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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Clinical Trial Budgets: Current Trends & Questions Answered – Part 2

In today’s challenging drug development landscape, clinical research sites often struggle with the completeness of budgets. Needs include covering costs, reinvesting in the assets needed to optimize research – such as technology – and responding promptly. In this two-part blog, Part I explored current industry trends, then delved into questions around best practices for improving the process. Part II answers questions regarding sponsor/CRO roles, fair market value, and technology use. We also address budgetary considerations for diversity, equity, and inclusion.

1. How can sponsors and CROs help sites expedite the budgeting process?

Sites may need to negotiate with a sponsor who says specific items are part of the cost of doing business . Sponsors use this approach to decrease the site’s overall budget – especially administrative and institutional fees. Yes, there is a cost to doing business, but your responsibility is to understand your hard lines and any possibilities for compromise.

Next, let’s consider the cost of archiving records for longer periods, even 25 years. Sites are shifting from a flat fee to a yearly fee for archiving. If your site currently uses flat fees, you might reevaluate that approach.

What about sponsors paying for startup time and effort if they pull out of a study? When a sponsor decides in the middle of negotiation not to move forward, ask them to partially reimburse startup costs – namely for scientific review – as you have invested time with the good intention of executing that trial.

Is there an industry standard for billing screen failures ? First, ask the sponsor to pay for the procedures performed at a screen failure visit. Alternately, reduce any ratios in the payment terms, stipulation, or prorated screen failure rates to ensure that the site is compensated. The next course of action is to apply a flat rate to screening visits.

Appropriate use criteria (AUC) relate to this year’s laws that sites must have a citation for required imaging timepoints and supporting documentation to bill certain scans to Medicare. How does AUC impact site budgets and negotiations? Sites must consult AUC before ordering advanced diagnostic imaging, leading to discrepancies in what the sponsor sees as a standard of care vs. what the site is comfortable billing. Sponsors may push back against imaging timepoints being considered research because of AUC. Explain the Medicare rule to the sponsor and emphasize that the site is at risk for billing compliance violations – not the sponsor

2. How does fair market value impact budgets?

Basically, fair market value (FMV) is the selling price agreed upon by a buyer and seller. Sponsors use FMV during negotiations to standardize the range of costs and avoid federal anti-kickback statutes, which prohibit giving certain sites discounts over others. It also applies to sites not giving discounts to certain sponsors over others in terms of covering their costs. Each institution should document its FMV policies for negotiation.

How does inflation impact FMV rates? Recently, we have seen sponsors strictly follow FMV policies during negotiations due to inflation and the need to control costs. This situation causes delays as both sides attempt to negotiate the best possible budget for their needs.

What are tactics to cover site costs , even if they aren’t aligned with the sponsor’s FMV determination? First, have a clear process for determining your costs – whether you use a percentage of Medicare rates or a research fee schedule. Note that research fee schedules are costs already reduced from retail rates, so if a research fee schedule is used, sites can’t accept less than those rates without operating at a loss to participate. To ensure these bottom-line site costs are covered, have them documented – including standard administrative fees and CPT-coded items from the research fee schedule. The more detailed and transparent the documentation is, the more likely the sponsor will cover those costs, even if they are outside the sponsor’s determined FMV costs.

3. How are growing trends such as clinical trial technology and diversity, equity, and inclusion impacting clinical trial budgets?

There is an industry trend toward using third-party vendors for budgeting and negotiation services. For example, WCG can help solidify processes for determining internal costs at your site – outlining fee documentation and justification. We offer weekly calls to discuss all projects in our queue and address any compliance questions as part of an effective strategy to launch and conduct studies more efficiently.

Real-World Perspective

Tzipora Kuba, PhD, CCRP, is manager of research finance for Hackensack Meridian Health. She shares her experience using WCG as a third-party provider for budgeting and negotiation services.

“Ours is a very busy oncology practice with multiple divisions. Working with WCG provides a fantastic relationship. We can easily submit studies, undergo Medicare coverage analysis, address budget negotiations, and then perform calendar building in our CTMS.

“WCG helps us stay on top of studies. We receive about ten new studies per week; with that volume, we could not keep up by training homegrown resources. Weekly calls help us review any delays or problems, with quick communication regarding issues to be escalated or input from investigators. We couldn’t do what we do without WCG.”

Using a  clinical trial management system (CTMS) helps with billing, invoicing, and tracking the status of all patients across every single investigator and every single study. It keeps track of status, revenue, costs, and invoice reconciliation. Without a CTMS, sites may leave money on the table in terms of invoicing sponsors. How can sites cover costs for these types of technologies? We see sites including CTMS setup and maintenance fees in their budgets as separate line items to capture the time associated with utilizing these technologies.

Next, we can consider the  feasibility process  for sites. Once there is an interest, and you have reviewed the protocol, determine whether you have competing studies. Also, do you have the patient population available? What about resources in terms of pharmacy, storage, and equipment? After thorough vetting, you can be positioned to proceed into Medicare coverage analysis and budget negotiation.

Sites ask about capturing the costs of  diversity, equity, and inclusion  (DE&I) initiatives across their clinical trials. You can request recruitment and advertising services from the sponsor to ensure diversity in patient populations. Then, overhead can capture the effort of increasing diversity and inclusion. Remember to address translation costs, often included as part of IRB fees.

Finally, let’s pinpoint  what sites miss  most often on invoicing. How can you stay on top of this process for all your clinical trials? Leveraging CTMS technology helps, but items such as dry ice fees can slip through the cracks if you order in bulk and not per study. You may miss invoicing of investigational new drug (IND) safety reports if they are not entered into the CTMS. Also, tracking the cost of re-consenting for amendments can be a challenge for study teams. Another area to watch is invoicing for imaging procedures. Often, budgets do not include imaging performed as part of a per-patient, per-visit fee, so these costs must be invoiced separately.

Today’s drug development landscape presents budgetary and negotiation challenges for clinical research sites, and WCG is pleased to help answer your questions.  Click here  if you missed Part I in this series – exploring current industry trends, then delving into best practices to help you fine-tune the budgeting process.

Do you need help handling clinical trial budgeting and negotiation?  Connect with WCG today .

Identify the problems, prioritize the solutions

Join the hundreds of sites and sponsors/CROs who, on average, reduce data entry time, by 80%, boost financial results, by 21%, increase trial study starts by 38%, and reduce start-up timelines by 37% using WCG’s end-to-end site optimization services.

MAGI 2024: The Clinical Research Conference

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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.

Guide to Choosing & Collaborating with a CRO

Last Updated on 

January 19, 2023

In the life sciences industry, the name of the game is often getting through preclinical studies and clinical trials. However, this feat is easier said than done. Many biotech, biopharma, pharma, and medical device companies need support to successfully conduct studies and trials.

Not every organization has the in-house capabilities, resources, and time to perform every trials-related task effectively and efficiently. When this is the case, businesses can rely on contract research organizations (CROs) for support with different stages of research and development.

This guide to CROs will help biotechnology, biopharmaceutical, and pharmaceutical companies select and collaborate with the right contract research organization, ensuring teams understand how CROs work, how to pick a good partner, and how to get full value out of these partnerships.

