities of project managers or those of other project-related specialists listed in their SOPs and project management plans. What is more, take a tip from insiders—if a project manager not only presents an issue of out-of-scope to Sponsor, but also comes up with a possible solution within the current study budget, it will be clear evidence of his professional competence and individual approach to clients. There might be some internal monetary resources if you look into the budget carefully. For example, depending on how the enrollment goes at each site, you can adjust monitoring frequency and extend the break between visits but make them longer. This is an opportunity to cut back on travel costs which, in case of big countries like Russia, might be quite significant. Besides, the CRO service cost for a two-day monitoring visit will be lower than two one-day visits, as the CRA will not have to spend additional time travelling to site. One more thing which can help avoid out-of-scope situations is an accurate and detailed budget grid. For example, the budget template of OCT Clinical CRO consists of over 400 items and covers all the tasks that will be done for a particular project, which provides maximum transparency and reduces the risks of hidden costs. Planning for the unexpected, such as costs associated with slow enrollment, protocol amendments, additional IMP imports and other contingencies—is, indeed, of paramount importance.

Irina Petrova , MD, is the Director of Clinical Operations,  OCT Clinical ​

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The Costs Considerations when Outsourcing to a CRO

Outsourcing as a business practice has been around for centuries and some economists would argue it has been around since man first started providing services to one another. The concept is based on the premise that a specialist company that focuses on a specific functional area can do a better job faster, and at less cost, than a generalist approach whereby you employ all functional areas needed internally. The practice has become entrenched in many areas of industry including the Pharmaceutical and Biotech industry and has fueled a boom in companies carrying the acronym CRO (Clinical Research Organization). Clinical outsourcing trends continues to raise  as more drug developers search for a either a functional service provider or a more small scale outsourcing approach.

Outsourcing in the clinical development area accelerated rapidly in the last 25 years fueled mainly by five main factors:

• Difficulty in aligning the varied clinical functional needs with multi-product and multi-phased developmental pipelines
• Increasing domestic internal costs
• Globalization to reduce overall development costs
• Harmonization efforts to facilitate globalization
• Technology advancements

The impact of technology in gathering and disseminating information is a primary driver of this expansion, which allows low-cost labor providers in developing countries to do the work cheaper than domestic workers.

However, the cost gains from outsourcing can be lost if you don’t have a strategic plan addressing critical deployment issues. Let’s take a look at the main cost factors companies need to assess to make an informed decision on whether to outsource or to do the services internally.

Fixed Versus Variable Costs

One of the drivers of outsourcing is the ability to convert normal fixed costs that absorb available capital to variable costs. This tactic adds significant economic value to the company. Instead of using scarce capital to employ potentially underutilized resources (and the facilities needed to support them as a fixed asset), you can employ a variable cost for the functional service when you need it. The impact on your burn rate if you are a biotech company can be significant and for pharmaceutical companies the economic value is boosted.

Employment Costs

A reduction in costs is another leading driver for choosing to outsource to a clinical research organization. It is important to analyze the true cost of the outsourced service compared to your internal cost. The overall cost of the labor is made up of several components. To evaluate the true wage cost between internal resources and the CRO, the following items must be considered:

• Hourly wage
• Benefit Cost
• Federal income taxes
• State or Provincial income taxes
• Local or City income taxes

CROs will typically roll all of these items into their hourly wage cost in their rate cards to come up with a fully loaded wage rate. Pharmaceutical and biotech companies typically look at only the hourly rate without the employment costs, which run around 34% in the United States (see Table A). Therefore, many internal cost analyses are understated by 34%. When considering the employment costs in developing countries, the difference can be significant. The difference between the United States and developing countries like India (16.75%) and China (20%) can be as much as 17%. The hourly wage rates in developing countries (Table B) are much lower than the developed countries, and this presents one of the major cost advantages for off-shoring labor in addition to less employment benefit taxes and facility costs.

Table A. Breakout of Employer Costs for employee compensation, September 2016. US Dept of Labour

source:  https://www.bls.gov/news.release/pdf/ecec.pdf  

Table B. Comparison of Hourly Compensation Costs in U.S Dollars. U.S Dept of Labour 2009

Overhead (General & Administration) Costs

A critical analysis of the true cost of a service for internal consumption requires you to look into your internal overhead costs. CROs will add overhead costs to their labor costs, which internal analyses rarely consider. The CRO overhead costs can range from 10% to 27%. Pharmaceutical companies’ G&A costs often run between 20% and 60%. Once you have your company’s G&A costs, you can apply this to your available labor costs. So, if your hourly wage for a full time principal statistician is $56 an hour, you would add 55% to that cost to come up with your fully loaded cost of $86.80. In some instances, the G&A cost difference may be small if choosing between a global full-service CRO or resourcing it internally.

The following are some overhead costs that impact total cost:

• Legal services
• Accounting services
• Marketing services
• Sales services
• Executive management
• Facility costs
• R&D costs
• Quality Assurance

CROs are typically lower priced (compared to your internal costs) due to their low overhead and labor and employment costs (depending on where they are located). The important criteria for a full service approach employed by a sponsor company require that the overhead cost for each functional area of expertise needs to be rolled up into the overall G&A cost. In the case of a full-service, global CRO, the difference could be less pronounced since they have similar organizational structures to the manufacturer, with the exception of R&D costs. The difference between the CRO and manufacturer’s costs could be as high as 40%.

Time Estimation

When determining outsourcing costs, you also need to estimate the amount of time needed to complete the task. To do so, you need a well written protocol that limits the interpretation of what is needed and how long it will take. The sponsor and CRO must be in agreement on the outcome to be achieved and the time associated with meeting that outcome. Once this agreement is reached, a true comparative cost can be attained.

If your company has a detailed time reporting system or sophisticated financial/CTMS operating software based on clinical trial tasks, then you can determine the time associated with that general task as a starting point. However, utilizing benchmarking as a tool to estimate costs has some inherent problems associated with its use. For instance, since it is based on historical data, it does not take into consideration new approaches and technology, or seasoned project managers who may be able to get the project running and finished faster.

Professional negotiators reducing initial estimates through reverse bid options, benchmarking, and the internal pressure to underestimate the project scope to get funding, all present a challenge to develop a true cost estimate of a particular task.

Scale of Management

The amount of time required to manage resources – especially when quality issues arise – also needs to be quantified. When a sponsor decides to develop a particular functional service they will need to employ a project manager and/or an alliance manager to work with the selected CRO. Depending on the scale of the project and the service required, this could include a team of individuals to ensure quality. Typically the scale of management within CROs is larger (meaning more people and projects are managed per person) than in pharmaceutical and biotech companies, which reduces the cost. It is not unusual for a CRO to have one project manager for multiple projects, whereas the sponsor will typically have one project manager for each project and will have layers within each supporting department reporting into them.

When evaluating the cost of management on whether to outsource or not, you also need to assess the internal management costs associated with each department that affects the project. Typically this area of cost is undervalued in the internal development assessment. And don’t forget to consider any resulting quality and time delays if the scale of management is too large.

Support Services

The fourth cost-related issue relates to the support services you will have to increase to bring additional resources on board: mainly the IT and facility requirements to employ the needed resources. If you consider the option of employing SAS programmers, for instance, you will have to provide a desk, computer, software, email, internet access, and IT support. You may even have to rent additional space. Typically CROs build into their cost models the support needed and offer different choices on where and how they interact with your assigned project manager. Conversely if you are not at full capacity with your facility and have more efficient IT support services than the CRO, then this cost difference could be minimal.

Recruitment Time

When comparing outsourcing to internal resources, many sponsors often overlook what it costs to recruit and hire personnel. To fill an open internal position typically can take up to six months. A CRO with recruitment staffing can typically employ and train a person in one to three months. Many CROs keep a pool of readily available candidates to fill positions as they come up.

The shorter the recruitment time, the faster you can get a product to market. Depending on the drug developed and the size of the market, saving one to three months can equate to millions of dollars, which can easily justify outsourcing a particular service.

Utilization Cost

Another issue to consider is the cost associated with carrying essential employees who are underemployed. Timing the utilization of the needed resource amongst all of your trials can be daunting, especially when you consider the number and different phases that have to be aligned with functional needs.

Having enough critical clinical staff on hand for when you need them is the main driving factor as to why many companies choose to outsource in the first place. Conversely, keeping certain clinical support staff around when you have only a few products in the pipeline will result in underutilization of the employee and drive up your costs. For instance, timing exactly when you will need a statistician among multiple clinical trials is challenging due to the feast and famine nature of their role during the trial. A lot of work is done up front creating the format of the tables to be used. Then, they have to wait for the data to come in to analyze it. Medical writing services also follow much the same routine in regard to the clinical development process, but can be utilized in other areas like publications to maximize utilization. CROs offer the opportunity to smooth out these utilization gaps when they occur.

At first, their service may appear more costly when compared on an hourly basis. However, if you consider the utilization cost of that internal person, the cost can be substantially less. To calculate the utilization rate of internal staff you need an accurate time reporting system and/or a Clinical Trial Management System (CTMS) which identifies actual tasks associated with that position. The counterbalance to underutilization of resources is the reduced training time it takes to get new resources up to speed. So when analyzing this cost, both areas need to be assessed.

Several important cost factors need to be considered to determine whether or not to outsource some or all of your clinical development and operational needs. Once you have calculated all of the cost factors, you are ready to evaluate the different outsourcing approaches and the strategies to maintain control of your trials . After evaluating all of these areas you will be ready to make an informed decision on whether to internally develop or outsource your needs.

At Quanticate we specialize in collecting, analyzing and reporting clinical and real world data, across   statistical programming, biostatistical consultancy, clinical data management, pharmacovigilance, medical writing and regulatory submission review services. W hatever the data, we’ve got you covered. If you are looking for support on any of the topics highlighted in this blog please   Submit a RFI  and member of our team will be in touch with you shortly.

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Clinical Researcher

Investigator Compensation: No One Size Fits All

Clinical Researcher December 21, 2021

Clinical Researcher—December 2021 (Volume 35, Issue 9)

PEER REVIEWED

Suzanne J. Rose, MS, PhD, CCRC, FACRP

Managing investigator payments is probably one of the most challenging aspects of conducting a clinical trial, but it seems that it is the best kept secret in our industry. It is the topic that generates the most interest when discussed with colleagues, but unlike other straightforward processes in our industry, the topic of investigator compensation is one that has guidelines but no specific steadfast rules to let us know if we are compensating appropriately or inappropriately. While there are several models that are discussed in the literature,{1–4} there is no clear consensus on which model is the best fit for each site.

The first stop in de-mystifying the conversation on investigator compensation is to identify and explain key operational and compliance factors for consideration, such as fair market value (FMV) and equity across specialties. Does one or can one size fit all? How much should we pay investigators for their work on a clinical trial and what laws govern investigator compensation so that we remain compliant? While it is important to understand the Stark Law and the Anti-Kickback Statue, and the exceptions and Safe Harbor that allow physician payments, these are excellently described elsewhere.{2}

We will therefore focus on FMV because amounts paid to investigators are considered part of their overall compensation amount and therefore subject to the FMV Guidelines. Importantly, both FMV and commercial reasonableness are important concepts in the Anti-Kickback Statute Safe Harbors and Stark exceptions.{2} In addition, as most principal investigators (PIs) are physicians, the American Medical Association (AMA) provides clear guidelines on managing conflicts of interest in the conduct of clinical trials, in that financial compensation should be at FMV and the rate of compensation per research participant should not change pursuant to the number of subjects enrolled by the physician.{5} Thus, the rate of payment for professional services should remain constant irrespective of the PI’s success enrolling or completing study subjects compared to their target.

