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  • Clinical Development Planning

Clinical Development Planning Made Personal

Efficiently and effectively address your unique program needs with custom clinical development plans..

From adaptive designs and basket studies to patient stratification, immune monitoring, and beyond, you can harness Precision’s comprehensive medical, scientific, operational, statistical, and regulatory expertise to propel therapeutic development and shorten your time to patient impact.

Successful clinical trials start with robust planning and comprehensive capabilities, particularly for cell and gene therapy studies, as well as biomarker-driven clinical trials.

Precision’s Capabilities in Clinical Development Planning

Clinical development plan (cdp) design.

The CDP is the blueprint of a drug’s entire clinical research strategy. It outlines the clinical program design, including development, assessment, decision points, personnel, and budgetary estimates.

Leveraging Precision’s comprehensive expertise in biomarker-driven studies allows you to confidently meet the needs of your project, bringing you closer to your desired endpoints.

  • Innovative Trial Designs
  • Review of Preclinical and/or Clinical Data
  • Assessment of Mechanisms of Action
  • Proposed Patient Population(s)
  • Proposed Dosing
  • Safety and Efficacy Data
  • Competitive Landscape
  • Proposed Synopsis(es)
  • Associated Timelines and Budget

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Target Product Profile (TPP) Creation

A TPP outlines the desired characteristics of a product. This includes intended use, target populations, and safety and efficacy characteristics, among other criteria.

Alongside Precision’s experts, you can analyze your unique criteria, prepare for best- and worst-case events, and catch the attention of the right funders and developers.

Submission Strategy and Regulatory Support

Pass through regulatory processes the first time with robust submission support for IND, NDA, MAA, and BLA to establish the regulatory pathway. Regulatory strategic and operational support for major filings includes writing and review of CTD Modules, as well as viability assessments for expedited or pediatric programs.

For example, recent pre-IND oncology filings and IND package support based on FDA feedback included:

  • Targeted nanoparticle with payload
  • Targeted fusion protein T-cell receptor/cytokine
  • Targeted antibody-drug conjugate
  • Vaccine with mutation-specific peptide and oncolytic virus
  • Antibody designed to alter targeting of cytokine to specific cell types
  • Small molecule oncolytics

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Precision’s Regulatory Strategy

Regulatory authority meetings.

  • Question development
  • Briefing document development
  • Meeting preparation support
  • Representative services

Expedited Programs

  • Fast-track designation
  • Breakthrough designation
  • Priority review
  • Priority medicine (PRIME)
  • Accelerated approval

Regulatory Submission

  • Regulatory strategic and operational support for major filings
  • Writing and review of CTD modules (IND/CTA/BLA/NDA/MAA)

Program Management

  • Regulatory program management IND/CTA development
  • GAP analysis
  • Regulatory project plans

Orphan Designation

  • Rare experience
  • US and EU Orphan drug applications

Pediatric Planning

  • Extensive population experience
  • Study and investigation plans
  • Pediatric rare disease designation

Case Studies in Clinical Development Planning and Study Optimization

Supporting a rare disease basket trial, contracted services:.

Precision supported a sponsor in planning conversations with their board to support the funding of a rare disease basket trial.

Deliverables:

A white paper supporting a basket study combined medical, regulatory, and statistical considerations. From that white paper, a slide deck summarizing the recommendations and alternative scenarios was developed.

The sponsor had a successful board meeting and is moving forward with IND submission.

BLA Submission Strategy and Planning

Precision’s regulatory and statistical teams supported a recent oncology study, which is planned to move to BLA submission upon unblinding of the pivotal trial.

Type C meeting request, preparation of the briefing document, and development of the strategy for integrated safety submission (ISS), including CDISC conversion.

The FDA provided written responses that were clear and supportive of the integration approach. This prework helped to set the foundation for the ISS strategy, inclusive of statistical, regulatory, and medical writing support for modules 2.5, 2.7.3, and 2.7.4 and all supporting documentation.

Support for pre-IND meetings and IND filings

Assistance for novel targeted therapies, including antibody-drug conjugates, gene therapy, nanoparticles, and engineered proteins.

Generation and support for meeting requests and meeting packages; assistance with IND.

Introduction of programs to the FDA; input received for IND content expectations; safe-to-proceed assessments for IND submissions.

Improved Market Access

As payer evaluation criteria continuously evolve, ensuring optimal access is an ever-present challenge, thus making early market access strategies essential to your program’s success.

Precision strategists and policy professionals can guide your next project’s development through the evolving regulatory pathway:

  • Early health economic modeling to inform randomized control trial (RCT) data collection to support economic value demonstration to payers and health technology assessments (HTAs)
  • Payer evidence planning to inform RCT data collection and that meets payers’ needs, reducing coverage restrictions
  • KOL mapping to identify sites and shape engagement strategy
  • Patient engagement programs
  • Scientific platform development

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Precision’s Market Access Services

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Value Study Development

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Launch Support

Start your journey to approval today, related clinical trial services, global cro capabilities.

Clinical trial sites and offices on 5 continents, alongside specialty and sample processing labs, provide the clinical reach and scale necessary to manage complex global programs.

Clinical Trial Design

Advanced trial-design approaches– including basket, umbrella, and adaptive trials– deliver biomarker driven clinical research. Deep experience in these highly complex trial designs maximizes both insights and efficiency.

Biostatistics

Seasoned biostatisticians and statistical programmers deliver insight into every trial phase, from study design to regulatory submissions, all backed by meticulous documentation and data monitoring.

Clinical Sample Management

Sample inventories from a global network of labs supply real-time processing in 55 countries; consolidated data from central labs, screening labs, and specialty labs with clinical data create actionable reports.

Therapeutic areas of excellence

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Precision for Medicine is part of the Precision Medicine Group, an integrated team of experts that extends Precision for Medicine’s therapeutic development capabilities beyond approval and into launch strategies, marketing communication, and payer insights. As one company, the Precision Medicine Group helps pharmaceutical and life-sciences clients conquer product development and commercialization challenges in a rapidly evolving environment.

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How to Create and Optimize a Clinical Development Plan

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A clinical development plan — a comprehensive strategy for developing an investigational product through regulatory submission — is a critical component of drug development and helps ensure that new therapies are safe, effective, and of high quality.  Here, I offer a high-level overview on steps to take to create a clinical development plan, how to optimize your plan as the program progresses, and why this comprehensive roadmap is so vital to the success of your development program.

How to create a clinical development plan

Creating a clinical development plan typically involves a multidisciplinary team that includes experts in clinical development, regulatory affairs, medical affairs, statistics, and other relevant areas. Consider the following steps when creating a clinical development plan:  

  • Target identification : The first step in creating a clinical development plan is to identify a target disease or condition that the drug is intended to treat.
  • Preclinical testing : Preclinical testing is then conducted in animal models to assess the drug’s safety and efficacy and determine the appropriate dose levels for use in human clinical trials.
  • Biomarker identification (if applicable): Determine what sort of biomarkers are planned to be assessed, and which of the seven categories the putative biomarker(s) fit into, e.g., diagnostic, prognostic, pharmacodynamic, or safety.
  • Phase I clinical trial design : The design of the Phase I clinical trial is then determined, including the number of subjects to be enrolled, the dose levels to be tested, and the endpoints to be measured. Work closely with clinical pharmacologists/toxicologists to optimize dosing evaluation and modeling for this Phase.
  • Phase II clinical trial design : Based on the results of the Phase I trial, the design of the Phase II clinical trial is determined. At this point, the efficacy assessments, endpoints, and applicable estimands should be determined. The safety assessments should be refined based on any information gathered from the Phase I study as well as pre-clinical information.
  • Phase III clinical trial design : Based on the results of the Phase II trial, the design of the Phase III clinical trial is determined, including the number of subjects to be enrolled, the estimands, and the endpoints to be measured. These trials are likely to be the most extensively described in the future package insert, so you want to be sure that they make a clear and convincing argument for why your product should be administered to the desired population in the tested manner in order to get the desired efficacious response.
  • Data analysis : Plans for data analysis are developed, including statistical methods and procedures for ensuring data quality.
  • Regulatory interactions : Plans for interacting with regulatory agencies, including submitting regulatory filings and conducting meetings with regulatory authorities, are developed.
  • Safety monitoring : Plans for monitoring the drug’s safety during clinical development and after it is approved for use are developed.
  • Pediatric study plans are developed, as required by US and EU authorities. These plans must address treatment for persons from 0–18 years old, though waivers may be granted for certain subsets and for certain products. These plans should be planned early on. It is best not to delay the planning until late in Phase III.

The clinical development plan is then reviewed and revised as needed to ensure that it meets regulatory requirements, addresses safety concerns, and provides a clear roadmap for the clinical development of the drug. The plan is a living document, updated regularly as new data becomes available and the development program progresses.  

How to optimize your clinical development plan  

Optimizing a clinical development plan involves making adjustments to ensure that the development program is designed to achieve the best possible outcome while minimizing risks and costs. It will involve expert input, careful consideration of the available data, and a willingness to adjust the plan as needed. Consider the following steps:  

  • Conduct a thorough review : The first step to optimize a clinical development plan is to thoroughly review the existing plan, including the available data and the regulatory landscape. This will help identify areas that need improvement or adjustment.
  • Consult with experts : Consult with experts in relevant areas, including clinical development, regulatory affairs, medical affairs, and statistics, to obtain their input and recommendations.
  • Refine the target population : Refine the target population by conducting additional analysis of patient demographics, disease characteristics, and other relevant factors to identify subgroups of patients that may benefit most from the drug.
  • Optimize the trial design : Optimize the trial design by adjusting the sample size, the number of study arms, and the selection of endpoints to increase the chances of demonstrating efficacy and safety.
  • Use adaptive trial designs : Consider using adaptive trial designs that allow for changes in the trial design based on interim data analysis to maximize efficiency and flexibility.
  • Incorporate biomarkers : Incorporate biomarkers into the trial design to identify patients most likely to respond to the drug and to monitor the drug’s efficacy and safety.
  • Use real-world evidence (RWE) : Consider incorporating RWE to optimize the study design, identify new patient populations, and enhance understanding of the drug’s real-world effectiveness.
  • Optimize the regulatory strategy : Work with regulatory agencies to optimize the regulatory strategy, including selecting endpoints and developing a compelling benefit-risk profile.