We’ll also review when it can make sense to lease lab equipment for in-house research and development alongside or in place of working with a CRO.

Need new or refurbished lab equipment? Excedr leases.

See our equipment list and browse a sample selection of what we can source. Or, if you’re ready, request an estimate.

What Is a Contract Research Organization?

A CRO is an individual or team that provides research services on a contract basis to other organizations in the life sciences, including pharmaceutical companies, biotechs, biopharmas, medical device companies, and even research institutions, government agencies, and foundations.

The services CROs provide to help develop drugs, medical devices, biologics, and other healthcare-based products include clinical trial support, laboratory testing, regulatory support, and more. Which services an organization or team offers will depend on their areas of focus and expertise, as well as the organization’s size and capabilities.

Outsourcing certain tasks and duties can allow companies to skip maintaining staff for these functions while still moving a drug or device from conception and development to FDA approval.

Contract research organizations typically work on a contract basis, providing services for specific projects or for a set period of time. This business model is designed to reduce drug development costs for companies and simplify entry into drug markets, and usually present a cost-effective alternative to in-house research and development for a wide variety of research-based labs and organizations that do not have the resources or expertise needed to perform certain research tasks on their own.

Working with a CRO can be an effective and efficient option if you’re working towards getting a product to market, but unsure if you want to take on the financial costs of building out an entire research team in addition to acquiring the necessary equipment and facilities to perform the tasks related to your clinical trials in-house.

In addition to a variety of services, CROs range in company size. This means, depending on your needs, you can find a small, specialized group or a larger, full-service organization that can handle all aspects of conducting research and clinical trials.

CROS will also carry out all of its work according to Good Clinical Practices (GCPs) that ensure high-quality studies and full compliance throughout your preclinical studies and clinical trials.

What Types of Services Do Contract Research Organizations Provide?

CROs offer a wide range of services to support the pharmaceutical, biotechnology, and medical device industries, from project, data, and site management, to clinical study management, research compliance and education, medicine and disease coding, validation, product development and commercialization, quality control, biostatistics, and much more.

Depending on the organization, the list can be quite extensive. Review the exact services each can provide. Understanding your requirements first and then assessing the scope of their services and resources needed can help you find a contract research organization that’s right for you.

Providing Laboratory Testing Services

CROs can provide specialized laboratory testing services, such as toxicology testing, microbiology testing, and pharmacokinetic studies. These services help companies assess the safety and efficacy of their products.

Supporting the Regulatory Process

Contract researchers can assist with the regulatory process and quality assurance, including preparing and submitting regulatory documents, such as registration and marketing applications, and providing guidance on compliance with regulatory requirements.

Conducting Preclinical Research

Contract researchers can also support drug discovery, product development, and conduct preclinical research on the safety and efficacy of new drugs, medical devices, and other products. This research typically involves animal testing and helps companies assess the potential risks and benefits of their products before they are tested in humans.

Conducting Clinical Trials

CROs can help design and manage clinical trials on behalf of other companies, from the initial planning stages to the analysis of the results. This may involve recruiting participants, collecting data, and monitoring the progress of the trial. When an organization offers clinical trial services and support, they might refer to themselves or be referred to as a clinical research organization.

Additional Research & Development Services

In addition to the services above, CROs can even help with other areas of research, including formulation development, process development, and analytical testing. These additional services can help laboratories improve the quality and effectiveness of their products.

What Types of Contract Research Organizations are There?

There are numerous types of CROs actively supporting the life sciences today. Their differences can range from the level of specialization—which types of studies they specialize in—the types of services they offer, company location or size, and much more.

Some organizations offer end-to-end services, providing support with preclinical studies, phase I, II, and III clinical research, and even commercialization They also tend to have expertise in a wider variety of therapeutic areas. Others tend to specialize in a certain stage of research and development, or may have expertise in a specific therapeutic area or industry.

Below are a few examples of different ways you can categorize contract research organizations.

Clinical Research Organizations

Clinical research organizations are CROs that specialize in conducting clinical trials on behalf of a client. They are usually responsible for designing the trial, recruiting participants, collecting data, and analyzing the results. In other words, they will handle clinical trial planning, data management, project management, site management, and trial monitoring.

These types of organizations can differ from other CROs who might provide services outside of clinical trials. Simply put, a contract research organization provides support to companies through a broad range of research support services, including study design, data management, and statistical analysis. These services can sometimes fall outside of clinical research and trials.

Laboratory Testing Organizations

Laboratory testing CROs provide specialized laboratory testing services, and may not provide clinical trial support. Instead, they’ll likely focus on a specific type of testing, such as toxicology or microbiology, or offer a range of services related to testing your product for a variety of reasons.

Regulatory Affairs Organizations

Some CROs specialize in regulatory affairs. This means they can provide support with a variety of the regulatory processes pharmaceutical, biotechnology, and medical device companies have to undertake and comply with. They can typically help companies prepare and submit regulatory documents, such as registration and marketing applications, and provide guidance on compliance with regulatory requirements.

Preclinical Research Organizations

Preclinical research CROs can help conduct research on the safety and efficacy of new drugs, medical devices, and other products before they are tested in humans during clinical trials. This type of research can involve animal testing and relies on a range of techniques, such as toxicity testing and pharmacokinetic studies. Some CROs that specialize in preclinical research can also help you when it comes time to conduct clinical trials, and vice versa.

How Are CROs Staffed?

Contract research organizations are staffed by a range of professionals with expertise in the pharmaceutical, biotechnology, and medical device industries. This can include clinical research professionals, laboratory technicians, regulatory affairs managers, preclinical research associates and scientists, and much more.

Clinical Research Professionals

Clinical research professionals, such as clinical research associates, clinical trial coordinators, and clinical trial managers, are responsible for planning, conducting, and managing a client’s clinical trials.

Regulatory Affairs Professionals

CROs that provide support with the regulatory process employ regulatory affairs professionals to help prepare and submit various regulatory documents. Regulatory affairs associates and managers can also provide guidance on compliance with different regulatory requirements the client will face.

Lab Professionals

Some CROS may employ laboratory professionals that are responsible for conducting tests and analyzing results. This can include laboratory technologists and technicians.

Preclinical Research Professionals

CROs that conduct preclinical research typically employ preclinical research professionals, such as preclinical research associates and preclinical research scientists. Like a clinical research coordinator or associate, these staff members are responsible for designing and conducting a client’s preclinical studies.

Additional Research & Development Professionals

In addition to various research associates, technicians, managers, and coordinators, CROs may also employ other types of R&D professionals. This can include formulation scientists, process engineers, and analytical chemists, who provide specialized research and development services for clients.

When Should You Use a Contract Research Organization?

There are several situations in which it can make sense to use a CRO to help with your business: lack of expertise or resources and cost or timeline inefficiencies are just two important reasons.

If you do not have the expertise or resources to conduct research and development in-house, CROs can provide the specialized expertise and resources needed to accelerate your research and fill in the gaps. This can be especially useful if you are a small company or if you are entering a new market or product area.