The concept of FMV extends back 120 years{6} and is described in the Code of Federal Regulations as “the price at which the property would change hands between a willing buyer and a willing seller, neither being under any compulsion to buy or to sell and both having reasonable knowledge of relevant facts.”{7} The Centers for Medicare and Medicare Services (CMS) defines market value as “the value in arm’s length transactions, consistent with the price an asset would bring as the result of bona fide bargaining between well-informed buyers and sellers who are not otherwise in a position to generate business for the other party.”{8} In 2003, FMV for research studies was first included in the Office of Inspector General (OIG) regulations stating “Payments for Research Services should be fair market value for legitimate, reasonable and necessary services.”{9}

However, even with the clear instructions above, the rules do not provide advice on determining the FMV, which puts sites at risk. If the investigator is paid above FMV, it can give the appearance that it would influence his or her decision to participate in the trial or to influence the outcome of the trial, thus placing the institution at risk from legal and regulatory perspectives. If PIs are paid below FMV, they may not be willing to participate fully or enroll research participants, which could impact relationships between sites and sponsors. At the end of the day, there is no perfect percentile that exists for FMV calculation, as FMV for an investigator truly depends on medical specialty, geography, and physician experience.{10}

However, the following are helpful hints for a site to stay in line with FMV:

• Determine a pricing strategy with the billing team: Engage the billing team as partners in the pricing strategy. An important goal of any research study should be to properly compensate the hospital or private site for investigator time.
• Update the fee schedules on a yearly basis: Variations in compensation rates should be monitored closely on an annual basis to ensure FMV is appropriate by region and specialty.
• Provide full justifications for all fees charged in a clinical trials budget: The budget negotiation should not be a guessing game or contentious. Clearly outline all fees and justifications therein. Provide justifications up front, not when asked for them.
• Engage internal support or external vendor to create research and/or administrative hourly compensation fee schedules: There are several firms that can assist in developing your organization’s internal compensation reference materials to be used in establishing the framework and market data consistent with your compensation philosophy related to physician research and/or administrative work effort. These firms can provide FMV payment (hourly rate) range recommendations for various physician specialties providing research and/or administrative services.

Finally, best practice is to create a FMV policy in writing to defend your site’s actions and to prove transparency. In addition, please remember that a physician’s “going rate” or past compensation does not necessarily constitute FMV; further, the values for administrative services most likely differ from those for clinical services. Therefore, it is important to engage a third-party vendor to clearly differentiate between research and/or administrative services.

PI Compensation Structure

Investigators can contribute to study in many ways,{1} and therefore the compensation should be fair, motivational, affordable, practical, legal, and agreeable.{3,4} To structure the investigator compensation model, we should include considerations for (clinical) relative value unit (RVU)–based services vs. administrative work in these models.

Relative Value Units (RVUs)

RVUs are measures constructed by Medicare to estimate productivity by calculating the relative level of physician time, skill, and expertise. Medicare relies on these measures to establish payment levels for physicians’ services which are then described by Current Procedural Terminology (CPT) codes. This compensation model is typical when a hospital also employs physician-investigators as clinicians, and they earn RVU credits when they perform clinical services with CPT codes that are part of the clinical trial.

It is helpful to utilize different terminology when incorporating research RVUs into an existing electronic medical record. To this end, we have established “research RVUs,” which are calculated per hospital policy as 1.5 times the Medicare rate across all specialties with one average RVU per visit type. At the end of the day, all RVUs end up in one bucket and look like regular RVUs. This way, regular patient visits are not seen as competition with research and the physicians are motivated to perform research in an existing RVU model.

When incorporating an RVU model into your investigator compensation program, it is important to remember that the model needs to account for research time with no corresponding CPT code. In addition, for study-specific oversight and research fees without CPT codes, the investigator cannot receive RVU credit and is paid according to FMV, as discussed previously.{2}

Compensation Models (External to RVUs)

Fixed Fee or Percentage: The site pays investigators a fixed fee or percentage for studies, regardless of their contributions. These options are simple to manage but difficult to assess if they accurately reflect the FMV of the investigators’ services.

Research Salary: At research sites where the investigators are employed by the site, investigators are paid a fixed salary for all their time spent working on clinical trials and all parties know the exact amount that will always be paid.

Hourly Wage: The site can compensate the investigator specialty-specific hourly rates for tracked time on a specific study along with activity performed. This can be seen as additional work by the investigator, who may balk at extra time spent on tracking their hours.

Fee for Service: The site compensates the investigator for specific services performed or time spent. This option is more time-consuming to administer, but strongly motivates investigators to perform the services they are contracted for.

Sub-Investigators: While the role of investigator is usually limited to a licensed physician, the sub-investigator role can be much more inclusive to include mid-level providers, such as physician assistants, nurse practitioners, and, at academic medical centers, residents and fellows. They play various roles in a study and are often essential for success of the trial. Fee for service typically works well for sub-investigators and can be tracked inside the budget, via a spreadsheet or clinical trial management system. It is important to understand any sub-investigator’s current payment structures inside the site or healthcare system and work with administration to ensure that salaried positions are capable of being compensated above and beyond their current salary structure, as well as being compensated for RVUs similar to their physician counterpart. At academic medical centers, payments to residents and fellows outside their salary will need to be carefully discussed and negotiated with the Graduate Medical Education Office and adhere to AMA guidelines.

Hybrid Model: In this model, a variety of the above options can be utilized. Fixed fees could be utilized for costs that are consistent from study to study, such as site initiation or monitoring visits. Fee for service would then be utilized for study procedures because they would be variable from visit to visit and study to study. An agreed-to administrative fee (in line with FMV) per visit type can also be included in this model along with research RVUs. The investigator then understands that compensation will be adjusted from study to study. This system is consistent with the financial success of the study while remaining within the regulatory guidelines.

Special considerations for all models:

• If the investigator is billing a third party/subject for routine services that are in the protocol, the site cannot also compensate for those services, meaning the physician or site cannot get paid twice.
• Ensure all investigators’ work and time efforts are documented clearly.
• Written contracts and expectations are vital and should follow the guidelines set forth in The Personal Services and Management Contracts Safe Harbor or The Personal Service Exception.{2}

Regardless of the compensation structure, at the end of the day, it is important to remember that according to the tenets set forth by the International Council for Harmonization’s Good Clinical Practice guidelines and the U.S. Food and Drug Administration, bonuses, finder’s fees, or pay-for-performance to PIs based on the number of participants enrolled in or completing the trial are completely unacceptable.{11}

Compensation Models for Different Types of Physicians: Private vs. Hospital Based

Hospital and Medical Group Physicians

When working with physicians inside our system, the use of the centralized research office is required. We provide a consistent process to all studies so that all budgeting, contracting, regulatory approvals, and staffing issues are covered from study start-up to close-out to provide a concerted approach. All research funds are routed directly to the centralized research office with quarterly reimbursement made to research partnering physicians. We draft a master agreement with each physician and then utilize sub-orders to outline each study reimbursement and what payment schedule will be. The compensation follows a hybrid model approach including fixed fees, fee-for-service, RVU considerations, and administrative oversite fees.

We do have physician groups that request the money be distributed evenly across investigators or returned to their departments. Alternately, in departments where the studies might be supported by only one or two investigators, they opt to be paid individually. We always have these discussions up front, so they understand the options available to them. This model allows great flexibility amongst our physician groups, and they are able to feel engaged in the conversation from start to finish.

Private Physicians

When working with private physicians, understand that they have the desire to keep their patient population yet also are aware of competitive study enrollment. Private PIs can use their own clinical research staff (if they have them) or utilize our site staff if they lack adequate study support. In this scenario, a master agreement is drafted with each private physician group and then sub-orders are utilized to outline each study reimbursement and what the payment schedule will be. Compensation is provided for specific services performed by private physicians and their research staff following a fee-for-service model.

When we work with private PIs who provide all the staffing for studies yet require the use of the physical hospital space, we draft a facility use agreement where we can charge for management of study drug, supplies, equipment, and oversite of any research billing that may occur. Some physicians find us so helpful to work with that they have stopped performing research procedures at other hospitals, which brings in revenue for the hospital and procedures we might not have captured previously.

Investigator compensation is not a one-size-fits-all model. It includes an open and honest discussion with the investigator in addition to adhering to FMV and staying within ethical guidelines. Investigators should be motivated, but not incentivized, to perform clinical trials and view this engagement as a partnership to enhance research efforts to better the lives of our patients.

• Bowler A. 2017. Effort-Based Salary Support for PI Oversight Charges.
• Cramer P. 2016. Investigator Compensation: Motivation vs. Regulatory Compliance. Journal of Clinical Research Best Practices 12(9). https://www.magiworld.org/Journal//2016/1609_Compensation_Rules.pdf
• Gibson M. 2016. Developing an Investigator Compensation Plan. Journal of Clinical Research Best Practices 12(9). https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwj81pmcsL70AhUloHIEHdeGCLQQFnoECAQQAQ&url=https%3A%2F%2Ffirstclinical.com%2Fjournal%2F2016%2F1609_Investigator_Compensation.pdf&usg=AOvVaw30RL0JLVKLcfsMUQNXLHfc
• Goldfarb NM. 2010. Investigator Compensation by the Research Site.
• AMA Code of Medical Ethics’ Opinions on Clinical Research. 2015. AMA Journal of Ethics 17(12):1136–41. https://doi.org/10.1001/journalofethics.2015.17.12.coet1-1512
• Fair Market Value Conundrum: Solutions for Sponsors and Sites. Applied Clinical Trials . http://www.appliedclinicaltrialsonline.com/fair-market-value-conundrum-solutions-sponsors-and-sites
• Electronic Code of Federal Regulations . https://www.ecfr.gov/
• In Public Health. Title 42 . 2011. Office of the Federal Register, National Archives and Records Administration. https://www.govinfo.gov/app/details/CFR-2011-title42-vol2/CFR-2011-title42-vol2-sec411-351
• 68 FR 23731—OIG Compliance Program Guidance for Pharmaceutical Manufacturers. Office of the Federal Register, National Archives and Records Administration. https://www.govinfo.gov/app/details/FR-2003-05-05/https%3A%2F%2Fwww.govinfo.gov%2Fapp%2Fdetails%2FFR-2003-05-05%2F03-10949
• Goldfarb NM. 2019. Why Fair Market Value is Not One Number. See also https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwi44InAsb70AhUfrHIEHVrIAIMQFnoECCAQAQ&url=https%3A%2F%2Fwww.magiworld.org%2Fjournal%2F2017%2F1712_FMV.pdf&usg=AOvVaw3TY-LmpHkjGmD8W67WQ-OM
• Clinical Investigator Payment Best Practices. Clinical Leader. https://www.clinicalleader.com/doc/clinical-investigator-payment-best-practices-0001

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Submission Process

Submission content, timeline of review, initiation, agreements & registration, safety reporting, progress reporting.

Sponsorship

Definition of Sponsor

Site/investigator selection, insurance & compensation, risk & quality management, data & records management, personal data protection.