The importance of the clinical development plan  

A clinical development plan is an essential component of drug development because it provides a comprehensive roadmap for the clinical trials required to demonstrate the safety and efficacy of a new drug or therapy. A thorough clinical development plan will:  

  • Ensure safety : A clinical development plan outlines the steps required to assess the drug’s safety in humans. By conducting clinical trials in a structured and systematic manner, potential safety issues can be identified early in the development process, allowing appropriate steps to be taken to address them.
  • Demonstrate efficacy : The clinical development plan outlines the steps required to demonstrate the efficacy of the drug in treating the target disease or condition. By conducting clinical trials in a structured and systematic manner, the drug’s effectiveness can be accurately assessed, and potential issues can be identified and addressed.
  • Provide a regulatory roadmap : The clinical development plan outlines the steps required to obtain regulatory approval for the drug. By adhering to the plan, developers can ensure they meet the regulatory requirements for drug development, which can help speed up the approval process.
  • Help manage resources : The clinical development plan provides a roadmap for allocating resources, including time, money, and personnel. By having a clear plan, developers can allocate resources more efficiently, reducing costs and maximizing the chances of success.

How to create a clinical development plan

At Cytel, our Therapeutic Development Team comprises experts who can support your team throughout the development lifecycle. Click the button below to speak with us about how we can help you create, refine, and optimize your clinical development plan to demonstrate the safety and efficacy of your drug, ensure compliance with regulatory requirements, and help manage your investment effectively.

Learn more about our Therapeutics Development Team

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How to Create a Comprehensive Clinical Development Strategy

The drug development process is a long and risky endeavor, with over 90% of new therapies that enter Phase 1 clinical trials ultimately failing to obtain regulatory marketing approval  [1] [i] . 

While necessary, demonstrating the efficacy and safety of a new compound alone is insufficient in assuring cost-effective development or successful launch and commercialization [2] .

Along the path to approval, Sponsors face many barriers that can complicate the development process, resulting in delays, cost overruns, or the end of a program entirely. 

A strategic, comprehensive clinical development plan (CDP) can help Sponsors optimize efficiency, control costs, plan timelines, and maximize the probability of success for a new drug program.

Such a strategy encompasses various aspects of a program and can yield several benefits for a company, including:

  • Early identification of potential pitfalls 
  • Optimization of study timelines and costs
  • Confidence among decision-makers and potential partners

Creating an effective CDP requires a consultative, multidisciplinary team of experts. A comprehensive drug development strategy typically includes  [3] :

  • A target product profile (TPP)  that defines the key characteristics of a drug product;
  • A regulatory strategy  that takes into consideration the current opinions of health authorities and the requirements of different jurisdictions;
  • A non-clinical plan  that looks at  in vitro  and  in vivo  reports and findings to ensure data are scientifically sound and adequate to support proposed clinical trials;
  • A clinical development plan  that strategically plans out the clinical trials required for market approval;
  • A Chemistry, Manufacturing, and Controls (CMC) strategy  that includes costs for drug supply and formulation strategy, including costs for any placebo or comparator drugs;
  • A commercial plan  that favorably positions your product with key opinion leaders and other stakeholders.

What should you include in your TPP?

The TPP defines the key characteristics of the marketed drug product [4] . It typically includes information such as: 

  • Indication or disease(s) to be treated;
  • Patient population(s) projected to be treated;
  • Therapeutic efficacy and clinical safety;
  • Formulations, dosing regimens, and administration; and
  • Potential drug-drug interactions and contraindications or precautions.

A TPP should be a living document that can help guide the design of all program activities, including non-clinical and clinical studies. As your TPP evolves, it will eventually provide the basis for preparing the final approved product label. 

Developing your Regulatory Strategy

The drug regulatory environment is complex and can vary significantly between regions and jurisdictions. Regulations may also evolve and develop during a product development life cycle, creating frustrating obstacles for a program without a sound regulatory strategy. 

Regulatory experts may help Sponsors determine a recommended pathway for approval and evaluate special options for accelerated review and approval.

Creating a timeline for major regulatory submissions and additional agency interactions, along with plans to ensure those interactions are effective, can clarify the process. 

The regulatory landscape can be complex, but no one wants to see a promising product stall due to poor regulatory planning. Working alongside a niche expert with experience with the FDA and other regulatory agencies can help you prepare key questions to ask and address as a product progresses through the clinical trial process.

Preparing your Non-Clinical Strategy

Advancing a drug into initial Phase 1 development requires the completion of a suite of non-clinical studies. These studies must comply with detailed regulatory guidelines such as GLP and ICH. They must provide enough rigor for regulatory agencies and oversight committees to agree that a drug is appropriate for human administration at planned doses in clinical trials [5] .  

Later clinical development and regulatory marketing approval require additional non-clinical studies. These non-clinical studies may include longer-duration toxicology and reproductive technology, carcinogenicity, and bio-distribution studies. Studies may also be needed to address concerns about a specific drug or its molecular target and mechanism of action.

As you prepare your non-clinical strategy, you should begin with a thorough technical, scientific, and regulatory review of all available non-clinical reports and findings (including  in vitro  and  in vivo  studies). Non-clinical experts should work closely with colleagues in other disciplines to assess whether the available data are scientifically sound and adequate to support proposed clinical trials and meet all relevant regulatory guidelines.

What is a Clinical Development Strategic Plan?

Clinical trials can be a program’s most expensive and high-risk component  [6] . These trials will also drive financial and resource decisions as the development of the asset matures.

To begin designing a clinical trial program, subject matter experts should review the preclinical profile of the new drug candidate and provide clinical trial design suggestions and proposed therapeutic use in patients. The medical and scientific rationale for the drug product should be assessed to ensure that the marketed product is likely to gain acceptance by healthcare providers, patients, and professional medical organizations.

The clinical plan may include information such as:

  • Trial details, from initial Phase 1 through Phase 3, including information like key endpoints, inclusion/exclusion criteria, and approximate subject numbers
  • A “proof-of-concept” definition that can help Sponsors make a “Go/NoGo” decision based on the efficacy performance of a drug candidate.
  • Post-approval plans for Phase 4 trials
  • A high-level timeline, including cost and resource commitments
  • A comprehensive risk management strategy

CMC Strategy

A CMC plan functions as a vital component of a fully integrated development plan by outlining the significant features of a drug supply and formulation strategy and any placebo or comparator drug supply needs. A CMC plan also assesses the estimated cost of goods for the drug substance and final market product, a critical factor in new drug development [7] .

Preparing a CMC strategy should begin with a thorough technical, scientific, and regulatory review of all available data on the drug substance or active pharmaceutical ingredient (API). Examining existing pilot drug formulations allows you to assess whether available CMC data can support proposed trials and meet relevant GMP regulatory requirements. That review can outline any additional CMC work needed during development.

Commercial Strategy Plan

Planning a commercial strategy begins with a thorough review and analysis of the competitive landscape for a product, considering efficacy, safety profile, costs, prescriber and patient satisfaction, and upcoming treatments in the pipeline.

An effective commercial strategy can [8] :

  • Inform differentiation from competitors;
  • Specify data that should be obtained to demonstrate value;
  • Help you favorably position a product with KOLs and other stakeholders.

Whether conducted during Phases 1-3 or following approval in Phase 4 studies, a competitive landscape analysis can influence the design of a program’s clinical trials. A commercial strategy identifies the most critical health economic endpoints to include in clinical trials. It can also suggest how to obtain relevant data via approaches other than traditional interventional clinical trials, such as real-world evidence (RWE).

Even at the very early stages of planning a drug development program, formulating a commercial strategy can identify critical success factors that might be overlooked. It can also recommend the best methods for effectively communicating results to stakeholders to maximize market access and the value of a new drug product.

In summary, a comprehensive development strategy is a vital tool for pharmaceutical and biotech companies. It helps navigate the complexities of drug development, minimizes risks, optimizes timelines and costs, improves regulatory success rates, and inspires confidence among decision-makers and potential partners. Most importantly, a comprehensive plan helps sponsors bring innovative medicines through the drug development pipeline faster – because patients are waiting.

clinical development plan in research

   [1]  Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022 Jul;12(7):3049-3062. doe: 10.1016/j.apsb.2022.02.002. Epub 2022 Feb 11. PMID: 35865092; PMCID: PMC9293739.

[2]  From idea to market: the drug approval process. M S Lipsky, L K Sharp The Journal of the American Board of Family Practice Sep 2001, 14 (5) 362-367

[3]  Elizabeth Kwong, Advancing Drug Discovery: A Pharmaceutics Perspective, Journal of Pharmaceutical Sciences, Volume 104, Issue 3,

2015, Pages 865-871, ISSN 0022-3549,  https://doi.org/10.1002/jps.24294 . (https://www.sciencedirect.com/science/article/pii/S0022354916300132)

[4]  Tebbey, P. W., & Rink, C. (2009). Target Product Profile: A Renaissance for its Definition and Use.  Journal of Medical Marketing ,  9 (4), 301–307.  https://doi.org/10.1057/jmm.2009.34

[5]  Gursharan Singh, Chapter 4 – Preclinical Drug Development, Editor(s): Divya Vohora, Gursharan Singh, Pharmaceutical Medicine and Translational Clinical Research, Academic Press, 2018, Pages 47-63, ISBN 9780128021033

[6]  Eisenstein EL, Collins R, Cracknell BS, et al. Sensible approaches for reducing clinical trial costs.  Clinical Trials . 2008;5(1):75-84. doi: 10.1177/1740774507087551

[7]  William F. Salminen, Olu Aloba, Angela Drew, Agnieszka Marcinowicz, Madelyn Huang, US FDA 505(b)(2) NDA clinical, CMC and regulatory strategy concepts to expedite drug development, Drug Discovery Today, Volume 28, Issue 7, 2023, 103618, ISSN 1359-6446

[8]  Paich, M., Peck, C. and Valant, J. (2011), Pharmaceutical market dynamics and strategic planning: a system dynamics perspective. Syst. Dyn. Rev., 27: 47-63.  https://doi.org/10.1002/sdr.458

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Clinical Development Plan (CDP)

Eu mdr compliance & strategic planning of medical devices.