If you need to outsource research and development activities to save time and money, a contract researcher can—depending on the fees the organization charges—provide cost-effective R&D support, freeing up your team to focus on other tasks. Outsourcing can help you save time and money, and potentially help you get to market faster.

If you need support with the regulatory process, a contract research organization can provide guidance and support throughout the regulatory process, including preparing and submitting regulatory documents. With proper regulatory support, you’ll ensure you are in compliance with regulatory requirements and avoid costly delays or mistakes.

If you need to conduct clinical trials but lack the resources to do so, a CRO can design and manage the clinical trials on your behalf, from the initial planning stages to analysis of the results, making it easier to effectively and efficiently gather the data you need to support the safety and efficacy of your products.

Or, if you need to conduct preclinical research, a contract service provider can help conduct preclinical research on your products to assess their safety and efficacy before you go to clinical trials. Working with a CRO during your preclinical studies can help you more effectively identify any potential risks or benefits before moving on to test in humans, potentially saving you time and money in the long run.

How Do You Choose a CRO to Work With?

When it comes time to choose a CRO to partner with, there will be several factors you’ll want to consider, including their level of organizational expertise and experience, the quality and compliance of their work, the cost and value for money, the organization’s ability to communicate and collaborate, and its timeliness and flexibility.

You will also need to find a contract research organization that has a proven track record supporting R&D in your specific therapeutic area or industry. Working with a contractor that doesn’t have experience doing so may inevitably lead to failure in preclinical or clinical research.

Expertise & Experience

The CRO should have extensive expertise and experience in the specific area you are looking for support in, whether it’s conducting clinical trials or running laboratory tests. It can be helpful to look at each organization’s track record or the types of clients they have worked with in the past to assess their level of expertise.

Quality & Compliance

The organization should demonstrate a strong commitment to quality and compliance, and should be able to provide evidence of their compliance with relevant regulations and standards. Like assessing their track record or client list, you can review a CRO’s quality management system and any certifications they have, such as ISO 9001 certification, to determine their levels of quality and compliance.

Cost & Value for Money

A contract researcher’s fees should be competitive and provide real value for money. In other words, the fees you pay should align with what you receive in return. To assess whether or not the organization’s worth their prices, you can sometimes ask for cost estimates for the services you are interested in and compare them to other CROs.

Communication & Collaboration

The CRO should be able to communicate effectively and collaborate with your team throughout the project. Poor communication and collaborative efforts can result in poor results and failed trials, so it’s important to establish whether or not the CRO is a strong communicator. If possible, you can ask for references from other clients and to speak with the CRO’s team directly to assess their communication and collaboration skills.

Timeliness & Flexibility

An organization should also be able to deliver the services you need in a timely manner and should be flexible enough to adapt to any changing needs or requirements. Ask about the CRO’s availability and their approach to managing project timelines to get a better idea of whether or not they can meet deadlines and remain flexible in the face of changes.

Facility Locations

A CROs location can also be an important consideration when selecting a partner. If the drug or device you are developing together is expected to be approved in a variety of nations or locations, it will be beneficial—perhaps even necessary—to hire a CRO that has experience with the approval process in each location.

They may have facilities and staff positioned in the target location and will have knowledge about local regulations for clinical studies and approval.

Furthermore, because you’re outsourcing the work, you can easily lose oversight of the project. When a CRO’s team is conducting day-to-day tasks in another location, supervision can be more difficult, or even impossible.  Comparing global CROs and local CROs and assessing how much supervision will be needed can help you understand whether or not location will be important in your selection.

Advantages & Disadvantages of Working with a CRO

Similar to working with a contract manufacturing organization (CMO), there are several advantages and disadvantages to working with a contract research organization.

The decision to use a CRO should be carefully considered, taking into account the potential drawbacks as well as the potential benefits.

• CROs have expertise and resources that may not be available in-house, such as specialized laboratory equipment or regulatory affairs experts. This can help you access the knowledge and capabilities you need to conduct research and development effectively.
• They can provide cost-effective support for research and development tasks, saving you time and money compared to conducting these activities in-house.
• They provide services on a contract basis, which can be more flexible than hiring permanent staff. This is especially useful if you have a specific project or a short-term need for research and development support.
• They typically have a strong commitment to quality and compliance, and are typically subject to strict regulatory requirements. This can help you ensure that your research and development activities are conducted according to the highest standards.
• They can often help you get to market faster by providing timely support for research and development activities, helping you stay ahead of the competition and capitalize on new opportunities.
• Using a CRO can sometimes be more expensive than conducting research in-house, as CROs typically charge a fee for their services.
• You may have less control over the research process, as the CRO will be responsible for conducting the study and collecting the data.
• If communication is poor, it can lead to misunderstandings and delays. Effective communication and collaboration between your company and the CRO is essential for the success of the research project.
• The quality of the research conducted by a CRO may vary depending on the experience and expertise of the individual CRO. It is important for the sponsoring company to carefully evaluate the CRO’s qualifications and track record before engaging them.

Lease with Excedr to Support In-House Research

Biotechnology, biopharmaceutical, and pharmaceutical companies often need support when it comes to preclinical, clinical trials, and other areas of research and development. There are a wide range of tasks, and not every company has systems and staff in place for every task or step.

However, rather than conduct the research in-house—spending the money to build out a team and acquire the necessary facilities and equipment and securing all the necessary compliance certifications—laboratories can outsource the research to contract research organizations.

CROs come in quite handy when startups, small- and medium-sized businesses, and even large enterprises need to increase R&D efficiencies and decrease the time and cost to approval and market. Using a CRO, on the other hand, can be a good option if you don’t have the expertise or resources to conduct the research yourself, or if you need access to specialized equipment or facilities.

CROs typically have extensive experience and expertise in conducting research studies, and can provide a range of services, including study design, data management, and statistical analysis.

However, using a CRO can be more expensive than conducting the research in-house, and you may have less control over the research process. If you do conduct research in-house, you will undoubtedly need to keep a variety of high-quality research equipment on-hand to gather and manage your data.

Not having the proper lab equipment, as you well know, can greatly affect the results of your work, making it necessary to keep up with technology and equip your lab with the right instrumentation.

Leasing lab equipment with Excedr can be a cost-effective option for life sciences and biotech companies when you want to reduce the upfront costs on the equipment, protect it with comprehensive service coverage, and remain flexible when a new and better technology inevitably becomes available.

Rather than sink your money into a fixed asset and take a huge chunk out of your R&D budget, leverage our leasing program instead. Doing so is an excellent choice when or if you need a specific piece of equipment that you don’t have in-house, or if you need to expand your existing laboratory facilities.

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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 ​

When FMVs Collide: Coming to Terms with Fair Market Value

With variation in costs between different stakeholders in clinical trials, there is often disagreement on fair market value.

Top 3 Most Read CRO/Sponsor Feature Articles of 2023

Authors highlighted outsourcing and the impact of the COVID-19 pandemic in these CRO/sponsor articles from 2023.

Anticipating Near-Term Structural Change in the Outsourcing Landscape

Can full-service outsourcing to CROs by large biopharma companies sustainably prosecute a clinical development portfolio?

Harmonizing Outsourcing to Keep Clinical Trials on Track

A shared partnership culture is critical in navigating today’s complex terrain.