Informed Consent

Documentation Requirements

Required elements, participant rights, emergencies, vulnerable populations, children/minors, pregnant women, fetuses & neonates, mentally impaired.

Investigational Products

Definition of Investigational Product

Manufacturing & import, quality requirements, product management, definition of specimen, specimen import & export, consent for specimen, requirements, additional resources.

Quick Facts

This profile covers the role of the Department of Health & Human Services (HHS) ’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct , 21CFR50 , and 21CFR312 . Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule ( Pre2018-ComRule and RevComRule ), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E . (Please note: ClinRegs does not provide information on state level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct , 21CFR50 , and 21CFR312 , the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92 , the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33 . Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) . Additionally, per USA-88 , the Office of Clinical Policy (OCLiP) develops good clinical practice and human subject protection policies, regulation, and guidance.

See USA-47 for a list of FDA clinical trials related guidance documents.

Office for Human Research Protections and Common Rule Agencies

Per USA-93 , the OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule ( Pre2018-ComRule and RevComRule ) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-65 for a list of US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65 ), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-55 and USA-74 , the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements decision charts consistent with the RevComRule , including how to determine if research is exempt, see USA-74 . For more information about the RevComRule , see USA-66 .

Per the RevComRule , the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65 ) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule . Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements decision charts consistent with the Pre2018-ComRule , including how to determine if research is exempt, see USA-74 .

See USA-54 for additional information regarding compliance with the Pre2018-ComRule and the RevComRule .

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50 . However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

Other Considerations

Per USA-16 , the US is a founding regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The US has adopted several ICH guidance documents, including the E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population ( US-ICH-E11 ), E17 General Principles for Planning and Design of Multiregional Clinical Trials ( US-ICH-E17 ), and E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) ( US-ICH-GCPs ), which are cited throughout this profile.

Contact Information

As per USA-81 , USA-91 , and USA-90 , the contact information for the FDA is as follows:

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Telephone (general inquiries): (888) 463-6332

CDER Telephone (drug information): (301) 796-3400 CDER Email: [email protected]

CBER Telephone: (800) 835-4709 or (240) 402-8010 CBER Email (manufacturers assistance): [email protected] CBER Email (imports): [email protected] CBER Email (exports): [email protected]

Office for Human Research Protections

Per USA-82 , the contact information for the OHRP is as follows:

Office for Human Research Protections 1101 Wootton Parkway, Suite 200 Rockville, MD 20852 Telephone: (866) 447-4777 or (240) 453-6900 Email (general inquiries): [email protected]

Department of Health & Human Services

According to USA-83 , the contact information for the HHS is as follows:

US Department of Health & Human Services Hubert H. Humphrey Building 200 Independence Avenue, S.W. Washington, D.C. 20201 Call Center: (877) 696-6775

In accordance with the FDCAct , 21CFR50 , and 21CFR312 , the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312 , institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42 , sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42 , the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.
• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD , non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination , in general, human research studies must be conducted under an IND if all of the following research conditions apply:

• A drug is involved as defined in the FDCAct
• A clinical investigation is being conducted as defined in 21CFR312
• The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct .

Further, per 21CFR312 and the G-IND-Determination , whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

Clinical Trial Review Process

As delineated in 21CFR312 , the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94 , the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312 , an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312 for more information on clinical holds.

According to USA-41 , with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312 , the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, on the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312 , if no subjects are entered into a clinical study two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95 , respectively.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

• Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
• Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
• Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
• Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct , as amended by the FDORA , for changes to the accelerated approval process.

The G-RWDRWE-Reg , issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17 ), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials .

For research involving cellular and gene therapy, see the guidance documents at USA-80 .

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct , FDARA , and USA-45 , the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). Per USA-43 , the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA.

As indicated in 21CFR50 , 21CFR56 , and 21CFR312 , the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50 , 21CFR56 , and 21CFR312 , all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule , for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule . Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Ethics Committee Composition

As stated in 21CFR56 , the Pre2018-ComRule , and the RevComRule , an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

• One (1) primarily focused on scientific issues
• One (1) focused on nonscientific issues
• One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in 21CFR56 , ECs must follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , ECs must establish and follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
• Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, the institution, the FDA, and the Department of Health & Human Services (HHS) ’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination.

21CFR56 , the Pre2018-ComRule , and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule , the RevComRule , and 21CFR56 .

See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56 , the Pre2018-ComRule , and the RevComRule , proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule , the RevComRule , 21CFR56 , the G-IRBProcs , and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule , the RevComRule , and the G-HHS-Inst-Engagemt , any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65 ) must also submit a written assurance of compliance to OHRP. According to USA-59 , the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-funded research. See USA-57 for more information on FWAs.

21CFR56 , 21CFR312 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56 , the Pre2018-ComRule , and the RevComRule , the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Role in Clinical Trial Approval Process

In accordance with 21CFR56 and 21CFR312 , the Food & Drug Administration (FDA) must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56 , the Pre2018-ComRule , and the RevComRule , the EC may approve, require modifications in (to secure approval), or disapprove the research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the Department of Health & Human Services (HHS) that must also comply with FDA regulations.

Per 21CFR56 , the Pre2018-ComRule , the RevComRule , and the G-IRBContRev , an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

Expedited Review

21CFR56 , the Pre2018-ComRule , and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

• Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
• Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
• Under the RevComRule , research for which limited EC review is a condition of exemption

21CFR56 , the Pre2018-ComRule , and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev , research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev .

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

• Research eligible for expedited review
• Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
• Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule , certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Per USA-54 , for secondary research that does not qualify for an exemption under the RevComRule , the applicant must either apply for a waiver of the informed consent requirement from the EC, obtain study-specific informed consent, or obtain broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

• Scholarly and journalistic activities
• Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
• Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

See the G-IRBFAQs , the G-OHRP-IRBApprvl , and USA-54 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.

Per the FDA’s G-IRBReview , an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview .

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule , the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-65 ) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule , per the NIHNotice16-094 and the NIHNotice17-076 , the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see the FDA’s G-CoopRes . For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS Office for Human Research Protections (OHRP) ’s G-ComRuleCnsstncy .

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

As delineated in 21CFR56 and 45CFR46-B-E , the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system ( USA-28 ) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP) .

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61 , EC registration with the HHS OHRP system ( USA-28 ) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56 , or by the HHS that the EC is in full compliance with 45CFR46-B-E . Neither EC competence nor expertise is assessed during the registration review process by either agency.

According to 21CFR56 and the G-IRBReg-FAQs , the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system ( USA-28 ). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs , any EC not already registered in the HHS OHRP system ( USA-28 ) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system ( USA-28 ) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements. See the G-IRBInspect for FDA inspection procedures of ECs.

Per the Pre2018-ComRule and RevComRule , institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-65 ) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59 , a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects ( Pre2018-ComRule or RevComRule ) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

Per USA-54 , institutions do not need to change an existing FWA because of the RevComRule . See USA-57 for more information on FWAs.

Per 45CFR46-B-E and USA-61 , all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system ( USA-28 ). An individual authorized to act on behalf of the institution operating the EC must submit the registration information. EC registration becomes effective for three (3) years when reviewed and approved by OHRP.

Per USA-59 , an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E , USA-58 , and USA-61 for detailed registration requirements and instructions.

As delineated in 21CFR312 , USA-42 , and USA-52 , the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA) 's review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination , whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct ) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312 , institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Submission

According to 21CFR312 , meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA .

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to the G-PharmeCTD , which implements FDCAct requirements, and as described in USA-34 and USA-53 , commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) . See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD , the G-eCTDTech , USA-35 , and USA-36 . Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs and USA-7 , eCTD submissions sized 10 GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (ESG) ( USA-44 ). However, the G-eCTDspecs adds that the FDA also recommends the use of USA-44 for submissions greater than 10 GB when possible. See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs , physical media greater than 10 GB should be submitted using a USB drive. For specific instructions on how to submit physical media, email CDER at [email protected] or CBER at [email protected] . See the G-eCTDspecs for additional physical media information.

The IND must be submitted in English. As indicated in 21CFR312 , the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

According to USA-41 and USA-94 , paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration Center for Drug Evaluation and Research (CDER) Central Document Room 5901-B Ammendale Rd. Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators) :

Food and Drug Administration Center for Drug Evaluation and Research (CDER) Therapeutic Biological Products Document Room 5901-B Ammendale Rd. Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration Center for Biologics Evaluation and Research (CBER) Document Control Center 10903 New Hampshire Avenue WO71, G112 Silver Spring, MD 20993-0002

(Note: Per USA-94 , CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

Based on information provided in 21CFR312 , for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports.

Ethics Review Submission

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

Regulatory Authority Requirements

As specified in 21CFR312 , an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

• Cover sheet (Form FDA 1571 ( USA-76 )) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
• Table of contents
• Introductory statement and general investigational plan
• Investigator’s brochure (IB)
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the IP
• Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
• Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312 . In addition, see USA-40 for other IND forms and instructions.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials .

The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc .

The FDCAct , as amended by the FDORA , requires sponsors to submit diversity action plans for certain clinical trials, such as a clinical investigation of a new drug that is a phase 3 study. See the FDORA for more details. (Note: The FDA’s guidance on diversity action plans is currently in draft. The ClinRegs team will continue to monitor this requirement and incorporate any updates as appropriate).

According to the G-PedStudyPlans , a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA) . An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans .

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ significantly regarding application content requirements. However, the requirements listed below comply with 21CFR56 as well as the US-ICH-GCPs and are basically consistent across all US ECs.

As per 21CFR56 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• Clinical protocol
• Informed consent forms (ICFs) and participant information (the RevComRule also requires information regarding whether informed consent was appropriately sought and documented, or waived)
• Participant recruitment procedures
• Safety information
• Participant payments and compensation
• Investigator(s) current Curriculum Vitaes (CVs)
• Additional required EC documentation
• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate; the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data

Per the RevComRule , where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56 , the Pre2018-ComRule , the RevComRule , and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

According to the US-ICH-GCPs , the clinical protocol should contain the following elements:

• General information
• Background information
• Trial objectives and purpose
• Trial design
• Participant selection/withdrawal
• Participant treatment
• Efficacy assessment
• Safety assessment
• Direct access to source data/documents
• Quality control/quality assurance
• Data handling/recordkeeping
• Financing/insurance
• Publication policy
• For complete protocol requirements, see section 6 of the US-ICH-GCPs .

Per the NIHNotice17-064 , and provided in USA-29 and USA-27 , the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

As delineated in 21CFR56 and 21CFR312 , institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA) 's review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Authority Approval

Per the FDCAct and 21CFR312 , initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312 , the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95 , respectively.

According to USA-41 and USA-42 , clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial. However, according to the US-ICH-GCPs , the institutional EC should review a proposed clinical trial within a reasonable time.

In accordance with 21CFR312 , USA-41 , and USA-42 , a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA) , which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56 , ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312 , once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTDiversity for FDA recommendations to sponsors on increasing enrollment of underrepresented populations in their clinical trials.

Clinical Trial Agreement

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs , the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 ( USA-77 ). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312 , the G-1572FAQs , and USA-40 for further information.

The US-ICH-GCPs indicates that the sponsor must obtain the investigator’s/institution’s agreement:

• To conduct the trial in compliance with good clinical practice (GCP), with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC;
• To comply with procedures for data recording/reporting;
• To permit monitoring, auditing, and inspection; and
• To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed.