The EU MDR Technical Documents (TD) now requires a new document known as the Clinical Development Plan (CDP). It is a valuable strategic document that can assist MedTech in aligning its development and regulatory requirements.

A Clinical Development Plan is required by section 1(a), eighth indent, of Annex XIV of the Medical Devices Regulation (EU) 2017/745 (MDR) . Annex XIV, section A of the MDR contains a definition of the CDP. A Clinical Development Plan is a strategy that shows progression from preliminary research, such as first-in-man studies, feasibility research, and pilot studies, to conclusive research, such as pivotal  clinical investigations  and a PMCF , with an indication of milestones and a description of prospective acceptance criteria. The European Medical Device Coordinating Group’s (MDCG) MDCG 2020-1 Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) provides additional help for this. The purpose of this guidance is to offer direction for medical device software. Insights about planning and the necessity of a Clinical Development Plan, for example, are contained that are relevant to various medical devices.

This paper aims to clarify the proper organisation of a CDP. It’s a useful early tool to make regulatory submissions easier while manufacturers are still developing their product (s).

Medical Device Clinical Development Plan CDP

Suggested document structure for CDP

A sample CDP is shown in the table over the page. The initial Business Development rationale is interpreted into the clinical usage parameters by the CDP, which is a key strategic document. It accomplishes this by outlining the medical device’s Intended Use , Intended Purpose , Patient Population, Intended User, Intended Environment, and the key operational principles. The CDP then aligns essential business functions by specifying key deliverables required to establish clinical claims, obtain CE marking , and identify important differential design (to obtain clinical and technical claims), all of which are necessary to facilitate the marketing and smooth market entry of the product.

It therefore makes sense that CDP shouldn’t be a stand-alone document, but rather a core one that unifies different business processes and outlines the crucial contributions that each department must make in order to obtain the CE mark, gain access to markets, and keep the device competitive.

Table 1 – Suggested CDP Structure

Cdp for alignment of terminology.

Terminology is crucial in regulatory contexts and frequently contributes to audit conclusions. Snags are encountered when transitioning from US, Australian, or EU MDD . By utilising information from your pre-existing CE marks, effective translation increases the efficiency of gaining markets. Early completion of this task allows your team to concentrate on the gaps that must be filled in order to comply with the GSPR.

CDP for new versus existing medical devices

With regards to any new devices where clinical evidence is still to be compiled, consideration must be dedicated to outline how pre-clinical data, first-in-man studies, feasibility, pilot, and pivotal studies can proceed to create the evidence needed to apply for the CE mark.

The content of the CDP is less clear for devices that are already in use. The procedures outlined above should have been followed, and the outcomes should have been covered in the CER, as these devices are already certified. The majority of CDP requirements do not apply to legacy devices, with the exception of the post-market clinical follow-up ( PMCF ) plan, according to MDCG guidance 2020-6 on the clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC. Milestones and acceptance criteria should be mentioned in the PMCF plan.

Life cycle management of clinical/performance data in clinical evaluation (MDR) / performance evaluation (IVDR) process

Over the course of the device’s lifespan, the manufacturer should actively and consistently monitor the device’s performance, effectiveness, and safety. The manufacturer must also specify how future product releases or claims will be handled to guarantee that the required clinical data is available to support the claims and their intended use. Such data should be subject to the Clinical Evaluation ( MDR ) / Performance Evaluation ( IVDR ) principles shown in Figure 1 from MDCG 2020-9 Figure 1 and Annex 1. Post-market information such as complaints, PMCF /PMPF data, REAL-WORLD PERFORMANCE data, direct end-user feedback, or newly published research / guidelines are just a few examples of post-market information that may be included.

Access to Real-World Performance data is made possible by the MDSW’s exceptional level of connectivity and can be utilised for a variety of things, including but not limited to:

  • timely detection and correction of malfunctions.
  • detection of systematic misuse.
  • understanding user interactions.
  • to conduct ongoing monitoring of Clinical Performance .
  • to improve effectiveness.
  • develop the claims in the Clinical Development Plan (MDR) or future releases.

Medical Device Clinical Development Plan CDP

Devices for which CDP obligations are less clear

The CDP is still required for devices that have already received CE marking under the MDR as well as for those that have already received CE marking under the MDR because it contains crucial PMS data gathering insights like the justification of the PMCF plan and potential future “Indications” that the manufacturer may work toward.

CLIN-r+ recommendations

In light of this, CLIN-r+ suggests that manufacturers create their CDPs, summarising the history of clinical evidence, citing reports, outlining the current state of the art, in addition to any ongoing activities.

The CER can be used to supplement such evidence and weigh the clinical advantages and disadvantages. The summary history component of the CDP will expand over time whilst the rest narrows down to just PMCF or future indications. In order to facilitate future filings, the CDP will give the Notified Body reviewer a guide of how the clinical data for a device has been put together as well as the manufacturer’s long-term goals.

CLIN-r+ offers a full clinical development service, as well as templates for any section of the Technical Documentation required, including the CDP. Our templates have been completely updated to reflect the most recent requirements. Get in touch!

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Drug Discovery and Development: A Step by Step Guide

clinical development plan in research

Drug discovery and development can be described as the sum total of steps taken by research-intensive entity to identify a new chemical or biological substance and transform it into a product approved for use by patients.

This highly knowledge and capital intensive process takes, on average, 10-15 years and over $2 billion (2021 figures), to pull off.

But exactly what is involved? Who does what and when? In this article, we outline key concepts of drug discovery and development, including target identification, clinical trials, pharmaceutical development and commercialisation.

Drug Development

Drug development covers all the activities undertaken to transform the compound obtained during drug discovery into a product that is approved for launch into the market by regulatory agencies. This is a pivotal process, and a lot rides on its success, thus, efficiency is absolutely critical, but mainly for two key points:

Firstly, development is expensive – accounting for 70% of the total R&D costs. Even though the number of projects is much smaller compared with those under discovery, the cost per project is significant, and increases exponentially as the project progresses through into the latter stages.

Secondly, speed is the essence in drug development as it determines how soon the company can start earning a return on the huge investment ploughed into the project. Besides, any delays eat away into exclusivity arrangements granted by patents and time before generic manufacturers can launch me-too products.

For clarity, drug development is presented as an operation that’s distinct from discovery. In reality, the distinction is not as clear cut. Often, different activities are being undertaken concurrently, and in deed, some processes that were traditionally undertaken much later on are increasingly being brought much forward. The idea is to identify compounds that have the highest chances of success much earlier and focus on those.

Components of drug development

The key activities involved in the development of a typical are summarised in the diagram below, showing the different tasks that are undertaken during this process. Generally, these tasks can be divided into three parts: technical; investigative and administrative.

General Perspective – New Drug Discovery and Development

T he process of creating a new drug product can be broadly divided into three main phases:

  • Drug discovery – entailing the conceptualisation of the therapeutic into a molecule with known pharmacologic effects
  • Drug development – covering the steps taken to convert the molecule above into an approved and registered drug product
  • Commercialisation – which includes all the steps taken to convert the product into an approved therapeutic, launch into the market and to generate sales

These processes are schematically illustrated below, which is greatly oversimplified:

clinical development plan in research

Historically, these functions were performed, respectively by the Research, Development and Marketing departments. Nowadays though, a number of these functions are outsourced to other companies that specialise in one or more aspects of these activities.

It’s worth emphasising that many activities described in the above scheme may proceed in parallel and other may spill out into other phases. For example, development activities, such as clinical trials or additional testing of formulations, generally continue well beyond registration of the drug product. Such tests may be driven by the requirement for more understanding about the new drug or the need to extend use beyond the main therapeutic applications.

The job of the discovery teams does not end with product registration and market launch. Many discovery scientists will carry out more research looking for other candidates to serves as backups in case the lead compound fails or as follow-on compounds that might have better safety or efficacy profiles over the lead compounds.

Finally, the three processes listed in the new drug development scheme above are not independent and consecutive. Rather, they are coordinated with each other because the performance of each process influences decisions taken in another stage.

Understandably, there are many competing interests as the new drug progresses through its journey. To successfully fit in and integrate all the different interests and cultures, effective project management skills are required.

Therapeutic Concept Selection

Therapeutic concept selection is about deciding whether or not to embark on a new 0project. Success at this stage is measured in terms of agreeing and signed off a drug discovery program with a clear-cut aim and timeline.

Exactly where the idea originates varies from company to company. Some companies have very strong exploratory research teams that undertake research internally and discover new knowledge on diseases and druggable targets. Others are more open minded, preferring to purchase new molecules in for further development. Often, it’s a mixture of both approaches.

Generally, the decision to select a particular program will be guided by three things: company strategy, technical capabilities and operational constraints.

  • Should the company do it? (Strategy)
  • Could the company do it? )scientific and technical capabilities)
  • Can the company deliver it? (operational constraints)

These three factors are summarised below:

clinical development plan in research

Drug Discovery

The drug discovery process technically starts with choice of a disease area and a definition of the therapeutic need that should be addressed. Once this is done, the process proceeds to identification of the physiological mechanisms that need to be targeted, and ideally, identification of a specific molecular ‘drug target’.