The Evolution of CRO and Sponsor Relationships

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Trust-based relationships form the foundation for successful trial management.

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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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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/

A Comprehensive Guide to Clinical Research Organizations (CROs)

Clinical Research Organizations (CROs) play a crucial role in the pharmaceutical, biotechnology, and medical device industries. They provide support to companies in the form of research services outsourced on a contract basis. In this comprehensive guide, we will explore what CROs are, who their clients are, the stages of the research process they are typically involved in, and delve into the exciting career opportunities within the field of clinical research.

Table of Contents

Introduction to Clinical Research Organizations (CROs)  The Role of CROs in the Research Process  Services Offered by CROs  Clients and Partners of CROs  Careers in Clinical Research  Clinical Research Associate (CRA) Roles and Responsibilities  Educational and Professional Requirements for Clinical Research  Careers Advancement Opportunities in Clinical Research  Tips for Success in Clinical Research  Careers Resources and Professional Organizations  Conclusion

Introduction to Clinical Research Organizations (CROs)

Clinical Research Organizations (CROs) are companies that provide support to the pharmaceutical, biotechnology, and medical device industries in the form of research services outsourced on a contract basis. They offer a wide range of services , including biopharmaceutical development, clinical development, clinical trials management, and pharmacovigilance. CROs aim to simplify the entry into drug markets and streamline the drug development process by providing specialized expertise and resources.

The Role of CROs in the Research Process

CROs play a crucial role in the research process, from the early stages of drug discovery and development to the final stages of clinical trials and commercialization. They work closely with their clients to design and execute clinical trials, ensuring adherence to regulatory requirements and ethical standards. CROs also provide support in data management, statistical analysis, and the preparation of regulatory submissions.

Services Offered by CROs

CROs offer a wide range of services to their clients, including but not limited to: 

Biopharmaceutical development : CROs assist in the development of new drugs, from preclinical studies to early-phase clinical trials. Clinical development: CROs design and manage clinical trials, ensuring compliance with regulatory requirements and ethical standards. 

Clinical trials management: CROs oversee all aspects of clinical trials, including site selection, patient recruitment, data collection, and safety monitoring. 

Pharmacovigilance : CROs monitor the safety of drugs and medical devices during clinical trials and after they are on the market. 

Real-world evidence and outcomes research : CROs collect and analyze data from real-world sources, such as electronic health records, to generate evidence on the safety and effectiveness of drugs and medical devices. CROs conduct studies to evaluate the effectiveness and safety of drugs and medical devices in real-world settings. 

Clients and Partners of CROs

CROs work with a diverse range of clients, including pharmaceutical  companies,  biotechnology firms, medical device manufacturers, research institutions, and government organizations . They collaborate closely with their clients to ensure that research studies are conducted efficiently, safely, and in compliance with regulatory requirements. CROs also partner with academic institutions and foundations to support their research initiatives.

Careers in Clinical Research

Clinical research offers exciting career opportunities for individuals interested in the scientific, regulatory, and operational aspects of drug development. 

Careers in clinical research span a wide range of roles, including Clinical Research Associate (CRA), Clinical Project Manager, Data Manager, Biostatistician, and Medical Writer, among others. These roles require a combination of scientific knowledge, attention to detail, critical thinking, and strong communication skills.

Clinical Research Associate (CRA) Roles and Responsibilities

Clinical Research Associates (CRAs) play a crucial role in the execution and monitoring of clinical trials. Their responsibilities include site selection and initiation, monitoring study progress, ensuring compliance with protocols and regulatory requirements, and maintaining accurate and complete documentation. CRAs work closely with investigators, study coordinators, and other stakeholders to ensure that trials are conducted safely and efficiently.

Educational and Professional Requirements for Clinical Research Careers

Careers in clinical research typically require a strong educational background in life sciences or a related field. Many positions, such as CRAs, require a bachelor's or master's degree in a scientific discipline. Professional certifications, such as the Certified Clinical Research Associate (CCRA) certification, can enhance career prospects and demonstrate expertise in the field.

Advancement Opportunities in Clinical Research

Clinical research offers ample opportunities for career advancement and professional growth. Experienced professionals can progress to more senior roles, such as Clinical Project Manager or Clinical Operations Director, where they oversee the planning and execution of multiple clinical trials. Continuing education, networking, and staying updated with industry trends are essential for career advancement in clinical research.

Tips for success in seeking a Career in Clinical Research

To succeed in clinical research careers, professionals should continuously develop their scientific knowledge, stay updated with regulatory requirements, and enhance their communication and project management skills. Networking, building relationships with key stakeholders, and seeking mentorship can also contribute to career advancement in the field.

Resources and Professional Organizations for Clinical Research Professionals

Several resources and professional organizations cater to the needs of clinical research professionals. These include industry publications, online forums, conferences, and professional associations. Organizations such as the Association of Clinical Research Professionals (ACRP) and the Society of Clinical Research Associates (SoCRA) provide educational resources, networking opportunities, and professional certifications for clinical research professionals.

Clinical Research Organizations (CROs) play a vital role in the pharmaceutical, biotechnology, and medical device industries by providing research services on a contract basis. They offer a wide range of services to support the development and execution of clinical trials, ensuring compliance with regulatory requirements and ethical standards. 

Careers in clinical research offer exciting opportunities for individuals interested in the scientific, regulatory, and operational aspects of drug development. By partnering with CROs and pursuing careers in clinical research, professionals can contribute to the advancement of medical science and the development of innovative therapies.

If you're interested in exploring careers opportunities in clinical research, view our current vacancies at ICON today.

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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.

COVID-19 Guidance :

As of May 12, 2023, the federal Public Health Emergency (PHR) for COVID-19, declared under Section 319 of the Public Health Service Act, has expired. See the  Fact Sheet: COVID-19 Public Health Emergency Transition Roadmap  released by the Department of Health & Human Services (HHS) for more details. The ClinRegs team will monitor any changes made to the COVID-19 guidance documents listed below and will update them accordingly.

Office for Human Research Protections:

• Exception to the Single IRB Review Requirements for Certain HHS-Conducted or -Supported Cooperative Research Activities Subject to the 2018 Requirements During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency  (October 8, 2020)  – as of the conclusion of the public health emergency on May 11, 2023, use of this exception will continue to apply to studies where the exception was initially granted during the emergency, but cannot be applied to additional studies. For more details, see this OHRP announcement .
• OHRP Guidance on Coronavirus  (April 8, 2020) – presents how HHS human subjects protection regulations (45 CFR part 46) apply to institutional and investigator actions responding to COVID-19. The guidance covers: Public Health and Clinical Activities; Excluded Public Health Surveillance Activities; Legally Required Reporting; Research Changes to Eliminate Apparent Immediate Hazards; Proposing and Reviewing Study Changes; and Whether Suspensions of Research Must be Reported.

National Institutes of Health:

Effective May 12, 2023, NIH will no longer issue Emergency Notices of Funding Opportunities related to COVID-19. Ongoing emergency awards will not be impacted and will retain all existing emergency flexibilities for the remained of the current competition segment. See NIH notice NOT-OD-23-095 for more details.