The sponsor and the investigator/institution must sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

The FDAMA , the FDAAA , and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank ( USA-78 ). Per the FDAAA and 42CFR11 , the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov ( USA-78 ).

See 42CFR11 , the NIHTrialInfo , and USA-49 for detailed information on ClinicalTrials.gov ( USA-78 ). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

Safety Reporting Definitions

In accordance with 21CFR312 , the G-IND-Safety , 42CFR11 , and USA-38 , the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US):

• Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
• Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
• Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
• Serious Adverse Event/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
• Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
• Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs , the Department of Health & Human Services (HHS) ’s 45CFR46 regulations (the Pre2018-ComRule , the RevComRule , and 45CFR46-B-E ) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs , the G-IRBRpting , the Pre2018-ComRule , and the RevComRule for further information.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-IND-Safety , the investigator must comply with the following reporting requirements:

• Serious adverse events, whether or not considered drug related, must be reported immediately to the sponsor
• Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
• Non-serious adverse events must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others where adverse events should be considered unanticipated problems

Sponsor Responsibilities

As delineated in 21CFR312 , the G-IND-Safety , and USA-38 , the sponsor must report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event .

The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312 and the G-IND-Safety , the sponsor must also report the following:

• Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report), whether or not conducted under an investigational new drug application (IND), and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312 and the G-IND-Safety for more details on these safety reporting requirements.

As part of the clinical trial results information submitted to ClinicalTrials.gov ( USA-78 ), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:

• All serious adverse events
• All adverse events, other than serious adverse events, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11 and USA-70 , this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov ( USA-78 ) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

As per 21CFR312 , the G-IND-Safety , and USA-38 , the sponsor must submit each safety report in a narrative format on Form FDA 3500A ( USA-75 ), or in an electronic format that the FDA can process, review, and archive, and be accompanied by Form FDA 1571 ( USA-76 ) (cover sheet).

As per the G-IND-Safety and USA-38 , the submission must be identified as follows:

• “IND safety report” for 15-day reports
• “7-day IND safety report” for unexpected fatal or life-threatening suspected adverse reaction reports
• “Follow-up IND safety report” for follow-up information

The report must be submitted to the appropriate review division (i.e., Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) ). Per USA-38 , the FDA recommends that sponsors submit safety reports electronically. Other means of rapid communication to the respective review division’s Regulatory Project Manager (e.g., telephone, facsimile transmission, email) may also be used. Per USA-90 , fatality reports to CBER should be sent to [email protected] .

Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign suspected adverse reaction reports on CIOMS Form I (See USA-13 and USA-3 ) instead of Form FDA 3500A ( USA-75 ). See USA-38 and USA-48 for additional information.

Interim and Annual Progress Reports

As per the US-ICH-GCPs , the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

As specified in 21CFR312 , the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56 and the US-ICH-GCPs the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

• Title, purpose, and description of patient population, and current status
• Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
• Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
• Description of the general investigational plan for the coming year
• Updated investigator’s brochure, if revised
• Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
• Brief summary of significant foreign marketing developments with the drug
• A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11 , trial updates must be submitted to ClinicalTrials.gov ( USA-78 ) according to the following guidelines:

• Not less than once every 12 months for updated general trial registration information
• Not later than 30 calendar days for any changes in overall recruitment status
• Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

Final Report

As indicated in 21CFR312 , an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

The US-ICH-GCPs also states that upon the trial’s completion, the investigator should inform the institution and the investigator/institution should provide the EC with a summary of the trial’s outcome, and supply the FDA with any additional report(s) required of the investigator/institution.

Additionally, per 42CFR11 and USA-70 , the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to USA-78 that indicates either: 1) the FDA has not yet approved, licensed, or cleared the IP being studied for marketing; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year. The results information must include data on the following:

• Participant flow
• Demographic and baseline characteristics
• Outcomes and statistical analysis
• Adverse events
• The protocol and statistical analysis plan
• Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.

As per 21CFR312 , 21CFR50 , and the US-ICH-GCPs , a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312 , 21CFR50 , and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO).

Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. However, per the US-ICH-GCPs , although a sponsor may transfer all trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.

As indicated in 21CFR312 , a sponsor may be either domestic or foreign.

As set forth in 21CFR312 and the US-ICH-GCPs , the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

• Signed investigator’s statement (Form FDA 1572 ( USA-77 ))
• Curriculum vitae
• Financial disclosure information

As addressed in the G-1572FAQs , Form FDA 1572 ( USA-77 ) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA) 's clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, prior to the start of the study, the sponsor must provide the investigator(s) with the protocol and the investigator’s brochure.

See G-InvstgtrResp for more information on investigator responsibilities.

As per the G-InvstgtrAdmin , the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50 and the G-DMCs , Data and Safety Monitoring Boards (DSMBs), (also known as a Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, as stated in 21CFR50 , the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation. See the G-DMCs for FDA recommendations on DSMB/DMC establishment.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-65 ), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72 , all National Institutes of Health (NIH) -funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS) /NIH requirements.

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a DSMB may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

For all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section , the RevComRule , and G-CoopRes for additional information.

The US-ICH-GCPs indicates that in the event of a multicenter clinical trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and given EC approval
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication among investigators is facilitated

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

The United States (US) regulations do not require insurance.

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).

Injury or Death

According to the US-ICH-GCPs , the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

As specified in 21CFR50 , the Pre2018-ComRule , the RevComRule , and US-ICH-GCPs , for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

Trial Participation

As per the FDA’s G-SbjctPayment , compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

Quality Assurance/Quality Control

Per the US-ICH-GCPs , the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

• During protocol development, identify processes and data that are critical to ensure participant protection and the reliability of trial results
• Identify risks to critical trial processes and data
• Evaluate the identified risks, against existing risk controls
• Decide which risks to reduce and/or which risks to accept
• Document quality management activities and communicate to those involved in or affected by these activities
• Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken

As stated in the US-ICH-GCPs , the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the US-ICH-GCPs , and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per the G-ICH-E19 , the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the G-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research.

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-6 for information on the National Institutes of Health (NIH) ’s data management and sharing policy, the NIHDataMngmnt , which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data.

Monitoring Requirements

As part of its QA system, the US-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the US-ICH-GCPs , and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with the sponsor’s own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
• Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA .

Premature Study Termination/Suspension

As delineated in 21CFR312 and the US-ICH-GCPs , if the sponsor determines the study presents an unreasonable and significant risk to the participants, the sponsor must discontinue the study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining drugs and provide the FDA with a full report on the sponsor’s actions.

According to the US-ICH-GCPs , if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

The G-InfrmdCnsnt , which is the FDA’s discussion of the regulations in 21CFR50 , further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an investigational product (IP) that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow-up may be available or necessary.

21CFR312 indicates that if the FDA terminates an investigational new drug application (IND) based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

Electronic Data Processing System

Per the US-ICH-GCPs , when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the US-ICH-GCPs for additional information.

Records Management

As set forth in 21CFR312 and the US-ICH-GCPs , the sponsor must retain all sponsor-specific essential documents pertaining to the trial for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if a NDA is not approved, until two (2) years after shipment and delivery of the drug for investigational use is discontinued and the Food & Drug Administration (FDA) has been notified. The sponsor should also inform the investigator(s)/institution(s) in writing of the need for record retention and when the trial-related records are no longer needed. Additionally, per 21CFR312 , the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

In addition, the US-ICH-GCPs states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

As stated in USA-86 , the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87 , the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164 ; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule ) and Food & Drug Administration (FDA) ( 21CFR50 and 21CFR56 ) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state level personal data protection requirements.)

Per the Privacy Rule, a covered entity means: a health plan; a health care clearinghouse; or a health care provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.

Data Protection

According to the FDA’s G-CertCnfdntlty , a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.

NIH Privacy Requirements

The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct , which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.

Consent for Processing Personal Data

Per USA-86 , the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:

• Documented EC or privacy board approval
• Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
• Research on protected health information of decedents
• Limited data sets with a data use agreement
• Research use/disclosure with individual authorization
• Accounting for research disclosures

See USA-86 for more information on these circumstances.

Obtaining Consent

In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on agency-specific compliance.) Department of Health & Human Services (HHS) -funded or sponsored clinical trials must also comply with 45CFR46-B-E . The FDA has also adopted the US-ICH-GCPs as guidance.

As per 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND).

Per the G-RevComRule-FDA , the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule , which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved ICF used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12 , two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov ( USA-78 ) and a docket folder on Regulations.gov ( USA-79 ). According to the RevComRule , if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.

According to 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the investigator must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or the legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

As indicated in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , none of the oral and written information concerning the research study should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Additionally, per the RevComRule , participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens. See USA-54 and USA-60 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50 , the Pre2018-ComRule , and the RevComRule , the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or a legal representative(s) or guardian(s) to read before it is signed.

See the FDA’s G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.

See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50 . Also, see USA-54 and USA-60 for additional information regarding informed consent.

According to 21CFR50 , the US-ICH-GCPs , and the G-IRBFAQs , the EC should determine the need to re-consent enrolled participants in the event of an ICF modification due to protocol changes or new information which may, in turn, affect the willingness of already enrolled participants to continue in the study. The communication of this information should be documented.

The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.

Language Requirements

21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or the legal representative(s) or guardian(s).

As delineated in the FDA’s G-InfrmdCnsnt , when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-InfrmdCnsnt and USA-63 for detailed information.

Documenting Consent

As set forth in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the participant and/or a legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant and/or a legal representative(s) or guardian(s). In addition, the RevComRule explicitly allows electronic signatures for consent documentation.

Per 21CFR50 , the Pre2018-ComRule , and the RevComRule , if the consent information is only presented orally using the short form, the participant and/or the legal representative(s) or guardian(s) must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant and/or the legal representative(s) or guardian(s). The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50 . The date consent was obtained should be recorded in this note.

According to the US-ICH-GCPs , where the participant is illiterate and/or the legal representative(s) and/or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:

• The written ICF and any other written information to be provided to the participant is read and explained to the participant or the legal representative(s)/guardian(s)
• The participant or the legal representative(s)/guardian(s), has orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Per the US-ICH-GCPs , before participating in the study, the participant or the legal representative(s)/guardian(s) should receive a copy of the signed and dated ICF.

Waiver of Consent

Per the Pre2018-ComRule and the RevComRule , the EC may waive the requirement to obtain a signed ICF if it finds any of the following:

• The ICF would risk a breach of confidentiality by linking the participant to the study
• The research presents minimal risk and involves no procedures for which written consent is required outside of the study

The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.

The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative(s)/guardian(s) with a written statement regarding the research.

In addition, the Pre2018-ComRule states that for an EC to approve a general waiver or alteration of consent, the EC must find that:

• The research involves no more than minimal risk
• The research could not practicably be carried out without the requested waiver or alteration
• If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format
• The waiver or alteration will not adversely affect the rights and welfare of the participants
• Whenever appropriate, the participant will be provided with additional pertinent information after participation

In the G-MinRiskWaiver , the FDA informs sponsors, investigators, and ECs that it does not intend to object to an EC waiving or altering informed consent requirements for certain minimal-risk, clinical investigations.

Furthermore, the Pre2018-ComRule , the RevComRule , and the G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.