During this phase, effort is focussed on identifying a lead chemical structure, designing, testing and fine-tuning it and ensure that it meets all the criteria required for development into a drug product.

An overview of the main stages that constitute a typical drug discovery project, from the point of identification of a target to the production of a candidate drug is shown below this process is shown below:

clinical development plan in research

Discovery can at first appear like a shot in the dark. At the start, scientists will be dealing with a huge number of compounds (10 20 ), which have to be filtered, mainly via computer simulations (in silico) into manageable number capable of being further optimised.

High throughput screening (HTS) is then applied to identify ‘HITS’ which demonstrate interesting activity. Since HTS can throw up a huge number of ‘HITS’ these are further optimised and validated to remove any artefacts or ‘noise’ from the screen.

A key aspect of validation stage is to find relationships between chemical structure and biological activity, and to find out if the compounds belong to any existing families of compounds (known as hits series).

Validated hits are therefore further studied, especially in terms of their pharmacokinetic profiles and toxicity. At this point, the number of compounds has reduced to a handful. It is these handful of substances that are subsequently entered into the lead optimisation programme.

Lead optimization is a critical process in drug discovery since it’s determines whether a suitable compound can be identified for taking forward into preclinical and clinical studies. Therefore, the goal of this stage is to scrutinise and fine-tune, typically in parallel, both the biological activity and the physicochemical properties of the lead series.

During this stage, rigorous data is generated in a precise, timely manner to quickly determine the compounds to progress the compounds, and the series, toward the ideal candidate profile. The higher the quality of these candidates, the higher the chances of successful progression into clinical trials.

“MAGIC BULLETS”

The term ‘magic bullet’ was coined by Paul Ehrlich (1854 – 1915), a Germany medical scientist and winner of the Nobel Prize in Physiology or Medicine in 1908. Ehrlich envisaged a compound (the bullet) capable of attacking a pathogen and destroying it while leaving its host intact. Nowadays, pharmaceutical scientists are developing targeted and personalised cancer therapies, and these, many argue, are modern realisations of Ehrlich’s idea.

clinical development plan in research

Technical development – solving technical issues related to synthesis and formulation of the drug substance with the aim of ensuring the quality and safety of the drug product. The key functions involved here are chemical, manufacturing and formulation development.

Investigative studies – establishing the safety and efficacy of the product, including assessment of whether it’s pharmacokinetically suitable for clinical use. The main function involved here are safety pharmacology, toxicology and clinical development.

Administrative functions – coordinating and managing quality control, logistics, communications and decision making to ensure high quality data are generated and to minimise any delays. The main function involved here is project management.

In addition, there will be a team coordinating and liaising with regulatory authories, collating data, liaising with material suppliers and writing dossiers for presentation to authorities in order to gain approval in a timely manner.

Pharmaceutical Development

This stage is also known as pharmaceutical development. Since pure drug substances are rarely suited for clinic use, they need to be formulated; by combining them with excipients, into tablets, capsules, injections, etc.

Pharmaceutical development refers to all the different tasks undertaken to transform the drug substance identified as a candidate during the discovery phase into a dosage form that is able to reliably deliver the drug into the body in a safe and reliable way.

Designing a formulation can be as equally time consuming and complex as drug discovery. In order to mitigate some of the issues that crop up, initial studies are undertaken during lead optimisation, before development actually starts.

For conventional drug substances, the desired route of administration is the oral route. Alternatives are considered, particularly if sufficient bioavailability cannot be achieved orally.

clinical development plan in research

The different tasks undertaken in pharmaceutical development can be grouped into two:

  • Preformulation studies which specifically investigate physical and chemical properties of the drug substance, such as solubility and dissolution rates; acidity and alkalinity (pKa), chemical and physical stability, lipophilicity, particle morphology, melting point and fracture behaviour, etc.
  • Formulation studies which are essentially, chemical engineering effort aimed at converting a powder or a liquid form of the drug substance into a stable and deliverable product. During this process, formulation scientists will take into account all the known properties of the drug substance and the desired drug delivery system that best meets the therapeutic objectives of the compound.

Clinical Development

Clinical development is an umbrella terms to describe the whole set of activities undertaken by the team in support of testing of a new drug substance in humans. It includes the following clinical trials, which refer to administration into man the new drug under controlled conditions to investigate bioavailability, efficacy, safety, tolerability and acceptability.

Clinical development of new drugs has been described as both a science and an art, since it requires technical expertise, sound judgement and commercial acumen.

Executed well, clinical development brings new medicines quickly and safely to patients who need them, while also managing to return on the financial investment.

At the time of writing this post In 2021, estimates of the investment required for clinical development studies vary, but most sources agree that, including the cost of failures and capital invested, the total cost of bringing a new drug to market is $2-3 billion, spread over a 12-year development cycle. Out of this cost, two-thirds is spent on clinical development.

The clinical development process is divided into four phases, summarised in the table below.

clinical development plan in research

  • Phase I: first introduction and safety assessment in man, typically in healthy volunteers
  • Phase II: early exploratory and dose-finding studies in patients
  • Phase III: large scale studies in patients
  • Phase IV: post-marketing safety monitoring of patients.

In almost every country on earth today, clinical trials are a legal requirement before a new drug can be sold or claims made for its safety of benefits. This does not include alternative remedies, however. In addition, all clinical trials, include Phase I studies, are subject to international, national and in most cases, institutional regulations.

The different international regulations and requirements are set out in guidelines published by the International Conference on Harmonisation (ICH), an organisation that was set up to harmonise pharmaceutical regulations across Europe, United States and Japan.

It is a requirement that clinical development procedures be done under ICH guidelines if the results are to be accepted for registration in the three ICH guidelines. This does not mean that the studies need to be done there – they only have to comply with these guidelines.

In addition to ICH guidelines, human studies are required to be undertaken according to an ethical framework defined code, known as the The Declaration of Helsinki (2000). This code, in a nutshell, requires the principal investigator (physician) to protect life, health, privacy and dignity.

Regulatory Affairs

A fundamental maxim in pharmaceutical new product development is the basic division of responsibilities whereby the health authority, such as the US FDA, is responsible for safeguarding the public’s health against defective and unsafe products, and the pharmaceutical company being responsible for all aspects of drug product development (quality, safety and efficacy).

The regulatory authority develops regulations and guidelines for companies and others in the value chain to follow. The approval of a pharmaceutical product is a contract between the regulatory authority on behalf of the public, and the pharmaceutical company.

The regulatory authority is responsible for approving clinical trial applications, approving marketing authorisation applications, and monitoring safety and efficacy claims of the marketed drugs. Authorities can withdraw the approval at any point where there are cases of non-compliance.

The conditions of the approval are set out in a dossier and appear in the prescribing information. Changes to these terms have to be pre-approved and authorised before they can be implemented.

Within pharmaceutical companies, the regulatory affairs department is the one responsible for obtaining approval for the new pharmaceutical product and working to ensure that this approval is maintained for as long as the company desires so.

Regulatory affairs professionals work at the interface between the regulatory authority and the project team, and they’re often the channel of communication between external and internal stake holders with respect project’s regulatory standing and progress.

Milestones and Decision Points

The decision to advance a drug candidate into early development is the first of several key strategic decision points in a new drug development project. The timing, naming and decision-making process vary from company to company, the one conceptualised below was developed by Norvatis:

clinical development plan in research

Early selection point (ESP

Is the decision to take the drug candidate molecule into early (preclinical) development.

Decision to develop in man (DDM)

Is the decision to enter the compound into Phase 1, based on information obtained during preclinical development phase. Once this decision is made, the company will aim to produce between 2 and 10kg of clinical grade material.

Full development decision point (FDP)

This point is reached after Phase I and Phase IIa studies have been completed. At this point, the company has some preliminary evidence about clinical efficacy in man. From here on, the project costs skyrocket and the company must be confident on commercial returns.

Submission decision point (SDP)

This is the final point when a decision is taken to apply for registration, based on the data collected and its quality.

Summary Points about Drug Discovery and Development

Pharmaceutical companies undertake research for commercial reasons and their overarching objective is a return on capital invested. This is not to say a few companies include altruistic motives, the fact of the matter is that it takes less priority.

For this reason, the research a company pursues has to be in line with its commercial goals. Curiosity-driven research is generally left to Universities and other institutes. That said, there are territories where the two universes overlap, namely, applied research. Many recent innovations in medicine, such as monoclonal antibodies, fall into this domain, and both pharmaceutical companies, and universities have contributed to their development.

Finally, it should be stated that drug discovery and development is unlike any other type of development or innovation process, such as developing a new car. Drug discovery and development carries far greater uncertainty, and the outcome is rarely assured.

Resources Used

Pharmacentral has a strict referencing policy and only uses peer-reviewed studies and reputable academic sources. We avoid use of personal anecdotes and opinions to ensure the content we present is accurate and reliable

  • R.G. Hill, H.P. Rang, Preface to 2nd Edition, in: R.G. Hill, H.P. Rang (Eds.) Drug Discovery and Development (Second Edition), Churchill Livingstone 2013
  • Orloff et a.,l The future of drug development: advancing clinical trial design. Nat Rev Drug Discov 8, 949–957 (2009). https://doi.org/10.1038/nrd3025

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Plan for clinical development of a new drug, from first application in man to drug registration; such a plan usually includes e.g.: overview of the therapeutic indication(s), target product profile, profile of competitive drugs, properties of the new substance, justification for development, overview of principle clinical trials with design and size, drug supplies, staffing requirements and financial resources; → see study list .

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General Principles of Preclinical Study Design

Wenlong huang.

Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

Nathalie Percie du Sert

NC3Rs, London, UK

Preclinical studies using animals to study the potential of a therapeutic drug or strategy are important steps before translation to clinical trials. However, evidence has shown that poor quality in the design and conduct of these studies has not only impeded clinical translation but also led to significant waste of valuable research resources. It is clear that experimental biases are related to the poor quality seen with preclinical studies. In this chapter, we will focus on hypothesis testing type of preclinical studies and explain general concepts and principles in relation to the design of in vivo experiments, provide definitions of experimental biases and how to avoid them, and discuss major sources contributing to experimental biases and how to mitigate these sources. We will also explore the differences between confirmatory and exploratory studies, and discuss available guidelines on preclinical studies and how to use them. This chapter, together with relevant information in other chapters in the handbook, provides a powerful tool to enhance scientific rigour for preclinical studies without restricting creativity.

This chapter will give an overview of some generic concepts pertinent to the design of preclinical research. The emphasis is on the requirements of in vivo experiments which use experimental animals to discover and validate new clinical therapeutic approaches. However, these general principles are, by and large, generically relevant to all areas of preclinical research. The overarching requirement should be that preclinical research should only be conducted to answer an important question for which a robust scrutiny of the available evidence demonstrates that the answer is not already known. Furthermore, such experiments must be designed, conducted, analysed and reported to the highest levels of rigour and transparency. Assessments of research outputs should focus more on these factors and less on any apparent “novelty”.

1. An Overview

Broadly, preclinical research can be classified into two distinct categories depending on the aim and purpose of the experiment, namely, “hypothesis generating” (exploratory) and “hypothesis testing” (confirmatory) research ( Fig. 1 ). Hypothesis generating studies are often scientifically-informed, curiosity and intuition-driven explorations which may generate testable theories regarding the pathophysiology of disease and potential drug targets. The freedom of researchers to explore such innovative ideas is the lifeblood of preclinical science and should not be stifled by excessive constraints in terms of experimental design and conduct. Nevertheless, in order to subsequently assess the veracity of hypotheses generated in this way, and certainly to justify clinical development of a therapeutic target, hypothesis testing studies which seek to show reproducible intervention effects in relevant animal models must be designed, conducted, analysed and reported to the highest possible levels of rigour and transparency. This will also contribute to reducing research “waste” ( Ioannidis et al. 2014 ; Macleod et al. 2014 ). Chapter “Resolving the Tension Between Exploration and Confirmation in Preclinical Biomedical Research” of the handbook will deal with exploratory and confirmatory studies in details. This chapter will only focus on general design principles for hypothesis testing studies. We will address the issue of design principles for hypothesis-generating studies at the end of this chapter. We advise that when researchers design and conduct hypothesis testing in vivo studies, they should conform to the general principles for the major domains that are outlined in Sect. 4 of the chapter and incorporate these principles into a protocol that can be registered and published. The purpose of using these principles is to enhance scientific rigour without restricting creativity. It is advisable that sometimes there can be exploratory elements within the same hypothesis testing studies; therefore, extra care in terms of applying these principles to reduce experimental biases would be needed before the start of the studies. This chapter will not cover reporting, which will be detailed in chapters “Minimum Information and Quality Standards for Conducting, Reporting, and Organizing In Vitro Research”, “Minimum Information in In Vivo Research”, and “Quality Governance in Biomedical Research” of the handbook.

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Comparison of exploratory (hypothesis generating) and confirmatory (hypothesis testing) preclinical studies. Descriptive statistics describes data and provides descriptions of the population, using numerical calculations, graphs, and tables. In contrast, inferential statistics predicts and infers about a population using a sample of data from the population, therefore one can take data from samples and make generalisation about a population

We would recommend that researchers who conduct hypothesis testing in vivo studies should prepare clear protocols, which include a statistical analysis plan, detailing how they are going to set up measures to address the major domains of experimental biases before the experiments start. Ideally, these protocols should be preregistered and/or published, so that the methods which will be used to reduce the impact of bias are documented in an a priori fashion. The process of peer review of a protocol prior to initiating experiments of course is a valuable opportunity for refinement and improvement. Registering protocols encourages rigour and transparency, even if the protocol is not peer-reviewed. Some journals are open to submissions of these types of protocols, such as BMJ Open Science, and many journals offer the Registered Reports format. In addition, there are online resources that allow researchers to preregister their experimental protocols, such as preclinical. eu and osf.io/registries.

2. General Scientific Methods for Designing In Vivo Experiments

Designing an in vivo experiment involves taking a number of decisions on different aspects of the experimental plan. Typically, a comparative experiment can be broken into several component parts.

2.1. Hypotheses and Effect Size

The objective is usually to test a hypothesis. On some occasions, two hypotheses may be postulated: the null hypothesis and the alternative hypothesis. The alternative hypothesis refers to the presumption that the experimental manipulation has an effect on the response measured; the null hypothesis is the hypothesis of no change, or no effect. In a statistical test, the p-value reports the probability of observing an effect as large or larger than the one being observed if the null hypothesis was true; the smaller the p -value, the least likely it is that the null hypothesis is true. The null hypothesis cannot be accepted or proven true. This also defines the effect of interest, i.e. the outcome that will be measured to test the hypothesis. The minimum effect size is the smallest effect the researcher designs the experiment to be able to detect and should be declared in the protocol; it is set up as the minimum difference which would be of biological relevance. The effect size is then used in the sample size calculation to ensure that the experiment is powered to detect only meaningful effects and does not generate statistically significant results that are not biologically relevant. In many cases, it will be hard to determine the minimum difference of biological relevance as for early stage experiments it might be completely unknown, or translatability between clinical relevance and experimental detection thresholds will be complex. There is no simple and easy answer to this question, but in general, a minimum effect size should be set so one can assume to have a beneficial effect for individuals rather than large cohorts, the difference must be experimentally testable and reasonable to achieve, and should have a rationale for translation into patients in the long run.

2.2. Groups, Experimental Unit and Sample Size

In comparative experiments, animals are split into groups, and each group is subjected to different interventions, such as a drug or vehicle injection, or a surgical procedure. The sample size is the number of experimental units per group; identifying the experimental unit underpins the reliability of the experiment, but it is often incorrectly identified ( Lazic et al. 2018 ). The experimental unit is the entity subjected to an intervention independently of all other units; it must be possible to assign any two experimental units to different comparison groups. For example, if the treatment is applied to individual mice by injection, the experimental unit may be the animal, in which case the number of experimental units per group and the number of animals per group is the same. However, if there is any contamination between mice within a cage, the treatment given to one mouse might influence other mice in that cage, and it would be more appropriate to subject all mice in one cage to the same treatment and treat the cage as the experimental unit. In another example, if the treatment is added to the water in a fish tank, two fish in the same tank cannot receive different treatments; thus the experimental unit is the tank, and the sample size is the number of tanks per group. Once identified, experimental units are allocated to the different comparison groups of the desired sample size; this is done using an appropriate method of randomisation to prevent selection bias (see Sect. 3 ). Each comparison group will be subjected to different interventions, at least one of which will be a control. The purpose of the control group is to allow the researcher to investigate the effect of a treatment and distinguish it from other confounding experimental effects. It is therefore crucial that any control group is treated exactly in the same way as the other comparison groups. Types of control group to consider include negative control, vehicle control, positive control, sham control, comparative control and naïve control ( Bate and Clark 2014 ).

2.3. Measurements and Outcome Measures

Measurements are taken to assess the results; these are recorded as outcome measures (also known as dependent variable). A number of outcome measures can be recorded in a single experiment, for example, if burrowing behaviour is measured, the outcome measure might be the weight of gravel displaced, or if neuronal density is measured from histological brain slides, the outcome measure might be the neuron count. The primary outcome measure should be identified in the planning stage of the experiment and stated in the protocol; it is the outcome of greatest importance, which will answer the main experimental question. The number of animals in the experiment is determined by the power needed to detect a difference in the primary outcome measure. A hypothesis testing experiment may also include additional outcome measures, i.e. secondary outcome measures, which can be used to generate hypotheses for follow-up experiments. Secondary outcome measures cannot be used to draw conclusions about the experiment if the experiment was not powered to detect a minimum difference for these outcome measures.

For the purpose of the statistical analysis, outcome measures fall into two broad categories: continuous or categorical. Continuous measures are sometimes referred to as quantitative data and are measured on a numerical scale. Continuous measures include truly continuous data but also discrete data. Examples of true continuous data include bodyweight, body temperature, blood/CSF concentration or time to event, while examples of discrete data include litter size, number of correct response or clinical score. Categorical responses are measured on a nonnumerical scale; they can be ordinal (e.g. severity score, mild/moderate/severe), nominal (e.g. behavioural response, left/middle/right arm maze) or binary (e.g. disease state, present/absent). Continuous responses may take longer to measure, but they contain more information. If possible, it is preferable to measure a continuous rather than categorical response because continuous data can be analysed using the parametric analyses, which have higher power; this reduces the sample size needed ( Bate and Clark 2014 ).

2.4. Independent Variables and Analysis

There are many ways to analyse data from in vivo experiments; the first step in devising the analysis plan is to identify the independent variables. There can be two broad types: independent variables of interest which the researcher specifically manipulates to test the hypothesis, for example, a drug with different doses, and nuisance variables, which are other sources of variability that may impact on the outcome measure, but are not of direct interest to the researcher. Examples of nuisance variables could be the day of the experiment, if animals used on different days, or baseline body weight or locomotor activity. Every experiment has nuisance variables. Identifying them at the protocol stage and accounting for them in the design and the analysis, for example, as blocking factors, or co-variables, increase the sensitivity of the experiment to detect changes induced by the independent variable(s) of interest. The analysis plan should be established before the experiment starts and any data is collected; it should also be included in the protocol. Additional analyses can be performed on the data, but if an analysis was not planned before the data was collected, it should be clearly reported as a post hoc or exploratory analysis. Exploratory analyses are at greater risk of yielding false positive results.