• Exceptions to Use of a Single IRB During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency  (Rescinded on May 11, 2023) - as of the conclusion of the public health emergency on May 11, 2023, the COVID-19 Single IRB exception has expired and cannot be applied to additional studies. All exceptions granted by NIH prior to May 11, 2023, will be effective for the duration of the research or the time they were granted, as indicated in the determination letters. See NIH notice  NOT-OD-23-097 for more details.

What Is the Cost of a Clinical Trial?

Patricio ledesma, clinical trial costs, 8 march, 2021.

Check the Clinical Trial Cost Calculator here and calculate your trial budget in seconds!

Please contact us and we will send you a ballpark clinical trial quotation within 48 hours.

Click here if you want to download a full clinical trial quote in PDF

Biotechnology and pharmaceutical companies need to know the cost of a clinical trial to plan the funding of their drug development programs.

In particular, U.S. biotech companies seeking to have their drug candidates approved by the Food and Drug Administration (FDA) need to be aware of the cost of conducting clinical trials in American clinical sites.

However, despite the critical importance of knowing the clinical trial bill, biotech companies in the early stages of drug development may have a difficult time to have a clear picture of all the costs involved in a clinical study.

Clinical Research Organizations (CROs) are companies specialized in managing clinical trials from beginning to end, and they can provide detailed clinical trial quotations to biotech firms, including all the expenses involved in a phase I, II or III study.

Therefore, biotech managers can get support from CROs to calculate how much their clinical trials will cost, including both CRO services and pass-through (third party) fees.

This article seeks to help biotech chief executive, operations, and financial officers in understanding the actual costs involved in the execution of a clinical trial.

If you want to receive a quick clinical trial quotation now via email, please contact us here .

What is a Clinical Research Organization (CRO)?

If you need a clinical trial quote, a Clinical Research Organization (CRO) is the type of company that can help you.

A CRO is a company dedicated to managing clinical trials taking care of all or several tasks involved in a clinical study, including regulatory affairs, site selection, onsite monitoring, data management, biostatistics, and medical writing, among others.

Since CROs have a global view of all the stages and elements of a clinical study, they are able to provide detailed budgets of all clinical trial expenses.

What is the cost of a clinical trial?

The costs of phase 1, 2, and 3 clinical trials conducted in the United States are in the range of US$1.4-6.6, 7.0-19.6, and 11.5-52.9 million respectively.

These numbers were calculated by Aylin Sertkaya et al. in their excellent article about key cost drivers of pharmaceutical clinical trials in the United States [1].

In any case, estimating the actual price of a clinical study is not easy given the various factors involved.

Let’s analyze these factors.

What are the main cost drivers in a clinical trial? 

The total cost of a clinical trial depends on many variables, but the main cost factors are: 

(1) the number of participants, and 

(2) the complexity of the clinical trial protocol.

Firstly, the number of participants in a clinical trial is highly related with the study phase.

For instance, phase 1 clinical trials — which are focused on evaluating drug safety — recruit an average of 20-80 patients.

Phase 2 trials — which analyze safety, dosing, and preliminary efficacy — normally include between 100 and 300 participants.

Later stage phase 3 clinical trials are larger studies assessing safety and efficacy and can enroll several patients depending on the therapeutic area (between 300-3,000 participants), as shown in Figure 1 below.

Figure 1: Clinical Trial Phases [2]

The number of participants in a clinical trial is a key overall cost driver because each recruited patient implies a fee to be paid by the Sponsor to the hospital, in order to cover medical tests and procedures.

Secondly, the complexity of the clinical trial protocol also has a direct impact on the trial cost.

For example, a long and complex cancer treatment —that may include several intravenous drug administration cycles up to disease progression— will involve several patient visits to the clinical sites, with the corresponding clinical tests (e.g. CT scans, ECG), which will significantly increase the expenses of the study.

On the other hand, a simple and short clinical study with few visits using an oral drug may include less per-protocol visits and tests, which will lower the site’s bill. 

Therefore, the clinical complexity and duration of a trial play a decisive role in the price of a clinical study.

In addition, there are other clinical trial cost factors like the technological tools and applications to be used, the number of external vendors needed (e.g. central laboratories and drug depots), and the countries in which the research is carried out.

Is conducting a clinical trial in the United States more expensive than doing it in other parts of the world?

In general yes. Conducting a clinical trial in the United States of America involves higher costs compared to running a study in other countries (e.g. Europe or Asia).

How much do phase 1 clinical trials cost?

The average cost of a phase 1 study conducted at a United States clinical site ranges from US$1.4 million to US$6.6 million, including estimated site overhead and monitoring costs [1].

How much do phase 2 clinical trials cost?

A phase 2 study in the U.S. costs from US$7.0 million (cardiovascular) to US$19.6 million (hematology) [1].

How much do phase 3 clinical trials cost?

Phase 3 clinical trials in the United States (many of them considered “pivotal”) range from US$11.5 million up to US$52.9 million [1].

Figure 2: Clinical Trial Cost by Phase and Therapeutic Area [1]

In another study performed by Thomas J. Moore et al [3], the estimated cost of pivotal clinical trials supporting the FDA approval of 101 approved drugs was a median of US$48 million (IQR US$20 million–US$102 million). 

Each individual pivotal trial cost a median of US$19 million (IQR US$12 million–US$33 million).

The estimated cost per patient was US$41,413 (IQR US$29,894–US$75,047), and each patient visit to the study clinic cost an estimated median of US$3,685 (IQR US$2,640–US$5,498).

How are clinical trial quotations normally structured by CROs? 

CROs structure their quotations in different ways, but normally they divide their budgets in two main categories: (1) CRO services, and (2) pass-through costs.

The CRO service category typically includes concepts such as:

• Regulatory affairs
• Site identification and selection
• Site contracting and payments
• Site initiation and activation
• Site management
• Onsite monitoring
• Drug safety management
• Drug logistics
• Biological sample logistics
• Clinical supplies logistics
• Medical writing
• Site close-out
• Project management
• Study files / document management
• Data management
• Statistical programming
• Quality control

The pass-through costs category normally includes the following items:

• Shipping costs
• Clinical supplies and packages
• Office supplies
• Fee per patient to be paid to the clinical site
• Publication fees
• Ethics / Regulatory agency evaluation fees
• Site contract fees
• Travel costs
• Drug distribution services
• Central laboratory services
• EDC system for data collection
• IRT system for drug management
• Radiological imaging platforms
• Electronic Trial Master File (eTMF)
• Drug safety platform

What are the more costly line items in a CRO clinical trial quote?

The more costly items in a clinical trial quote are site management and project management costs (CRO direct services). In addition, the most significant pass-through expense is the fee to be paid to the clinical sites for each recruited patient (i.e. costs of clinical procedures and tests).

How much do hospitals charge for each patient treated in a clinical trial?

The amount of money to be paid by the Sponsor to the clinical sites in which the patients are treated —to cover medical procedures and tests— varies across study types, but in the U.S. this can go from US$20,000 up to US$70,000 per patient. 

How much does an electronic data capture (EDC) system cost?

In a clinical trial, an EDC system is a tool used by clinical sites to enter clinical data.