Based on 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• The study purpose, procedures, and expected duration of the trial
• Identification of any experimental procedures
• Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
• Any expected benefits to the participant
• Disclosure of appropriate alternative procedures that might be advantageous to the participant
• Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Contact information for relevant individuals to contact in the event of a trial-related injury
• That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
• Foreseeable circumstances under which the investigator may remove the participant without consent
• Any expenses the participant needs to pay to participate in the trial
• The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
• Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
• Approximate number of participants in the study

As per 21CFR50 , for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov , as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

In the G-InfrmdCnsnt , the FDA also recommends the consent document advise participants that data collected on them up until the point of their withdrawal from a study will remain part of the study database and may not be removed. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50 .

The RevComRule also requires the following statements to be included in the ICF:

• Whether research results will be disclosed to participants
• Whether or not the participant’s information or biospecimens will be used or distributed for future research
• That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit
• Whether biospecimens research may include whole genome sequencing

Compensation Disclosure

The FDA’s G-InfrmdCnsnt further states that if no compensation in the event of injury is available, the consent process should include a statement informing the participant. See the G-InfrmdCnsnt for an example statement.

In accordance with 21CFR50 , 21CFR312 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the United States’ (US) ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , a potential participant and/or a legal representative(s) or guardian(s) must be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , a potential research participant and/or a legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per 21CFR50 , the Pre2018-ComRule , and the RevComRule , participants should be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained. Per the US-ICH-GCPs , all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. It is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The RevComRule does allow the use of identifiable private information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for additional information on identifiable private information or biospecimens, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The G-InfrmdCnsnt , which is the Food & Drug Administration (FDA) ’s discussion of the regulations in 21CFR50 , delineates how data should be handled when an enrolled participant decides to withdraw from a trial. Data collected on participants up to the time of withdrawal from clinical investigations of drugs conducted under an investigational new drug application (IND) must remain in the study database to maintain the scientific validity of the research. The FDA recommends that participants be advised in the consent document that the data collected on them up until the point of their withdrawal will remain part of the study database and may not be removed. If a participant withdraws from the interventional portion of the clinical investigation but agrees to continued follow-up not addressed in the original consent document, the investigator must obtain the participant’s informed consent for this limited participation using an EC-approved consent document. If a participant withdraws from the interventional portion of a clinical investigation and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access the participant’s medical record or other confidential records that would require additional consent from the participant. However, such records may be accessed consistent with the original consent process, without additional consent, to obtain information collected prior to the participant’s withdrawal from the study. See the G-InfrmdCnsnt for additional information.

The Right of Inquiry/Appeal

21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs state that the research participant and/or a legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

The Right to Safety and Welfare

The US-ICH-GCPs clearly states that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

21CFR50 , 21CFR56 , the US-ICH-GCPs , and the G-ICEmrgncyReqs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by life-threatening medical emergencies, public health emergencies, or military operations.

Medical Emergencies

As per the US-ICH-GCPs , in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or a legal representative(s) or guardian(s), or if an effective treatment is lacking but the investigational product (IP) could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) must approve the protocol in advance. The participant and/or the legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

Emergency Use Situation

21CFR56 describes emergency use as the use of a test article, such as an IP, on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain EC approval.

21CFR50 and the G-EmrgncyUse indicate that even in an emergency use situation, obtaining participant consent is required unless the investigator and a physician not participating in the trial certify in writing the following:

• The participant is confronted by a life-threatening situation
• Informed consent cannot be obtained due to an inability to communicate with the participant
• Time is insufficient to obtain consent from the participant’s legal representative(s) and/or guardian(s)
• No alternative methods of approved or generally recognized therapy are available

Per 21CFR50 and the G-EmrgncyUse , if immediate use of the IP is, in the investigator's opinion, required to preserve the participant’s life and time is not sufficient to obtain an independent physician’s determination prior to using the IP, the investigator’s determinations should be carried out. However, within five (5) working days following the use of the IP, the investigator’s decision must be reviewed and evaluated in writing by a physician not participating in the investigation. According to 21CFR50 , 21CFR56 , and the G-EmrgncyUse , the investigator must also notify the EC within five (5) working days.

21CFR56 , the G-EmrgncyUse , and the G-IRBFAQs further state that following emergency use of the IP, EC review and approval is required for any subsequent use of the IP.

Emergency Research

The G-ICEmrgncyReqs defines emergency research as a planned clinical investigation that requires prior written Food & Drug Administration (FDA) authorization to proceed, and involves participant(s) who are in a life-threatening situation for which available treatments or in vitro diagnostic tests are unproven or unsatisfactory.

21CFR50 and the G-ICEmrgncyReqs delineate that for emergency research, the EC may approve the investigation without requiring the consent of all the participants if the EC (with the concurrence of a licensed physician who is an EC member or EC consultant, and not otherwise participating in the investigation) finds and documents the following:

• The participants are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence is necessary to determine the safety and effectiveness of particular interventions
• Obtaining informed consent is not feasible because: (i) the participants will not be able to give their informed consent as a result of their medical condition; (ii) the intervention under investigation must be administered before consent from the participants’ legal representative(s) and/or guardian(s) is feasible; and (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation
• Participation in the research holds out the prospect of direct benefit to the participants
• The clinical investigation could not practicably be carried out without the waiver
• The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legal representative and/or guardian for each participant within that window of time and, if feasible, to asking them for consent within that window rather than proceeding without consent
• The EC has reviewed and approved informed consent procedures and an informed consent document consistent with 21CFR50
• Additional protections of the rights and welfare of the participants will be provided

See 21CFR50 and the G-ICEmrgncyReqs for more details.

USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative(s) and/or guardian(s), no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.

Military Operations

21CFR50 and 10USC55 indicate that in the case of IP administration to a member of the armed forces in connection with participation in a particular military operation, the requirement for the member’s prior consent may be waived only by the US President. The US President may grant the waiver only after determining, in writing, that obtaining consent is not feasible; is contrary to the best interests of the military personnel; or is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.

As per 21CFR56 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

21CFR56 and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Per 21CFR56 and US-ICH-GCPs , other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations. The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

For more guidance documents related to vulnerable populations, see USA-64 .

See the Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these vulnerable populations.

As set forth in 21CFR50 and 45CFR46-B-E , children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the study will be conducted. USA-25 further states that the age of majority in most states is 18 and therefore for legal purposes, children are those individuals who have not reached the age of 18. See USA-25 for a table delineating the legal age of majority by state in the United States (US).

Per the Pre2018-ComRule and the RevComRule , children require additional safeguards to be included in any research study in order to protect their rights and welfare. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

As delineated in the US-ICH-GCPs , when the research participant is a minor, informed consent should be obtained from a legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and in terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.

For all clinical trials that do not involve greater than minimal risk, 21CFR50 and 45CFR46-B-E state that a study may only be conducted if adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s).

For all clinical trials that involve greater than minimal risk but present the prospect of direct benefit to the child, 21CFR50 and 45CFR46-B-E indicate that a study may only be conducted if the following applies:

• The risk is justified by the anticipated benefit to the child
• The anticipated benefit is greater than or equal to the available alternative approaches
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardians

For all clinical trials involving children/minors that involve greater than minimal risk and do not present the prospect of direct benefit to the child, but will likely result in increased knowledge about the child’s disorder or condition, 21CFR50 and the 45CFR46-B-E state that a study may only be conducted if the following applies:

• The risk is slightly greater than minimal
• The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social, or educational situation
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)

For all clinical trials that present a reasonable opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors but is not otherwise approvable per 21CFR50 and 45CFR46-B-E , a study may only be conducted if the following applies:

• The institutional ethics committee (EC) (institutional review board (IRB) in the US) finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and,
• The Commissioner of Food and Drugs consults with an expert panel and has an opportunity for public review and comment to determine that the investigation satisfies the conditions of one (1) of the other earlier described research types, or the following conditions are met: the investigation will be conducted in accordance with sound ethical principles and adequate provisions are made for soliciting the assent of children and the permission of their legal representative(s) or guardian(s)

Per the RevComRule , certain exemptions may apply to observational research involving children. See the RevComRule for details.

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11 and USA-60 . Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50 .

Assent Requirements

Per 21CFR50 and 45CFR46-B-E , when determining whether children/minors are capable of providing assent, the EC must consider their age, maturity, and psychological state. Assent from a child/minor is not necessary for proceeding with the clinical trial if the following applies:

• The capability of some or all of the children/minors is so limited that they cannot reasonably be consulted
• The trial presents a potential direct benefit that is important to the health or well-being of the children/minors and is only available through the investigation

Further, the EC may waive assent, even if the children/minors are capable of providing assent, if it finds and documents the following:

• Trial involves no more than minimal risk
• The waiver will not negatively affect the rights and welfare of the children/minors
• The trial could not be implemented without the waiver
• The children/minors will be given additional information after participation, whenever appropriate

When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented. 21CFR50 and 45CFR46-B-E do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:

• When there is greater than minimal risk to the child with no direct benefit to the child, but the study will likely result in increased knowledge about the child’s disorder or condition
• Research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors, but is not otherwise approvable

Exceptions to the two (2) legal representatives’ and/or guardians’ consent requirement are when one (1) legal representative or guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) legal representative or guardian has legal responsibility for the care and custody of the child.

The G-InfrmdCnsnt indicates that when obtaining legal representative or guardian permission, in the event that the legal representative(s) or guardian(s) of a child does not understand English, the permission must be obtained and documented in a language that is understandable to the legal representative(s) or guardian(s). The child who will be participating in the research should not be used as an interpreter for the legal representative(s) or guardian(s), even if the child is fluent in English and may be able to assent. Further, legal representative or guardian permission and child assent should be viewed as an ongoing process throughout the duration of a clinical investigation. If and when a child who was enrolled in a clinical investigation with legal representative or guardian permission reaches the legal age of consent, that participant no longer meets the definition of a child under 21CFR50 , and the investigator should obtain the participant’s informed consent prior to performing any further research interventions and/or procedures involving that participant. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50 .

As per 21CFR50 and 45CFR46-B-E , for studies involving women of childbearing age or who are pregnant, a statement should be provided in the informed consent form (ICF) indicating that the treatment or procedure may involve risks to the participant, embryo, or fetus, which are currently unforeseeable. According to the US-ICH-GCPs , the ICF should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

Per the Pre2018-ComRule , pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare. Furthermore, according to the RevComRule , all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

All Department of Health & Human Services (HHS) -sponsored or -funded research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates must comply with Subpart B of 45CFR46-B-E .

Pregnant Women and Fetuses

As per 45CFR46-B-E , pregnant women and fetuses may participate in research if all of the following criteria are met:

• Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
• Risk to the fetus is caused solely by procedures that provide potential direct benefit to the woman or fetus. If there is no potential direct benefit, then the risk to the fetus cannot be greater than minimal, and the intent of the study is to develop important biomedical knowledge that cannot be obtained otherwise
• Least possible risk involved for achieving the research objectives
• Consent is obtained from the woman for studies that provide potential direct benefit to the pregnant woman and/or fetus, and studies with minimal risk to the fetus conducted to develop important biomedical knowledge that cannot be obtained otherwise
• Consent is obtained from the pregnant woman and the father if the study provides potential direct benefit solely to the fetus. Paternal consent is not required if the father is unavailable, incompetent, temporarily incapacitated, or the pregnancy was a result of incest or rape
• All individuals providing consent are fully informed about the foreseeable impact on the fetus or neonate
• No inducements will be offered to terminate a pregnancy
• Participants will not be involved in determining the timing, method, or procedures for terminating a pregnancy
• Participants will not be involved in determining the viability of a neonate

45CFR46-B-E states that neonates may not be involved in research unless all of the following criteria are met:

• All individuals providing consent are fully informed about the foreseeable impact on the neonate

Neonates of uncertain viability may not be involved in research unless the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the following additional conditions are met:

• Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise and there is no added risk resulting from the research
• Informed consent is obtained from either parent, or if neither parent is able to provide consent, then consent is obtained from the neonate’s legal representative and/or guardian. Paternal consent is not required if pregnancy was a result of incest or rape.