3. Experimental Biases: Definitions and Methods to Reduce Them

For any researcher who intends to carry out preclinical in vivo studies, it is important to understand what experimental biases are. First, we need to know the definition of bias. It is the inadequacies in the design, conduct, analysis or reporting of an experiment that cause systematic distortion of the estimated intervention effect away from the “truth” ( Altman et al. 2001 ; van der Worp et al. 2010 ), and it will significantly confound in vivo studies and reduce their internal validity. Sources of bias are multiple and in many cases context dependant. In this overview chapter, it is not possible to give an exhaustive list of potential sources of bias, and it behoves the researcher to systematically identify all potential significant sources of bias for the particular experiment being in planned and to design appropriate mitigation tactics into the protocol. Major known types of biases include selection bias, performance bias, detection bias, and attrition bias. Table 1 gives the definition of each type of bias and describe the methods to reduce them.

Researchers who conduct hypothesis testing in vivo animal work should understand the importance of limiting the impact of experimental biases in the design, conduct, analysis and reporting of in vivo experiments. Experimental biases can cause significant weakness in the design, conduct and analysis of in vivo animal studies, which can produce misleading results and waste valuable resources. In biomedical research, many effects of interventions are fairly small, and small effects therefore are difficult to distinguish from experimental biases ( Ioannidis et al. 2014 ). Evidence (1960–2012 from PubMed) shows that adequate steps to reduce biases, e.g. blinded assessment of outcome and randomisation, have not been taken in more than 20% and 50% of biomedical studies, respectively, leading to inflated estimates of effectiveness, e.g. in the fields of preclinical stroke, multiple sclerosis, Parkinson’s disease, bone cancer pain and myocardial infarction research ( Currie et al. 2013 ; Macleod et al. 2008 ; Rooke et al. 2011 ; Sena et al. 2007 ; van Hout et al. 2016 ; Vesterinen et al. 2010 ) and consequently significant research waste ( Ioannidis et al. 2014 ; Macleod et al. 2014 , 2015 ). Therefore, it is imperative that biomedical researchers should spend efforts on improvements in the quality of their studies using the methods described in this chapter to reduce experimental biases which will lead to increased effect-to-bias ratio.

However, it is worth pointing out that the notion that experimental biases could significantly impact on in vivo animal studies is often assumed because they are believed to be important in clinical research. Therefore, such an assumption may be flawed, as the body of evidence showing the importance of bias-reducing methods such as randomisation, blinding, etc. for animal studies is still limited and most of the evidence is indirect. Furthermore, there may also be sources of bias which impact on preclinical studies which are currently unknown. Thus, systematic review and metaanalysis of in vivo studies have shown that papers that do not report bias-reducing methods report larger effect sizes ( Vesterinen et al. 2010 ). However, these studies are based on reported data alone, and therefore there might be a difference between what researchers do and what they report in their publications ( Reichlin et al. 2016 ). Reporting of the precise details of bias reduction methods is often scanty, and therefore accurate assessment of the precise method and rigour of such procedures is challenging. Moreover, those papers that do not report one bias-reducing method, e.g. randomisation, also tend to not report other bias-reducing methods, e.g. blinding and sample size calculation, suggesting that there could be interactions between these methods.

4. Experimental Biases: Major Domains and General Principles

In this section, we will describe the major domains, in other words, sources that could contribute to experimental bias if not carefully considered and if mitigating tactics are not included in the design of hypothesis testing experiments before data collection starts. These include sample size estimation, randomisation, allocation concealment, blinding, primary and secondary outcome measures and inclusion/exclusion criteria. General descriptions for these domains ( Macleod et al. 2009 ; Rice et al. 2008 ; Rice 2010 ; van der Worp et al. 2010 ) are shown in the following Table 2 . It is important to note that these domains are key things to be included in a protocol as mentioned in Sect. 1 .

General principles to reduce experimental bias in each of the above-mentioned domains ( Andrews et al. 2016 ; Knopp et al. 2015 ) are outlined in the following Table 3 .

5. Existing Guidelines and How to Use Them

There are resources to assist investigators in designing rigorous protocols and identify sources of bias. Cross-referencing to experimental reporting guidelines and checklists (e.g. ARRIVE (NC3Rs 2018a) , the NIH guidelines ( NIH 2018a ) and the Nature reporting of animal studies checklist ( Nature 2013 )) can be informative and helpful when planning an experimental protocol. However, it is important to bear in mind that these are primarily designed for reporting purposes and are not specifically designed for use in assisting with experimental design. There are more comprehensive planning guidelines specifically aiming at early experimental design stage. Henderson et al. identified 26 guidelines for in vivo experiments in animals in 2012 ( Henderson et al. 2013 ) (and a few more have been published since, like PREPARE ( Smith et al. 2018 ), developed by the NORECEPA (Norway’s National Consensus Platform for the advancement of the 3Rs), and PPRECISE for the field of pain research ( Andrews et al. 2016 )). Most of them have been developed for a specific research field but carry ideas and principles that can be transferred to all forms of in vivo experiments. Notable are, for example, the very detailed Lambeth Conventions ( Curtis et al. 2013 ) (developed for cardiac arrhythmia research), from Alzheimer’s research recommendations by Shineman et al. (2011) and generally applicable call by Landis et al. (2012) .

The authors of many of these guidelines state that their list might need adaption to the specific experiment. This is pointing out the general shortcoming that a fixed-item list can hardly foresee and account for any possible experimental situation and a blind ticking of boxes ticking of boxes is unlikely to improve experimental design. Such guidelines rather serve an educational purpose of making researchers aware of possible pitfalls and biases before the experimental conduct.

Two examples for a more adaptive and reactive way to serve a similar purpose should be stated: the NIH pages on rigour and reproducibility ( NIH 2018b ) provide in-depth information and collect important publications and workshop updates on these topics and have a funding scheme specifically for rigour and reproducibility. Second, using the Experimental Design Assistant (EDA) ( NC3Rs 2018b ; Percie du Sert et al. 2017 ) developed by the UK’s National Centre for the 3Rs (NC3Rs), a free to use online platform guiding researchers through experimental planning will give researchers the opportunity to adopt guideline and rigour principles precisely to their needs. The researcher creates a flow diagram of their experimental set-up grouped in three domains: the experiment (general questions on hypotheses and aims, animals used, animal strains, etc.), the practical steps (experimental conduct, assessment, etc.) and the analysis stage (e.g. outcome measures, statistical methods, data processing). Unlike a fixed checklist, the EDA checks the specific design as presented by the experimenter within the tool using logic algorithms. The user is then faced with the flaws the EDA identified and can adjust their design accordingly. This process can go through multiple rounds, by that forming a dynamic feedback loop educating the researcher and providing more nuanced assistance than a static checklist can.

While this process, however valid, might take time, the following steps of the EDA actively guide researchers through crucial and complex questions of the experiment, by suggesting fitting methods of statistical analyses of the experiment and subsequently carrying out sample size calculations. The EDA can then also generate a randomization sequence or compile a report of the planned experiment that can, e.g. be part of a preregistration of the experimental protocol.

6. Exploratory and Confirmatory Research

It is necessary to understand that there are in general two types of preclinical research, namely, exploratory and confirmatory research, respectively. Figure 1 shows that exploratory studies mainly aim to produce theories regarding the pathophysiology of disease (hypothesis generating), while confirmatory studies seek to reproduce exploratory findings as clearly defined intervention effects in relevant animal models (hypothesis testing). The next chapter will deal with exploratory and confirmatory studies in details. Similar standards of rigour are advisable for both forms of studies; this may be achieved by conforming to the general principles for the major domains that are outlined in Table 2 and incorporating these principles into a protocol that can be registered and published. It is important to note that both exploratory and confirmatory research can be closely linked: sometimes there can be exploratory and confirmatory components within the same studies. For example, a newly generated knockout mouse model is used to examine the effect of knockout on one specific phenotype (hypothesis testing–confirmatory) but may also describe a variety of other phenotypic characteristics as well (hypothesis generating–exploratory). Therefore, extra care in terms of applying these principles to reduce experimental bias would be needed before the commence of the studies. It also worth noting that sometimes it might not be compulsory or necessary to use some of the principles during exploratory studies such as sample size estimation and blinding which are albeit of highest importance in confirmatory research.

However, it is necessary to recognise how hypothesis confirming and hypothesis generating research relate to each other: while confirmatory research can turn into exploratory (e.g. if the findings are contrary to the hypothesis, this can lead to a new hypothesis that can be tested in a separate experiment), under no circumstances exploratory findings should be disseminated as the result of hypothesis confirming research by fitting a hypothesis to your results, i.e. to your p -values (often called HARKing = hypothesising after results are known or p -hacking = sifting through a multitude of p -values to find one below 0.05).

In conclusion, this chapter provides general concepts and principles that are important for the design and conduct of preclinical in vivo experiments, including experimental biases and how to reduce these biases in order to achieve the highest levels of rigour for hypothesis generating research using animals. The chapter should be used in conjunction with other relevant chapters in the handbook such as chapters “Blinding and Randomization”, “Minimum Information and Quality Standards for Conducting, Reporting, and Organizing In Vitro Research”, “Minimum Information in In Vivo Research”, “A Reckless Guide to P -Values: Local Evidence, Global Errors”, and “Quality Governance in Biomedical Research”.

Contributor Information

Wenlong Huang, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

Nathalie Percie du Sert, NC3Rs, London, UK.

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Creating a Clinical Development Plan After Clinical Research Training

September 6, 2022

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If you’re getting started in the clinical research program at AAPS, you can expect to cover the organization of clinical trials as well as the development and monitoring of a clinical plan. To get you started, here are some key things to consider when creating a clinical development plan. 

Consider the Goals and Life Cycle of a Clinical Product 

A good CDP starts by defining the product profile : the reason for producing the product and its intended effect. From there, you can set the goals and objectives for the clinical development of a product. The CDP needs to cover the different stages of a clinical trial, with plans to evaluate and assess the original goals at each stage. 

Generally, pharmaceutical companies will be seeking new drug solutions to an existing or growing health problem. In that case, the CDP will need to consider the relative goals of the new product compared to other products out there. It will also rely on scientific data to set the minimum requirements for safety and efficacy. 