The cost of an EDC software —license and hosting price— is in the range of US$1,000 and US$5,000 per month of usage, depending on the type of solution.

This price does not include the initial services required to design, document, implement, test, and validate the EDC tool.

Please read the following article to learn more about EDC software costs: How Much Does an Electronic Case Report Form (eCRF) Cost?

How much does it cost to manufacture a drug for a clinical trial?

The answer to this question depends on many factors, but usually the manufacturing of a drug product batch for a clinical trial may be in the average range of US$300,000 to 1 million.

This does not include the cost of producing the drug substance or active pharmaceutical ingredient (API).

Please read the following article to learn more about drug manufacturing costs in the context of clinical trials: How Much Does it Cost to Manufacture a Drug for a Clinical Trial?

How much does it cost to pack, label, store, and distribute a drug in a clinical trial?

The cost of packaging, labeling, storing, and distributing a drug in a clinical trial may be in the range of US$40,000 to 100,000 per study.

The cost of managing drugs in a clinical trial depends on the quantity of drug required, the number of hospitals, the temperature conditions, the number of shipments from source to depot, and the number of shipments from depot to sites.

Please read the following article to obtain more information about drug packaging, labeling, storage, and distribution costs in the context of clinical trials: What is the Cost of Packaging, Labeling, Storing, and Distributing Drugs in a Clinical Trial?

A CRO can help you come up with a more precise calculation for your specific clinical trial.

Click here if you want to download a full clinical trial quote in PDF  

References:

[1] Key cost drivers of pharmaceutical clinical trials in the United States. Aylin Sertkaya, Hui-Hsing Wong, Amber Jessup, and Trinidad Beleche.

[2] Image by ILD Collaborative.

[3] Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015–2017: a cross-sectional study.

Patricio Ledesma ( B.Eng Concordia University, Montreal, Canada and Master’s Degree in Clinical Trials, University of Seville, Spain) is the Head of Clinical Operations and Founder at Sofpromed CRO. Patricio is a professional consultant providing comprehensive, one-stop expert advice and guidance to biotechnology and pharmaceutical companies worldwide in the field of clinical trials and drug development. He is personally and enthusiastically devoted to helping biotech Chief Executive, Operations, Scientific, Medical, and Regulatory Officers in the planning and execution of phase I-IV clinical trials across North America, Europe, Asia-Pacific, Latin America, and Middle East regions. You can contact Patricio at: +34 607 939 266   [email protected]  

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Patricio Ledesma ( B.Eng Concordia University, Montreal, Canada and Master’s Degree in Clinical Trials, University of Seville, Spain) is the Head of Clinical Operations and Founder at Sofpromed CRO. Patricio is a professional consultant providing comprehensive, one-stop expert advice and guidance to biotechnology and pharmaceutical companies worldwide in the field of clinical trials and drug development. He is personally and enthusiastically devoted to helping biotech Chief Executive, Operations, Scientific, Medical, and Regulatory Officers in the planning and execution of phase I-IV clinical trials across North America, Europe, Asia-Pacific, Latin America, and Middle East regions. You can contact Patricio at: +34 607 939 266  [email protected]  

Clinical Research FAQs

See below for our most frequently asked questions.  If the information below doesn't answer your questions, please email us at [email protected]. 

There are a lot of paths to become a CRA.  Depending on where you are in your career, you may wish to begin networking with individuals in your area who are already working as a monitor.  You could also become a SOCRA member and take advantage of the online membership directory to email other research professionals in your area.   You can apply for membership here .  Individuals already working in the field can give you the best advice regarding local training and employment opportunities.  

You could also consider attending our Monitoring + GCP Workshop.  It is taught by two subject-matter experts that have a lot of valuable information and are available to speak with and advise attendees.  Find more information about this course here . 

There is also a monitoring track at our upcoming annual conference in September being held virtually.  Find more information about the Annual Conference here .  You can find the agenda here . 

We also offer a SOCRA CCRP Certification for Clinical Research Professionals.  It is not specifically a CRA certification, but encompasses all the industry regulations and guidelines that CRPs operate under.  For more information, click here . 

SOCRA members work in all fields of research. Across fields, a common bond exists among those who are involved in clinical research. With changes occurring daily in the health-care field, we must all stay abreast of the latest developments and practices which affect us and our work.  SOCRA membership provides opportunities for education, networking, and career growth. Membership is available to all clinical research professionals who work with cooperative research groups, academic, government, and private institutions, pharmaceutical and biotechnology companies, device manufacturers, CROs, SMOs, independent research and development organizations, and those who are involved in the management of clinical trials.

You can apply for SOCRA membership using the link here.

Membership fees ($75 USD/year) are processed immediately and are not refundable or transferable. The membership packet / receipt is mailed at the beginning of the following month in which payment is received.

Belonging to SOCRA, a professional organization with more than 15,000 members, provides you with the information and resources you need to advance your career and enhance your professionalism.  Membership benefits include access to the following:

High Quality Professional Education (now available live in-person and virtually) 

Global Network of over 15,000 clinical research professionals

Local Education through SOCRA Chapter Network

Leadership Opportunities

Member Discounts

SOCRA Source Quarterly Journal 

For details on the top reasons to belong, follow the link here.

SOCRA is a membership organization and relies on its membership involvement and support to help the society grow. Members are encouraged to become actively involved as speakers for our educational courses, poster presenters at the Annual Conference Poster Program, authors in the SOCRA Source Journal, or volunteer board members.  There are numerous other activities including SOCRA's local Chapter Network.  By working together, we can ensure that SOCRA meets the needs of the industry. For more information, visit our website here or contact our office at [email protected] .

SOCRA conducts a salary survey every 5 years. Our last survey was conducted in 2020, and those results are available at no cost here .  We will begin preparing our 2025 survey next year.

You also can refer to  www.salary.com , where you can select a position and location and receive the latest results of their studies.

There are some helpful links below that can give you information about the SOCRA certification program and exam.  Please review and contact our office if you have any questions. You reach our Certification department by email at [email protected] or by calling our office at 215-822-8644.

SOCRA Certified Clinical Research Professional (CCRP)  

Eligibility

Exam Schedule

Computer Based Testing

Application

Preparing for the exam

You can apply early (up to 3 months) and will be pre-approved pending confirmation by your employer that you are still employed as a clinical research professional at the time of the exam. Please contact our Certification department if you have any questions by emailing [email protected] or by calling our office at 215-822-8644.  For more information on the CCRP exam application, visit the link on our website here.

SOCRA hosts over 90 paper and pencil exams each year across the U.S. and Canada.  You can find the exam schedule for SOCRA sponsored sites using the link below:

https://www.socra.org/certification/ccrp-certification-exam/exam-schedule/

We are always adding exam dates and locations to our SOCRA hosted schedule so feel free to check back periodically.

Please note that computer based testing/retesting is now available at area test centers. There is no need to wait a lengthy period or travel to a sponsored site on the exam schedule.  If needed, you can take a look at your local centers using the linke below:

https://candidate.psiexams.com/testdate/testdate.jsp

Under Select Organization, select Certification/Professional Orgs.  Under Select Sponsor, scroll down and select Society of Clinical Research Associates.  Under Select License, select CCRP then hit Continue at the bottom of the page.