Nonviable neonates may not be involved in research unless the following additional conditions are met:

• Vital functions will not be maintained artificially
• Research will not terminate the heartbeat or respiration
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
• Consent is obtained from both parents. If neither parent is able to provide consent, informed consent of one (1) parent will suffice. Paternal consent is not required if pregnancy was a result of incest or rape. Consent of a legal representative or guardian of either or both parents will not suffice.

Viable neonates may only be included in research to the extent permitted by and in accordance with the RevComRule and subparts B and D of 45CFR46-B-E .

21CFR56 , 45CFR46-B-E , and the US-ICH-GCPs include prisoners in their description of vulnerable populations. As set forth in 45CFR46-B-E , a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.

Per the Pre2018-ComRule and the RevComRule , prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare. As delineated in the RevComRule , none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

45CFR46-B-E states that prisoners may participate in biomedical or behavioral research conducted or supported by the Department of Health & Human Services (HHS) only if the following criteria are met:

• The institution conducting the research has certified to the HHS Secretary that the research has been approved by the institutional ethics committees (EC) (institutional review board (IRB) in the United States (US)); research involves minimal risk; and studies focus on the possible causes, effects, and processes of incarceration and criminal behavior, prisons as institutional structures, or prisoners as incarcerated persons
• Research should focus on conditions specifically affecting prisoners as a class, or practices that have the intent and likelihood of improving the health or well-being of participants only after the HHS Secretary has consulted the appropriate experts, and a Federal Register notice is published indicating intent to approve such research

See USA-62 for more HHS information on prisoner research.

As per 45CFR46-B-E , ECs have additional approval responsibilities when reviewing research studies involving prisoners. An EC must only approve these studies if it determines that:

• The research under review represents one (1) of the permissible categories of research delineated in Subpart C
• The prisoner’s judgement will not be impaired by any possible advantages accruing to the prisoner through participation in the research, when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison
• Research risks are commensurate with those that would be accepted by non-prisoner volunteers
• Procedures for participant selection within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners
• Information is presented in a language understandable to the prisoner population
• Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on parole
• As needed, adequate provisions have been made for follow-up examination or care of participants, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact

See Subpart C of 45CFR46-B-E for additional EC requirements related to prisoner research.

In accordance with 21CFR56 , the Pre2018-ComRule , and the US-ICH-GCPs , an institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent. According to the G-InfrmdCnsnt , which is the Food & Drug Administration (FDA) ’s discussion of the regulations in 21CFR50 , impaired consent capacity may involve partial impairment, impairment that fluctuates over time, or complete impairment. Consent capacity can be affected by a wide range of disorders and conditions, such as dementia, stroke, traumatic brain injury, intellectual and developmental disabilities, serious mental illness, intoxication, and delirium.

Per the Pre2018-ComRule and the RevComRule , this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

USA-60 further indicates that while Department of Health & Human Services (HHS) regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

As stated in the FDA’s G-InfrmdCnsnt , ECs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Considerations that may help address these challenges and provide additional safeguards include:

• Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional

• Establishing a waiting period in the decision-making process to allow additional time for decision-making

• Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible

• Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire

• Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline

• Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes

• Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented

• Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time

• Determining whether the EC or a third party should observe the consent process

See the G-InfrmdCnsnt for additional information and FDA discussion of the regulations in 21CFR50 .

As delineated in 21CFR312 , an investigational new drug is defined as a new drug or biological drug that is used in a clinical investigation. This includes a biological product that is used in vitro for diagnostic purposes. The terms ‘investigational drug’ and ‘investigational new drug’ are deemed to be synonymous for the purposes of this part.

Additionally, the US-ICH-GCPs defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Manufacturing

According to 21CFR312 and USA-42 , the Food & Drug Administration (FDA) is responsible for authorizing the manufacture of investigational products (IPs) (also known as investigational new drugs in the United States (US)).

Per 21CFR312 , sponsors that use an IP not already subject to a manufacturer’s investigational new drug application (IND) or marketing application are required to provide all of the technical chemistry, manufacturing, and control (CMC) information outlined in the application content and format requirements section of 21CFR312 , unless such information may be referenced from applicable scientific literature. Sponsors using an IP already subject to a manufacturer’s application should follow the same general application format but may, if authorized by the manufacturer, refer to the manufacturer’s application to provide the technical (CMC) information supporting the proposed clinical investigation.

Moreover, as stated in 21CFR312 , a sponsor may ship an IP to the investigators named in the IND under the following conditions:

• Thirty (30) days after the FDA receives the IND, or
• FDA provides earlier authorization to ship the IP

The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210 , the G-CGMP-Phase1 , and the G-INDPrep . The US-ICH-GCPs also states that the sponsor must ensure that the products are manufactured in accordance with GMPs.

As set forth in 21CFR312 , the FDA is also responsible for authorizing the import and export of IPs. An IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements:

• The IP consignee is the IND sponsor, or
• The consignee is a qualified investigator named in the IND, or
• The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP

Investigator's Brochure

In accordance with 21CFR312 and the US-ICH-GCPs , the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational new drug(s)/investigational product(s) (IPs) obtained through the earlier research phases. The sponsor must also update the IB as significant new information becomes available.

As specified in 21CFR312 and the US-ICH-GCPs , the IB must provide coverage of the following areas (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• A brief description of the drug substance and the formulation, including the structural formula, if known
• A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans
• A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans
• A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies
• A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug
• Summary of data and guidance for the investigator

See 21CFR312 and the US-ICH-GCPs for detailed IB content guidelines.

For investigational new drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.120 of 21CFR312 for detailed requirements.

Quality Management

According to USA-39 , submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA) .

The US-ICH-GCPs state that the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Investigational new drug/investigational product (IP) labeling in the United States (US) must comply with the requirements set forth in Section 312.6 of 21CFR312 , which include the following:

• The immediate package of an IP intended for human use must bear a label with the following statement: “Caution: New Drug-Limited by Federal (or US) law to investigational use”
• The label or labeling of an IP must not bear any false or misleading statements and must not represent that the IP is safe or effective for the purposes for which it is being investigated

The appropriate Food & Drug Administration (FDA) Center Director may grant an exception or alternative to the requirements above for specific lots, batches, or other units of a human drug or biological product that is or will be included in the Strategic National Stockpile.

In addition, the US-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Supply, Storage, and Handling Requirements

As defined in the US-ICH-GCPs , the sponsor must supply the investigator(s)/institution(s) with the investigational new drug(s)/investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Per 21CFR312 , the US-ICH-GCPs , the G-CGMP-Phase1 , and the G-INDPrep , the sponsor must ensure the following (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• IP product quality and stability over the period of use
• IP manufactured according to any applicable good manufacturing practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Acceptable storage temperatures, conditions, and times for the IP
• Timely delivery of the IP(s)

Refer to the US-ICH-GCPs , the G-CGMP-Phase1 , and the G-INDPrep for detailed sponsor-related IP requirements.

Record Requirements

According to 21CFR312 , the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. The sponsor is also required to maintain records showing financial interest paid to investigators. See 21CFR312 for more details.

As per 21CFR312 and the US-ICH-GCPs , the sponsor and the investigator(s) must retain the clinical investigation records and reports for two (2) years after a marketing application (known as a New Drug Application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the Food & Drug Administration (FDA) has been so notified.

A specimen, referred to as patient specimen in 49CFR173 , is defined as human or animal material collected directly from humans or animals and transported for research, diagnosis, investigational activities, or disease treatment or prevention. Patient specimen includes excreta, secreta, blood and its components, tissue and tissue swabs, body parts, and specimens in transport media (e.g., transwabs, culture media, and blood culture bottles).

In addition, 42CFR73 defines specimen as samples of material from humans, animals, plants, or the environment or isolates or cultures from such samples for diagnosis, verification, or proficiency testing.

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.)

Import/Export

The import and export of human specimens, also known as patient/diagnostic specimens/substances or human biological materials in the United States (US), is governed by several federal agencies working cooperatively to ensure the safe transport of these materials. These agencies include, but are not limited to, the Department of Transportation (DOT) ’s Pipeline and Hazardous Materials Safety Administration (PHMSA) , the Centers for Disease Control and Prevention (CDC) ’s Import Permit Program (IPP) , the Department of Health & Human Services (HHS) , the United States Postal Service (USPS) , and the International Air Transport Association (IATA) . The IATA has also adopted all of the hazardous materials requirements set forth in the Technical Instructions for the Safe Transport of Dangerous Goods by Air ( USA-10 ) published biannually by the United Nations (UN) ’ International Civil Aviation Organization (ICAO) .

Infectious Specimens

Per 49CFR173 , 42CFR73 , 42CFR71 , USA-21 , USA-4 , USA-11 , and USA-31 , DOT’s PHMSA, IATA, USPS, and CDC’s IPP refer to an infectious specimen/substance as a Division 6.2 material (Category A or Category B), or a select agent, etiologic agent, toxin, or a vector of human disease. The CDC’s IPP is specifically responsible for the importation of infectious specimens/substances/biological agents/vectors of human disease per 42CFR71 and for regulating the possession, use, and transfer of select agents and toxins per 42CFR73 . See 42CFR71 , 42CFR73 , USA-31 , and USA-73 for further information and permit applications for these import/transfer programs.

Additionally, the Department of Commerce (DOC) ’s Bureau of Industry and Security is responsible for regulating the export of a wide range of infectious specimens that may require a DOC license. Refer to the Commerce Control List (CCL) in 15CFR774 and USA-30 to determine if a DOC export permit is required for specific specimens.

According to 49CFR173 , USA-21 , and USA-4 , certain materials and specimens are exempt from the DOT’s PHMSA, IATA, and USPS requirements for import/export of infectious specimens. These include materials that do not contain infectious substances; non-infectious biological materials from humans, animals, or plants; and specimens for which there is a low probability that the sample is infectious. Exempt human or animal specimens are not subject to regulation as hazardous materials but are subject to specific packaging procedures that must be followed when shipped. Please refer to 49CFR173 , USA-21 , USA-4 , and USA-11 for detailed DOT, IATA, and USPS shipping instructions.

NIH Specimen Requirements

The HHS’ National Institutes of Health (NIH) researchers must also comply with all applicable federal and international air and ground transport laws and regulations. Researchers must also receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens to the NIH. Detailed instructions about how to proceed are outlined in USA-71 .

Per USA-2 , the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.

As delineated in the G-IC-IVDs , the Food & Drug Administration (FDA) only provides informed consent guidance with respect to its regulations governing the informed consent requirement when human specimens are used for FDA-regulated in vitro diagnostic device investigations.

Informed consent requirements guiding Department of Health & Human Services (HHS) -conducted or -supported research on human research participants is regulated by the Pre2018-ComRule and 45CFR46-B-E .