Using practical and current real cases, AAPS provides students in clinical research courses with the foundation and practical knowledge to build the framework of a sound clinical development plan. 

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A good clinical development plan should lay out the goals of the new product

Use Your Regulatory Knowledge from Clinical Research Courses 

The ultimate aim of a clinical development plan is to obtain regulatory approval for a new pharmaceutical product. That means an understanding of current regulatory standards is essential, including those relating to:

  • The safety & maintenance of research sites
  • The consent of trial subjects
  • The qualifications of clinical personnel 
  • Record-keeping 

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A CDP aims to get regulatory approval for a new product

A good clinical development plan needs to account for the legal parameters surrounding a clinical research project and makes it clear what documentation is needed at each stage. This will ensure that a trial can go ahead as planned and that its results are deemed valid. Clinical research training at AAPS will focus on the Canadian regulatory agencies, as well as international guidelines and standard operating procedures. Students will learn about the required documentation for a clinical development plan to ensure compliance at every stage.

clinical research courses

Clinical research training will teach you about regulatory standards for a CDP

Include Estimates for Project Resources 

Clinical trials are long and costly procedures. To ensure they run smoothly, it’s important to develop a plan that accounts for the time and money that needs to be spent on each stage of the trial. This includes:

  • The hiring of personnel 
  • Deadlines for decision-making
  • The estimated cost 
  • Timelines for post-approval activities 

With a clear CDP, clinical professionals can ensure they are on schedule for the trial, approval, and release of new products. At AAPS, you’ll cover on-site budget management for a clinical research project, including planning and preparing costs for each stage.

Are you interested in earning your clinical research diploma ?

Contact AAPS to learn more about our program. 

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Research Strategic Plan

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In 2019, the Department of Medicine invested considerable effort and resources to devising a strategic plan that will provide a roadmap for our research mission today and into the future.

This work was guided by a Research Planning Committee that convened throughout the first half of 2019, reviewing the current state of research in the Department, generating recommendations for strengthening our research efforts, and developing the following plan. Many of our faculty and research administrators participated and contributed ideas as part of this process—through interviews, a survey, and robust discussions at the 2019 Research Retreat.

The result of this combined effort is the clear, direct, ambitious, and ultimately achievable research strategic plan that follows.

We identified five strategies for achieving our vision.

We will foster the success of our current faculty by enhancing our faculty development, mentoring, and funding programs while also strengthening the pipeline of the next generation of outstanding investigators in Medicine.

Lead: Andrew Alspaugh, MD

Initiatives:

  • Strengthen faculty career development programs (Xunrong Luo, Matthew Crowley)
  • Build a diverse and inclusive Department of Medicine (Laura Svetkey, Julius Wilder)
  • Foster a culture of outstanding mentorship in the Department (Alspaugh, Cathleen Colon-Emeric)
  • Expand physician-scientist recruitment and programmatic support (Rodger Liddle, Matt Hirschey)
  • Launch a Department partnership hires program (Xunrong Luo, Chris Holley)
  • Expand cadre of independent PhD investigators (Scott Palmer, Amy Porter-Tacoronte)

We will enhance our partnerships with other departments, centers, institutes, schools, and programs across Duke University.

Lead:  David Simel, MD, vice chair for veterans affairs

  • Duke Clinical Research Institute
  • Duke Cancer Institute
  • Durham VA Medical Center
  • Duke Molecular Physiology Institute
  • Pratt School of Engineering and MEDx
  • Duke Human Vaccine Institute
  • Duke Global Health Institute
  • Center for Applied Genomics and Precision Medicine

We will solidify a leadership position in data science by leveraging the clinical disease expertise of our faculty; building our data assets; and improving our data collection, storage and analytics resources.

Lead: Chetan Patel, MD, vice chair for clinical affairs

  • Cultivate DOM data assets into open science platform
  • Augment biostatistics & bioinformatics resources
  • Create new leadership role for data science
  • Implement learning health units
  • Continue implementation of Science Culture and Accountability Plan

We will foster a community and culture of rich scientific investigation by making research easier while achieving the highest levels of research integrity.

Lead: Erica Malkasian

  • Provide outstanding grants and administrative support to investigators
  • Position Duke as a leader in site-based research
  • Develop next-generation biorepository capabilities
  • Catalyze innovation and entrepreneurship
  • Expand international research efforts

We will invest in emerging research content and method areas that leverage our strengths and address important unmet patient-centered medical needs.

Lead: Heather Whitson, MD

Cross-cutting themes:

  • Immunology, inflammation & fibrosis
  • Aging, resilience & pain
  • Energy, obesity & metabolic disease
  • Precision medicine
  • Population health & disparities research

To learn more about our research strategies and initiatives, contact

  • Scott Palmer, MD, MHS, Vice Chair for Research
  • Saini Pillai, MBA, Senior Program Coordinator, Research

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  • Review Article
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  • Published: 04 March 2024

New clinical trial design in precision medicine: discovery, development and direction

  • Xiao-Peng Duan   ORCID: orcid.org/0000-0002-2421-1756 1   na1 ,
  • Bao-Dong Qin 1   na1 ,
  • Xiao-Dong Jiao 1   na1 ,
  • Ke Liu 1   na1 ,
  • Zhan Wang 1   na1 &
  • Yuan-Sheng Zang 1  

Signal Transduction and Targeted Therapy volume  9 , Article number:  57 ( 2024 ) Cite this article

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  • Cancer genomics
  • Diagnostics
  • Drug development
  • Molecular medicine
  • Outcomes research

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the “Precision Pro”, “Dynamic Precision”, and “Intelligent Precision”. This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

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Pharmacogenomics: current status and future perspectives

Munir Pirmohamed

Introduction

In 2003, the human genome project (HGP) was completed, leading to a deeper understanding of clinical medicine. The accomplishment of HGP has been considered as the cradle of precision medicine. 1 In 2011, the National Research Council of the United States proposed the concept of “precision medicine” in the article “Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Human Disease”. In 2015, Barack Obama launched the precision medicine initiative as a bold new research effort to revolutionize health and disease treatment. This program promoted the rapid dissemination of precision medicine worldwide. 2 Moreover, the availability of high-throughput gene sequencing technology, 3 as well as the importance of proteomics, metabolomics, transcriptomics, and epigenetics spurred interest in thoroughly understanding human disease, 4 , 5 , 6 , 7 , 8 eventually accelerating the development of precision medicine. Precision medicine has been defined in a variety of ways depending on the perspective of researchers. Commonly, precision medicine is defined as an evolving approach to disease prevention and treatment that incorporates an individual’s genetic, environmental, and lifestyle factors. 9 This strategy yields useful information that moves from the conventional “one-size-fits-all” approaches to selective approaches governed by individual variability. 10 This novel healthcare model has the capacity to facilitate the efficient and accurate identification of the optimal care for individual patients. Although the definition has evolved over several years, genomics information often serves as the basis of precision medicine and is used to develop individualized precision management, especially for precision treatment. 11

Traditionally, clinical treatment strategies have been approved based on average-population-benefit decisions derived from the randomized clinical trials of unselected patients, which were the cornerstone of traditional drug approvals. Tissue-of-origin trials are drug-centered, which refers to investigations that provide one drug to all patients. Patients are selected for trial inclusion based on commonalities such as disease. However, as multi-omics sequencing technology has developed and become widely used, it has been increasingly recognized that individuals with certain diseases are complex and different from each other. 12 , 13 Due to the significant heterogeneity of participants enrolled in traditional “one-size-fits-all” trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed. With increased interest and effort being put toward patient-centered trials, it is essential to recognize the importance of genomic alterations and further develop biomarker-guided therapies in clinical trials. 14 Significant methodological advances in biomarker-guided clinical trial designs have been made toward patient-centered trials, including the basket, umbrella, and platform trial designs under the master protocol framework. 15 , 16 A master protocol refers to a single, overarching design that can assess multiple hypotheses with the general goal of improving efficiency and constructing uniformity through standardized trial procedures during the development and evaluation of different interventions. 17 Master protocols are often divided into three new trial designs: basket, umbrella, and platform trials. A basket trial refers to using the same drug or intervention to treat patients who share a common characteristic, such as a genetic alteration or a specific biomarker. 18 Currently, basket trials are commonly used in the field of precision oncology, and they have been formulated to investigate the efficacy of molecular-targeted therapies for oncogene-defined subsets of cancers across different tumor histologies. 19 , 20 , 21 An umbrella trial refers to designs where multiple therapies or interventions for patients with a certain disease are stratified into subgroups according to different characteristics that include clinical features and molecular alternations. 15 , 20 In 2018, the Food and Drug Administration (FDA) released a guidance document describing recommendations for basket and umbrella trials, providing support for these new designs. A recent investigation found that the number of basket and umbrella trials has rapidly increased, suggesting a wider dissemination of these trial designs. 22 Both basket and umbrella trials use a molecular screening protocol that either permits the enrollment of different diseases with a certain characteristic or a certain disease with different subtypes. However, both of these trials were designed using a fixed protocol at a specific time point. This fixed model greatly limits the efficiency of clinical trials with the rapid development of precision medicine, requiring a new clinical trial design that would be adaptable and responsive to emerging evidence. Hence, a new trial design called the platform trial has recently been proposed, which could be used to greatly accelerate the efficiency of clinical trials. Platform trials, also referred to as multi-arm, multi-stage design trials, are trials that continuously assess several interventions against a certain disease and adapt the trial design based on the accumulated data. 23 , 24 This design allows for the early termination of ineffective interventions and flexibility in adding new interventions during the trial.

Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research has focused on methodologies, but there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. We then discuss the future directions of these new trial designs in view of the “precision pro”, “dynamic precision”, and “intelligent precision”. By expounding the underlying logic, this review aims to assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs. This review will also support cancer research-related scientists in understanding the logic of clinicians, thereby improving the transformation efficiency.