For more information on Computer Based testing visit the link below: https://www.socra.org/certification/ccrp-certification-exam/computer-based-testing/

To prepare for the exam, a candidate should study the detailed exam outline (link below) and consider the knowledge, skills, and abilities needed to perform the duties of a clinical research professional (CRP). Satisfactory completion of the CCRP® certification examination indicates that the candidate has met all the eligibility criteria and has demonstrated knowledge of the key duties/tasks of a CRP.

Candidates can find the exam outline using the link below:

https://www.socra.org/certification/ccrp-certification-exam/exam-outline/

For an overview of preparing for the exam, visit the link below:

https://www.socra.org/certification/ccrp-certification-exam/preparing-for-the-exam /

We do not have a practice test, but the link above provides sample questions.

Additional resources can be found using the link below: https://www.socra.org/certification/ccrp-certification-exam/preparation-resources/

Please remember that the examination assesses your knowledge and understanding of the United States Code of Federal Regulations and the International Conference of Harmonisation E6 & E2A Guidelines. It does not assess state, local, provincial, Ministry of Health, or institutional policy.  Additionally, you will not be asked regulation numbers. However, you should be very familiar with the content of the regulation, especially regarding timelines for compliance.  You should know who needs to be reported to and when given a particular circumstance . And you should be clear what FDA requires, especially if your company SOPs differ – even if they are more stringent.  You should always answer based on what FDA requires.

SOCRA chapters are designed to help SOCRA members obtain CE towards Recertification at no cost.  For that reason we do ask that the chapter chair person be CCRP certified so that they can help answer questions from members or perspective members about SOCRA and the exam process.  There are no dues or fees and no money should exchange hands so there is minimal paperwork as we try to keep the process as simple as possible.

As chapter chair, your main responsibilities are getting a speaker, a room and giving us the announcement to review and distribute to the geographic area you specify.

If you’d like to move forward with starting a Chapter please email [email protected] . and request a copy of our SOCRA Chapter Policy and Toolkit.  For more information on chapters or to find a chapter near you, visit the link below:

https://www.socra.org/chapters/about-chapters/

 You can offer SOCRA CE’s for your upcoming educational program, event, or conference. SOCRA doesn't "approve" other education, however, we try to keep it as simple as possible.  As long as the education you offer pertains to research regulations, operations and management, and is also specific to the therapeutic area of research in which the candidate participates, it can be used for SOCRA recertification.

In order for SOCRA to accept CE’s for this program, attendees would need a certificate of attendance.  On the certificate, you would need to add the following: "The Society of Clinical Research Associates (SOCRA - www.socra.org) accepts documentation of candidate participation in continuing education programs for recertification if the program is applicable to clinical research regulations, operations or management, or to the candidate’s clinical research therapeutic area. This program offers __ hours of CE credit."

Contact us at [email protected] with any questions. 

Below is a list of various ways you can acquire CE as a SOCRA Member.

SOCRA Source Self Studies: To receive CE you can complete the SOCRA Source Self Studies included in each issue of the SOCRA Source which is  currently being published electronically in February, May, August, and November. We send out an email notification when the Source is available electronically and you can also find the current issue along with past issues in the SOCRA Educational Portal  -

You may earn 1 CE each in the Regulatory category for a maximum of 12 credits. (free of charge – Source issues are complimentary with SOCRA membership)

Annual Conference Opening Plenary Sessions:  We record Opening Plenary Sessions at SOCRA’s Annual Conference each year. These sessions can be found on the SOCRA YouTube Channel – https://www.youtube.com/c/socra . If you do choose to review these sessions for CE, a summary of studied material (minimum 250 words) is to be submitted. Recordings must be one hour in length for each hour claimed. (free of charge)

Collaborative Institutional Training Initiative (CITI) Program: CITI is a collaboration between the University of Miami and the Fred Hutchinson Cancer Research Center to develop a web based training program in human research subject protections. SOCRA has joined CITI to offer SOCRA members free entry-level basic courses in the areas listed below. (free of charge for SOCRA members)

Human Subjects Research – up to 9 CE

Good Clinical Practice (GCP) – up to 13 CE

Health Information Privacy and Security (HIPS) – up to 3  CE

Responsible Conduct of Research (RCR) – up to 4 CE  

How to enroll in a CITI Program: https://www.socra.org/membership/member-benefits/citi-program/ .

CITI - SOCRA Quick Reference CE Chart: https://www.socra.org/assets/Certification/CITI-COURSES-for-SOCRA-CE.pdf

SOCRA Online Courses: For 1 CE (Free of charge to SOCRA members), SOCRA offers online courses covering various topics relevant to Clinical Research Professionals including: Part I - Informed Consent for Research: Operationalizing the Process, Part II - Informed Consent for Research: The Importance of Quality for Understanding, A Primer on Clinical Research, Sponsor Responsibilities, Institutional Review Boards (IRB), Regulatory Updates for Clinical Research Professionals – RECERTIFICATION, Bedside Nursing "Want to Write a Research Protocol?", Bedside Nursing "From Clinical Inquiry to Conducting Nursing Research"

See a list of online course offerings: https://www.socra.org/conferences-and-education/clinical-research-courses-online/

SOCRA Live Conferences: SOCRA offers a robust portfolio of live in-person and virtual conferences, workshops, and courses to keep you at the forefront of the industry and support your continuing educational goals. (cost for each course varies)

See all live in-person course offerings: https://www.socra.org/conferences-and-education/training-conferences-workshops-courses/

See all live in-person course offerings: https://www.socra.org/conferences-and-education/live-webinars/

See the events calendar for upcoming courses: https://www.socra.org/conferences-and-education/events-calendar/

FDA Training: Visit the FDA links below to complete the trainings they have available. (free of charge)

FDA Continuing Education Courses: https://www.fda.gov/Training/ForHealthProfessionals/ucm545645.htm FDA Overview of Biosimilar Products – 1.5 CE Drug Efficacy, Safety, Quality, and Beyond – 1.5 CE Leveraging Health Literacy and Patient Preferences to Reduce Hypoglycemic Events in Patients with Type 2 Diabetes – 1 CE Device FDA Continuing Education Courses: https://www.fda.gov/Training/CDRHLearn/default.htm National Drug Abuse Treatment Clinical Trials Network (NIAID) Learning Center: NIAID offers GCP training. This training is separated into 4 parts and offers 4 CE. (free of charge) NIAID GCP Course: https://gcp.nidatraining.org/

Many IRBs have webinars on their websites as well. (For example, Quorum and Forte): If you do choose to review these sessions for CE, a summary of studied material (minimum 250 words) is to be submitted. (free of charge)

**For any course, training or webinar that does not provide a certificate upon completion, a summary of studied material is to be submitted (minimum 250 words) in lieu of the certificate.

We have a simple online process for requesting receipts. Please visit the link below to complete the form to request a receipt:

https://www.socra.org/contact-socra/payment-info-request-form/

If you have any other issues with the receipt, you can contact our Accounting Department at [email protected] or by calling our office at 215-822-8644.