Per the Pre2018-ComRule and the G-SpecimensResrch , the HHS views research involving human subject specimens as research involving human participants and subject to informed consent requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. The RevComRule further defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. See the Pre2018-ComRule , RevComRule , the G-SpecimensResrch , USA-2 , USA-9 , and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, as defined by the HHS’ National Institutes of Health (NIH) in USA-72 , research with specimens, cells, cell lines, or data involves human subjects when:

• The specimens, cells, or data must be or must have been obtained from individuals who are alive, and must be or must have been obtained by an investigator conducting research; and
• The investigator either must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals, or must be obtaining or have obtained individually identifiable private information.

See USA-72 for detailed frequently asked questions (FAQs) on this topic.

Per the Pre2018-ComRule , the RevComRule , and USA-2 , prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or a legal representative(s). See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The RevComRule requires the informed consent form to provide one (1) of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

• A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility
• A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
• A statement that the subject's biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit
• Whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen)

Furthermore, the RevComRule delineates the requirements of broad consent—an alternative consent process—for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. Broad consent requires that the following information be provided to the participant and/or the legal representative(s) or guardian(s):

• Certain basic elements from the normal consent process related to risks, benefits, confidentiality, voluntary statement, commercial profit, contact information, and whole genome sequencing elements
• Types of research that may be conducted
• A description of the information or biospecimens that might be used in future research, whether sharing might occur; and the types of institutions or researchers that might conduct research
• A description of the length of time that the information or biospecimens may be stored, maintained, and used
• A statement that participants will or will not be informed of the details of any specific research studies that might be subsequently conducted
• A statement that research results either will or will not be disclosed to participants
• An explanation of whom to contact for answers to questions about the subject's rights and about storage and use of the subject's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the research could not practicably be carried out without the information in that form. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information on broad consent and informed consent waivers.

The HHS’ G-StoredData-Tissues and USA-2 recommend that the following be included in informed consent documents for biospecimen collection:

• A clear description of the operation of the biospecimen resource including details such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen
• Conditions under which samples and data will be released to recipient investigators
• Procedures for protecting the privacy of human research participants and confidentiality of data
• Specific descriptions of the nature and purpose of the research
• Information about the consequences of DNA typing if human genetic research is anticipated

(See the Required Elements and Participant Rights sections for additional information on informed consent).

Country Announcement

See the United States updates page for details on recent revisions to the profile.

COUNTRY NEWS (Information Not Yet Incorporated Into Country Profile):

New FDA Final Rule Issued for Informed Consent Exceptions for Minimal Risk Clinical Investigations The Food and Drug Administration (FDA) issued a final rule , which went into effect on January 22, 2024. The final rule allows an institutional review board (IRB) to waive or alter certain informed consent elements, or waive the informed consent requirement for certain FDA-regulated minimal risk clinical investigations.

• Whitepapers
• Ethics in Clinical Research
• Participant Recruitment

Clinical Trial Recruitment Practices: The Evolution of Ethical Considerations

Over the last few decades, the process of clinical trial conduct has evolved significantly. Clinical trial recruitment is one of these key areas. In addition to the advances in recruitment advertising through social media and other technologies, there are a number of practices that used to be considered acceptable, and even standard, which are no longer considered acceptable. In many cases, this is related to an increasing awareness and effort to avoid potential conflicts of interest for investigators, study teams, and referring physicians. At the same time, other practices, such as study sponsors providing direct staffing support for busy clinical sites, have become more popular.

This paper reviews practices related to clinical trial recruitment, with consideration of which are considered acceptable under current best practice, ethical and regulatory standards.

Practices Generally Considered Acceptable

1: payments to referral sources based on time and effort.

While the payment of “finder’s fees” to referral sources is considered unacceptable, it is usually considered appropriate to compensate a referral source for the time and effort that they spend on the referral process.

For example, if the nurse at a primary care center spends 6 hours looking at medical records to identify patients who may be eligible for the study, and calling those patients to tell them about the study and how to get more information if they are interested, it would be appropriate to compensate the nurse’s time at fair market value. It is important to remember that the compensation would be paid, regardless of whether any of the referred patients end up enrolled in the study, or even whether they screen for the study. Although this is generally considered acceptable by most oversight bodies (such as Institutional Review Boards (IRBs)), there are some ethicists who disapprove of this practice.

2: Assistance with trial-related site travel expenses

For many years, study sites have reimbursed trial participants for expenses related to study visits including such things as parking fees at the clinical site, cab fare to the clinical site, meals during long study visits, and sometimes even expenses like child care. For some studies, this may even be extended to include reimbursements for air travel and hotel stays when study participation requires long distance travel.

Generally, researchers, IRBs and sponsors agree that participation in clinical research should not incur additional expenses for the trial participant that they would not have encountered had they not been in the study. Therefore reimbursement of these expenses, or providing services to avoid the expenses (like giving meal or taxi vouchers), is both respectful and appropriate.

More recently, sponsors and sites have tried to facilitate the participation in research by providing transportation to clinical sites for study visits through third-party ride-service vendors like Uber™ or Lyft™, where the cost of the transportation can be directly billed to the site or sponsor. Although this is essentially the same concept as providing reimbursement for parking, or a taxi voucher, some IRBs and sites have been hesitant to use these services for reasons that are not clear. Although these on-demand services are novel for many people, there is no unique ethical or regulatory concern introduced that should prevent the use of these services to reduce the burden of participation.

3: Support for site study activities including recruitment

In studies with biopharma or other sponsors who provide funding, indirect costs in the contract often go toward the salary support for study staff who are tasked with multiple study-related activities, including subject recruitment/enrollment. In some cases, the study site contract may provide salary support as a direct cost, with team members assigned to the project for a certain percentage of time proportional to that support.

It is also fairly common for sponsors or CROs to provide extra temporary staffing support to a study site when activity is high; for example, to send a Clinical Research Associate to the site to help enter data into case report forms or answer data queries in advance of a data base lock deadline when the site finds itself understaffed. FDA has considered and accepted this practice of having study staff that is not in the direct employ of the investigator. 1

The appropriate participation of these supplementary team members requires that they work under the direction of the investigator, who remains responsible for all site activities related to the study, that they are trained for the tasks they are conducting, and that their responsibilities are documented as necessary in the delegation of authority log at the site.

An emerging type of support for study activities is the use of enrollment assistants at clinical sites. These are study team members who have salary support from the sponsor, but are assigned to, and work under, the direction of the site staff or investigator to support activities related to identifying potential study participants. Depending on the site needs and the study, their activities may include contacting referral sites to make them aware of the study, reviewing medical records to identify potential participants, outreach to potential participants, and pre-screening or screening activities. As with support for other study site functions, there are no regulatory or ethical prohibitions on staffing of this kind, assuming that the financial support of these staffers are time-based (not based on referrals or enrollment numbers), and that there are no other direct or indirect incentives related to enrollment which could create a conflict of interests.

Practices Generally Considered Problematic

1: site payments based on enrollment numbers.

Several years ago, it was not uncommon for sponsors to include recruitment-based incentive gifts or payments incorporated into study site contracts. These incentives could be seen in several forms:

• As a “per subject” payment for study costs which increased in amount after a certain enrollment target was reached (e.g., $2000/ subject for the first 10 subjects, $3000/subject for the next 10 subjects)
• As a bonus payment either to the site or directly to a member of the study team when an enrollment target was reached, or for the first site in a multicenter study which reached an enrollment target (e.g., first site to randomize 10 participants got a $5000 bonus to the study staff)

Sometimes there were efforts to make bonuses more acceptable by providing them as reimbursement for travel to a conference, or as equipment or educational materials for the study site or study team, (textbooks, etc).

Essentially, these kinds of bonus payments are now considered unacceptable. It is now recognized that providing direct financial incentives to the study staff for the enrollment of participants creates an unacceptable conflict of interests. Even without consciously doing so, the staff may encourage or pressure potential study participants to enroll, so that they can obtain the financial rewards. They may even be motivated — again, perhaps even without consciously doing so — to assess eligibility criteria less rigorously, or to be less critical in assessing the signs or symptoms of a potential participant that would otherwise be exclusionary or questionable, when rewards are promised.

Both sponsors and research sites, for the most part, now recognize this conflict and neither offer nor expect this kind of recruitment bonus. Recruitment plans that include these incentives are still occasionally seen, often when the study is being sponsored or managed by a less-experienced team, or when recruitment plans are developed by firms that specialize in marketing and commercial projects outside of the health sciences field, and when these teams have not thought through the conflicts these situations present.

2: Payments to referral sources based on successful enrollment of referrals (finder’s fees)

In some studies, the study site may encourage the referral of potential study subjects from other physicians or healthcare facilities. For example, a psychiatrist participating in a study for a new antidepressant might send a letter to local primary care physicians, suggesting that patients in the primary care practice who are not responding well to standard therapies may be candidates for the clinical trial, and that the primary care doctor provide information about the study to these patients.

Payments for successful referrals—referrals that result in enrollment of a study subject—are often referred to as “finder’s fees.” While there is no specific regulation that prevents the payment of finder’s fees, they are generally considered inappropriate because they create a conflict of interests. The promise of payment for successful enrollment may induce the referring physician to strongly encourage a patient to join the study even if the patient expresses doubts, or even to refer patients who aren’t really appropriate for the study but might slip through the screening process. These payments also conflict with the Code of Ethics of the American Medical Association, which prohibits referral payments to physicians, specifically stating that, “Offering or accepting payment for referring patients to research studies (finder’s fees) is also unethical.” 2

Conclusions

Study site recruitment practices have evolved over the last several years, with a broader overall view in the industry of the issues of conflict of interests and the protection of research participants from the impact of these conflicts. Most of the practices that historically raised concerns are rarely seen in the conduct of clinical trials today. Newer models of supporting recruitment efforts, such as supplementing site staff with additional staff focused on enrollment efforts, are generally considered to be ethically appropriate as long as payment is not based on recruitment efficacy, and the investigator retains oversight of all site activities.

• Guidance for Industry- Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects, Department of Health and Human Services, Food and Drug Administration, October 2009. Section III(A)(4)(a), What Are an Investigator’s Responsibilities for Oversight of Other Parties Involved in the Conduct of a Clinical Trial?
• American Medical Association Code of Medical Ethics, Opinion 6.02; Feesplitting: Referral to Health Care Facilities

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Home » Blog » CCRP Certification: ACRP vs. SOCRA

CCRP Certification: ACRP vs. SOCRA

Table of Contents

The Value of Certification & Certifying Organizations

In addition to experience and career accomplishments, CCRP certification can provide added credentials for CRAs to progress further. It is common to see job advertisements that list certification as one of the preferred quality a candidate should possess. CCRP certification shows that a CRA is willing to go the extra step to pursue professional certification.

Below, I’ll talk about the 2 main clinical research organizations (ACRP and SOCRA) that are well recognized among those in the industry and the type of certifications that they offer.

The Association of Clinical Research Professionals (ACRP)

The Association of Clinical Research Professionals (ACRP) is one of the two clinical research professional organizations that are well recognized. ACRP is the older (established in 1976) and the larger of the two organizations, with more members worldwide.

ACRP offers membership, certifications, classes, conferences, career resources, and job postings. ACRP also offers an online forum and local chapter meeting around the world for networking opportunities and learning events.