The certification period is three years, beginning on the date of most recent certification and ending on the certification expiration date.   All CE must be accrued during this time period. Certificants must have completed 45 hours (45 credits) of CE during their certification period. A minimum of 22 CE must be related to Clinical Research regulations, policy, etc. The remaining CE may relate to your Therapeutic or Professional Area. 1 CE will be awarded for the successful completion of the recertification continuing competence learning module. Only educational hours may be claimed for CE; you may not claim CE credit for your work hours. In order to maintain active certification status, the CCRP® must apply for renewal of certification to the Certification Committee every three years.  For more information, visit the link below:

https://www.socra.org/certification/maintenance-of-certification/requirements-for-maintaining-certification/

We offer a robust portfolio of live and virtual conferences, workshops, and courses to keep you at the forefront of the industry and support your continuing educational goals. Visit the link here to take a look at upcoming courses happening near you. We also offer the SOCRA chapter program designed to offer colleagues a way to acquire continuing education credit for SOCRA CCRP recertification and to become involved with SOCRA’s local educational programming. Such programming is of no cost to SOCRA members. Check out the link here to find a local chapter near you or email us at [email protected] to find out how you can start one!

To start, we suggest networking with individuals in your area who are already working in clinical research.  You can do this through the SOCRA LinkedIn page or group.  You could also become a SOCRA member and take advantage of the online membership directory to email other research professionals in your area.   You can apply for membership  here .  Individuals already working in the field can give you the best advice regarding local training and employment opportunities.

You can also network by attending local SOCRA chapter meetings.  The chapter list can be viewed here .  You don’t have to be a member to attend your first meeting, and this is a great place to meet people and learn about clinical research.  

You could also consider attending one of our live workshops and conferences.  They offer a lot of current information, are a great opportunity to network with other research professionals, and give you the opportunity to speak with subject matter expects.  In light of COVID-19, many of our programs are now offered virtually.  View the event calendar here . 

We also offer free GCP training to update your knowledge of the clinical research regulations which you will have access to through your membership.  As you know, the Good Clinical Practice (GCP) regulations are set by the government (FDA) for managing clinical research trials so that data collection and management techniques are consistent regardless of where the patient is seen, so that the results of numerous sites can be evaluated together.  Having the trainings on your resume could be beneficial during your job search.  You must have your SOCRA ID to access the training, but you may go to the training website to review the various offerings here.

Resources & FAQ

• Professional Key Competencies
• Useful Links
• Professional Development Support

Clinical Trials Regulation

On 31 January 2022, the Regulation repealed the  Clinical Trials Directive (EC) No. 2001/20/EC  and national implementing legislation in the EU Member States, which regulated clinical trials in the EU until the Regulation's entry into application.

A transition period applies to clinical trial submission under the Regulation.

Consult the Regulation:

• Clinical Trials Regulation (Regulation (EU) No 536/2014)

Also on this topic

• Clinical Trials Information System

Aims and benefits

The  Clinical Trials Regulation harmonises the processes for  assessment and supervision of clinical trials throughout the EU. 

The evaluation, authorisation and supervision of clinical trials are the responsibilities of EU Member States and European Economic Area (EEA) countries. 

Prior to the Regulation, clinical trial sponsors had to submit clinical trial applications   separately to national competent authorities and ethics committees in each country to gain regulatory approval to run a clinical trial.

The Regulation enables sponsors to submit one online application via a single online platform known as the  Clinical Trials Information System  (CTIS) for approval to run a clinical trial in several European countries, making it more efficient to carry out such multinational trials. 

The Regulation also makes it more efficient for EU Member States to evaluate and authorise such applications together, via the  Clinical Trials Information System .

The purpose is to foster innovation and research in the EU, facilitating the conduct of larger clinical trials in multiple EU Member States/EEA countries. 

Other key benefits of the Regulation include:

• improving information-sharing and collective decision-making on clinical trials;
• increasing transparency of information on clinical trials;
• ensuring high standards of safety for all participants in EU clinical trials.

Under the Regulation, clinical trial sponsors must submit all new clinical trial applications in the  Clinical Trials Information System  (CTIS) from 31 January 2023. National regulators in the EU Member States and EU/EEA countries also use CTIS. 

The system:

• enables sponsors to apply for clinical trial authorisation in up to 30 European countries with a single online application;
• allows national regulators to collaboratively process clinical trial applications in more than one country, request further information, authorise or refuse a trial and oversee an authorised trial;
• facilitates the expansion of trials to other EEA countries;
• enables transparency and access to information for any party interested in clinical trials conducted in the EEA through a searchable public website.

CTIS went live on 31 January 2022 together with the public Clinical Trials website . For more information, see: 

• Development of the Clinical Trials Information System
• Clinical Trials website

Transition period for clinical trial sponsors

Under the Clinical Trials Regulation, EU Member States and EEA countries use the Clinical Trials Information System (CTIS) to carry out their legal responsibilities to assess and oversee clinical trials from 31 January 2022:

• for the first year of implementation and until 30 January 2023, clinical trial sponsors could choose whether to apply to start a clinical trial via the Clinical Trials Information System or under the Clinical Trials Directive;
• from 31 January 2023 onwards, clinical trial sponsors need to apply to start a clinical trial via the Clinical Trials Information System;
• from 31 January 2025, any trials approved under the Clinical Trials Directive that continue running will need to comply with the Clinical Trials Regulation and their sponsors must have recorded information on them in CTIS.

EMA encourages sponsors to use the transition period to ensure their information on clinical trials is recorded in CTIS in a timely manner. 

Guidance is available from the European medicines regulatory network on the CTIS website to support sponsors with transitioning their ongoing trials to CTIS:

• Clinical Trials Information System: Guidance and Q&As: Transitioning trials

Questions and answers about CTIS and the Clinical Trials Regulation

EMA's Query Management Working Group prepared a document to address the main questions received from sponsor associations about CTIS and the Clinical Trials Regulation.

EMA published this document in February 2023.

Questions and answers by the Query Management Working Group on CTIS and the CTR

Progress on implementation of the Regulation

Under the  Accelerating Clinical Trials EU (ACT EU) initiative , the European medicines regulatory network publishes statistics on the authorisation of clinical trials in the European Union (EU) and European Economic Area (EEA) every month. This information provides an insight into how the Clinical Trials Regulation is transforming the clinical-trial environment in the EU / EEA.

The reports include information on the number of clinical trial applications submitted, as well as the number of clinical trials authorised and not authorised by national regulatory authorities.

The reports are available on the ACT EU website at the link below:

• ACT EU: Documents: Implementation of the Clinical Trial Regulation

External links

• European Union clinical trials register

Related content

• Clinical Trials Information System: training and support  
• Clinical Trials Information System (CTIS): online modular training programme
• Clinical trials in human medicines  
• Data submission on investigational medicines: guidance for clinical trial sponsors

Related EU legislation

• Clinical Trials Regulation EU No. 536/2014
• Clinical Trials Directive (EC) No. 2001/20/EC  (repealed by the Clinical Trials Regulation on 31 January 2022)
• Clinical trials
• Regulatory and procedural guidance
• Research and development

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