For certification, ACRP offers a certification for clinical research coordinators (CRC), which is called Certified Clinical Research Coordinator (CCRC). I had a CCRC certification when I was working at a hospital site as a CRC. ACRP also offers a certification for clinical research associates (CRA), which is called Certified Clinical Research Associate (CCRA). Below are some steps for a CRA to become a certified CCRA through ACRP:

• Become an ACRP member ($150 annual membership fee in United States, $60 annual membership fee for emerging market – electronic membership)
• Register for CRA certification exam ($460 – $600 fee, must meet one of the eligibility options below and provide detailed CV/resume and job description.
• Take and pass the CCRA examination
• Renew CCRA your certification every 2 years ($215 – $325 renewal fee)
• Report twenty-four (24) contact hours / points every two (2) years -or-
• Take the current Certification Exam

The Society of Clinical Research Associates (SOCRA)

The Society of Clinical Research Associates (SOCRA) is the newer of the two clinical research professional organizations. It was established in 1991. Similar to ACRP, SOCRA is well recognized among those in the industry. SOCRA offers membership, certifications, classes, conferences, career resources, and job posting. SOCRA does not offer an online forum, but SOCRA does have local chapter meetings around the world for networking opportunities and learning events.

As for certification, SOCRA is different than ACRP in its approach. Instead of offering separate certification for Clinical Research Coordinators (CRC) and Clinical Research Associates (CRA), SOCRA offers one certification for both. This is called the Certified Clinical Research Professional CCRP certification. I got my CCRP certification through SOCRA. Below are some steps for a CRA to become a certified CCRP through SOCRA:

• Become a SOCRA member ($75 annual membership fee)
• Register for the CCRP certification exam ($395 fee, must meet one of the eligibility options below and provide detailed CV/resume, verification of employment, and job description. Click here for more details.
• Take and pass the CCRP certification exam
• Renew your CCRP certification every 3 years (maintain membership during the 3 year period, $75 fee per year plus a $100 processing fee)
• Report 45 continuing education hours every three (3) years AND
• Take the recertification knowledge quiz (open-book quiz)

ACRP vs. SOCRA CCRP Certification

Both ACRP and SOCRA are well recognized among those in the industry. The decision to choose between ACRP and SOCRA for a CRA may come down to the consideration below:

Which organization do you want to be a member of?

• ACRP is older and has more members
• ACRP is has an online forum

Which eligibility requirements do you meet?

• SOCRA’s CCRP certification is available to anyone who has worked full time in the field of clinical research for at least 2 years as a Clinical Research Professional.
• ACRP’s CCRA certification is available to only those meeting specific CRA/monitoring job functions

How much studying are you willing to put into to passing the exam?

• SOCRA’s CCRP certification exam is easier (unofficial opinion from my own experience and from what I heard from friends and colleagues over the years).

How often do you need to renew the certification and the number of continuing education credit needed?

• ACRP requires 24 credits every 2 years (12 credits/year)
• SOCRA requires 45 credits every 3 years (15 credits/year)

How much does it cost for membership and maintaining your certification?

Below are some estimates of total cost (assuming membership is maintained during renewal period)

Why I Chose SOCRA CCRP Certification

I had ACRP’s CCRC certification when I was a CRC in 2010. I chose not to renew the CCRC certification after becoming a CRA soon after. I have been SOCRA CCRP certified since September 2013. The reason I chose SOCRA’s CCRP certification was due to the lower cost and the longer period of renewal.

For those considering SOCRA’s CCRP certification, I have a study guide that helped me pass the exam with 96% out of 100% grade ( click here to see my score). This study guide contains the notes that I compiled for my own study.

Even though materials on the notes are from publicly available sources (ICH GCP, FDA’s CFR, resources from internet, etc.), I find the vast amount of information to be overwhelming, especially with limited study time in between my daily workload.

This study guide includes summaries of information in an easy-to-read format, as well as my own knowledge and experience in clinical research. I bring both clinical research coordinator (CRC) and clinical research associate (CRA) perspectives, as I had worked in both roles in my career. Visit the homepage to learn more!

Ernie Sakchalathorn

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April 23, 2024

Related Announcements

• February 3, 2023 - Ruth L. Kirschstein National Research Service Award (NRSA) Stipends, Tuition/Fees and Other Budgetary Levels Effective for Fiscal Year 2023. See Notice NOT-OD-23-076

Agency for Healthcare Research and Quality ( AHRQ ) 

Health Resources and Services Administration ( HRSA )

This Notice supersedes  NOT-OD-23-076  and establishes stipend levels for fiscal year (FY) 2024 Kirschstein-NRSA awards for undergraduate, predoctoral, and postdoctoral trainees and fellows, as shown in the tables below which reflects the Further Consolidated Appropriations Act, 2024 ( Public Law 118-047 ), signed into law on March 23, 2024. NIH is being responsive, as much as possible given the constrained budget environment, to the Advisory Committee to the Director Working Group on Re-Envisioning NIH-Supported Postdoctoral Training report recommendations. In fact, FY 2024 stipend levels for predoctoral and postdoctoral trainees and fellows represents the largest year-over-year increase in recent history. We are committed to reaching the $70,000 recommendation over the next 3-4 years, as appropriations allow.  The Training Related Expenses and Institutional Allowances for predoctoral and postdoctoral trainees and fellows reflect a moderate increase. The Tuition and Fees for all educational levels remain unchanged from the prior budget year. See  NIH Funding Strategies for guidance on current NIH Fiscal Operations.

The budgetary categories described in this Notice apply only to Kirschstein-NRSA awards made with FY 2024 funds. All FY 2024 awards previously issued using  NOT-OD-23-076 will be revised to adjust funding to the FY 2024 levels. Appointments to institutional training grants that have already been awarded in FY 2024 must be amended to reflect the FY 2024 stipend levels once the training grant award has been adjusted by NIH. Amended appointments must be submitted through xTrain in the eRA Commons. Retroactive adjustments or supplementation of stipends or other budgetary categories with Kirschstein-NRSA funds for an award made prior to October 1, 2023, are not permitted.

Stipends Effective with all Kirschstein-NRSA awards made on or after October 1, 2023, the following annual stipend levels apply to all individuals receiving support through institutional research training grants or individual fellowships.

Undergraduates: For institutional training grants supporting undergraduate trainees (T34, TL4), appointments for undergraduate candidates will continue to be made by distinct categories (i.e., Freshmen/Sophomores and Juniors/Seniors), but the stipend levels for the categories will be the same:

Predoctoral Trainees and Fellows: For institutional training grants (T32, T35, T90, TL1) and individual fellowships (F30, F31), one stipend level is used for all predoctoral candidates, regardless of the level of experience.

Postdoctoral Trainees and Fellows: For institutional training grants (T32, T90, TL1) and individual fellowships (F32), the stipend level for the entire first year of support is determined by the number of full years of relevant postdoctoral experience when the award is issued. Relevant experience may include research experience (including industrial), teaching assistantship, internship, residency, clinical duties, or other time spent in a health-related field beyond that of the qualifying doctoral degree. Once the appropriate stipend level has been determined, the trainee or fellow must be paid at that level for the entire grant year. The stipend for each additional year of Kirschstein-NRSA support is the next level in the stipend structure and does not change mid-year.

Senior Fellows (F33 only): The stipend level must be commensurate with the base salary or remuneration that would have been paid by the institution with which the individual is permanently affiliated when the award is issued but cannot exceed the current Kirschstein-NRSA stipend limit set by the NIH for those with 7 or more years of experience. The level of Kirschstein-NRSA support will take into account concurrent salary support provided by the institution and the policy of the sponsoring institution. NIH support does not provide fringe benefits for senior fellows.

Relevant Policies Current stipend levels are to be used in the preparation of future competing and non-competing NRSA institutional training grant and individual fellowship applications. They will be administratively applied to all applications currently in the review process.

NRSA support is limited to 5 years for predoctoral trainees (6 years for dual-degree training), and 3 years for postdoctoral fellows. The NIH provides eight levels of postdoctoral stipends to accommodate individuals who complete other forms of health-related training prior to accepting a Kirschstein-NRSA supported position. (The presence of eight discrete levels of experience, however, does not constitute an endorsement of extended periods of postdoctoral research training).

It should be noted that the maximum amount that NIH will award to support the compensation package for a graduate student research assistant remains at the zero level postdoctoral stipend, as described in  the NIH Grants Policy Statement 2.3.7.9 .

Tuition and Fees, Training Related Expenses, and Institutional Allowance for Kirschstein-NRSA Recipients

The NIH will provide funds for Tuition and Fees, Training Related Expenses, and Institutional Allowance as detailed below.

A. Tuition and Fees

Undergraduate and Predoctoral Trainees and Fellows: For institutional training grants (T32, T34, T35, T90, TL1, TL4) and individual fellowships (F30, F31), an amount per predoctoral trainee or fellow equal to 60% of the actual tuition level at the applicant institution, up to $16,000 per year, will be provided. If the trainee or fellow is enrolled in a program that supports formally combined, dual-degree training (e.g., MD/PhD, DO/PhD, DDS/PhD, AuD/PhD, DVM/PhD), the amount provided per trainee or fellow will be 60% of the actual tuition level, up to $21,000 per year.

Postdoctoral Trainees and Fellows: For institutional training grants (T32, T90, TL1) and individual fellowships (F32, F33), an amount per postdoctoral trainee or fellow equal to 60% of the actual tuition level at the applicant institution, up to $4,500 per year, will be provided. If the trainee or fellow is enrolled in a program that supports postdoctoral individuals in formal degree-granting training, an amount per postdoctoral trainee or fellow equal to 60% of the actual tuition level at the applicant institution, up to $16,000 per year, will be provided.

B. Training Related Expenses on Institutional Training Grants

For institutional training grants (T32, T35, T90, TL1), these expenses (including health insurance costs) for predoctoral and postdoctoral trainees will be paid at the amounts shown below for all competing and non-competing awards made with FY 2024 funds.

• Predoctoral Trainees:  $4,750
• Postdoctoral Trainees:  $12,400

C. Institutional Allowance for Individual Fellows

This allowance for predoctoral and postdoctoral fellows will be paid at the amounts shown below for all competing and non-competing awards made with FY 2024 funds.

Institutional Allowance for individual fellows (F30, F31, F32, F33) sponsored by non-Federal Public, Private, and Non-Profit Institutions (Domestic & Foreign, including health insurance):

• Predoctoral Fellows:  $4,750
• Postdoctoral Fellows:  $12,400

Institutional Allowance for individual fellows (F30, F31, F32, F33) sponsored by Federal and For-Profit Institutions (including health insurance):

• Predoctoral Fellows:  $3,650
• Postdoctoral Fellows:  $11,300

Please direct all inquiries to:

Specific questions concerning this notice or other policies relating to training grants or fellowships should be directed to the grants management office in the appropriate  NIH Institute or Center ,  AHRQ , or  HRSA .

General inquiries concerning NRSA stipend and tuition policies should be directed to:  

NIH Division of Biomedical Research Workforce Office of Extramural Research National Institutes of Health (NIH) Website: https://researchtraining.nih.gov   Email: [email protected]   AHRQ Division of Research Education Office of Extramural Research, Education, and Priority Populations Agency for Healthcare Research and Quality (AHRQ) Email: [email protected]  

HRSA Paul Jung, M.D. Director, Division of Medicine and Dentistry Bureau of Health Workforce Health Resources and Services Administration (HRSA) Email:  [email protected]

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