Discovery: clinical dilemma prompting an exploration of new biomarker-guided trial design

The current landscape of precision medicine was established based on the understanding of potential molecular phenotypes in diseases and attempts to target these molecular phenotypes (Fig. 1 ). The development of precision medicine was driven by the mapping of the human genome and the maturity of next-generation sequencing (NGS). 25 , 26 Advancements in sequencing technologies have significantly improved the ability to rapidly and comprehensively identify genetic phenotypes. In particular, recent high-throughput next-generation sequencing advancements have promoted the rapid and simultaneous detection of all types of gene alterations, mainly including gene mutations, rearrangements, and copy number changes. 27 , 28 This has fueled more efforts towards precision medicine, in which therapies are chosen in accordance with genetic alterations. These innovative treatments are commonly referred to as biomarker-guided therapies, and an increasing number of diseases may derive clinical benefits from this strategy. For example, a prospective clinical sequencing project of 10,000 patients led by the Memorial Sloan-Kettering Cancer Center (MSKCC) showed that there are potentially treatable genetic changes in over 36% of patients with advanced cancers. 29 In addition, innovations in the development of drugs that target specific disease-driving gene alterations have accelerated the introduction and expansion of biomarker-guided therapies. Historically, this treatment strategy originated in oncology and has evolved and matured in the field of precision oncology. It is now also applied in multiple other clinical scenarios, such as diabetes, cardiovascular, kidney, and neurological diseases. 30 , 31 , 32 , 33

figure 1

The biological logic of new biomarker-guided clinical trial design in precision medicine. The essence of precision medicine is to explore the unknown relationship between drugs, targets, and diseases in the human body. The left and right arms represent the drugs and diseases, respectively. The circles distributed throughout the lungs and body represent the therapeutic targets. The world of precision medicine in human body is an undeveloped ocean, containing extensive therapeutic targets represented by colorful circles based on next-generation sequencing and other biological technologies. The diseases such as lung cancer are classified into different subtypes based on different therapeutic targets. The molecular subtype-guided therapy in a certain disease is the biological logic of umbrella trial design. A certain target may appear in the lungs and other parts of the body with similar biological characteristics. Based on the successful treatment experience of lung cancer, exploring the therapeutic potential of a certain target for the disease of other body parts is the underlying logic of the basket trial design. The dynamic concept conveyed by the diffuse distribution of circles in the ocean is the core of platform trial design. The biomarker-guided ship of precision medicine clinical trial design is constantly advancing, riding the wind and waves in the undeveloped ocean of precision medicine

The proof-of-concept for biomarker-guided therapy was initiated from the success of imatinib for patients with chronic myelogenous leukemia (CML) harboring the BCR-ABL translocation. This genomic-driven targeted therapy resulted in a remarkable survival improvement, leading the life expectancy of patients with CML to approach that of the general population. 34 Subsequently, drugs targeting the EGFR, ALK, ROS1, MET-mutant lung cancer, HER2-overexpression breast cancer and gastric cancer, and BRAF V600E mutant melanoma have dramatically improved the prognosis of these patients. These significant clinical benefits from therapies that target patient genomic aberrations have propelled a paradigm of choosing therapy strategies based on an individual’s molecular profile. Subsequent clinical trials have begun to enroll patients based on their genetic phenotypes, and many standardized biomarker-guided treatment protocols have been developed from these clinical trials. For instance, evidence from several large-scale clinical trials has promoted first/second/third EGFR-tyrosine kinase inhibitor (TKI) as the standard-of-care among non-small-cell lung cancer (NSCLC) patients with EGFR-sensitive mutation. 35 , 36 , 37

However, some standard regimens, even under the guidance of phase III clinical trials, have fallen far behind the growing therapeutic demand. The difficulties associated with the approvals of new drugs, as well as the long duration of these processes, also exacerbate the dilemma. 38 , 39 In addition, conventional trial designs cannot be used to assess the efficacy of one regimen across different diseases or that of multiple regimens in a certain disease but with different features. Therefore, the efficient exploration of new trial designs on the therapeutic potential of drugs is a concern for trial-related clinicians and researchers. Master protocol frameworks have been proposed as a vital strategy to comprehensively and adaptively evaluate treatments in precision medicine. 15 , 16 A typical representative model of a master protocol has emerged that includes basket, umbrella, and platform trials (Fig. 2 ). 15 , 16 Recently, the number of these new trial designs has increased dramatically, and it is assumed that this trend will persist in the following years. 22

figure 2

The pattern of the basket, umbrella, and platform trial design. The basket trials aim to evaluate the efficacy of a certain biomarker in multiple diseases or different tissue types (such as cancer). Recruitment is completed by screening patients with the same therapeutic target through next-generation sequence and other biologic technologies. The umbrella trials aim to reclassify a certain traditional disease type based on potential therapeutic biomarkers. Recruited patients are assigned to different molecular subgroups and matched with corresponding drugs. The platform trials aim to continuously screen biomarkers and drugs for a certain disease. The biomarker subgroups and treatment types are dynamically added or removed under the constraints of the master protocol. At the initial stage, screening for biomarkers such as A, B, C, and negative, is conducted and patients are assigned to the biomarker-guided cohorts. Considering that each target may correspond to multiple drugs, a control group and one to multiple experimental groups (drug 1 and 2 in biomarker A group, drug 3 in biomarker B group, drug 4 in biomarker negative group) are set up in each cohort. If the experimental drug 2 is more effective than the current standard therapy of biomarker A group, it will replace the original standard as the new control group. During the course of trials, new treatment cohorts can be included in the corresponding biomarker-guided group if new drug 5 or 6 are available. When new biomarker D and corresponding drug 7 are available, the new biomarker D-guided group will be established. If a biomarker-guided group currently lacks standard control treatment, a single experimental group with efficacy termination threshold set is considered feasible

Basket trial design guided by the pan-cancer proliferation-driven molecular phenotype

In oncology research, therapies based on similar molecular alterations distributed in different anatomical cancer types accelerate the clinical expansion of antitumor drugs, such as the approval indications of imatinib across multiple cancer types and the progress of the molecular analysis for therapy choice (MATCH) plan that matches drugs with molecular phenotypes. 40 , 41 , 42 , 43 Specifically, in 2014, the American Association for Cancer Research (AACR) proposed the “basket trial”, a phase II clinical trial that classifies treatments according to the universal and proliferation-driven molecular phenotype rather than pathology. The principle of a basket trial design is derived from a deep understanding of the pan-cancer proliferation-driven molecular phenotype.

The overexpression of HER2 in breast and bladder cancers is associated with chemotherapy resistance, elucidating the pan-cancer proliferation-driven molecular phenotype. In 1987, Di Fiore et al. discovered the proto-oncogenic effect of HER2 protein. 44 The amplification or overexpression of HER2 was identified in 20–30% of patients with breast cancer and was associated with a lower chemotherapy remission rate and duration than those in patients with HER2-negative disease. 45 , 46 , 47 Fortunately, anti-HER2 therapy combined with chemotherapy has been shown to prolong the duration of response and overall survival of breast cancer patients with HER2 overexpression for three and five months, respectively. 48 Similarly, the rate of strong HER2 membrane staining (IHC2 + /3 + ) in advanced bladder cancer has been reported to be ~26%, which is similar to that in metastatic breast cancer, and chemotherapy resistance has been reported. 49 The addition of trastuzumab to chemotherapy has been shown to significantly reduce the tumor size of bladder cancer with HER2 overexpression. 50 Faced with the same biological characteristics and therapeutic prognosis among different tumor species, researchers have become aware of the cross-tumor proliferation-driven capability of this particular molecular phenotype, and they have begun to explore the therapeutic value of HER2 overexpression in pan-cancer. Inevitably, the amplification or overexpression rates of HER2 in ovarian, endometrial, pancreatic, colon, gastric, small cell lung, renal, and prostate cancers ranges from ~10–40%, and the standardized evaluation result of pan-cancer is similar. 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 Furthermore, anti-HER2 combined with chemotherapy has been reported to achieve objective response rates (ORR) of 7.3%, 24.5%, and 47% in patients with HER2 overexpression in ovarian cancer, NSCLC, and gastric and gastroesophageal junction cancers, respectively. 58 , 60 , 61 , 62 The “single-target to multi-drugs” model, which extended the benefits of chemotherapy-refractory HER2 overexpression in breast and bladder cancers to pan-cancer, was the prototype for the basket trial.

The comparison between the limited efficacy of chemotherapy, non-ALK-TKI therapy, and the high effectiveness of ALK-TKI therapy indicated the dominant proliferation-driven position of ALK fusion mutations in lung cancer, which, in basket trials, was the key condition for using ALK inhibitors alone without chemotherapy. The ALK mutation was initially identified in anaplastic large-cell lymphoma and was named “ALK lymphoma” based on the morphological homogeneity. 63 , 64 However, because of the preferred chemotherapy response of lymphoma and a lack of awareness of the proliferation-driven molecular phenotype, the therapeutic value of the ALK fusion mutation remained unknown until the ALK-EML4 fusion was distinguished in NSCLC in 2007. 65 The limited remission rates of conventional therapies indicate that ALK fusion mutations have powerful proliferation-driven capacities beyond growth factors and cell division signals. 66 , 67 Indeed, this was confirmed by the excellent 57% ORR following treatment of ALK fusion NSCLC with ALK inhibitors. 68 In 2012, the concept of “ALKoma” to define solid tumors with ALK mutations was proposed, where the ALK fusion mutation was recognized as a pan-cancer therapy goal due to its strong proliferation-driven ability. The ALK inhibitor, crizotinib, achieved 90% and 86% ORR and 80% and 36% complete response in anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastoma (IMT), respectively. 69 Subsequently, ALK inhibitors were shown to be effective in malignant peritoneal mesothelioma, neuroblastoma, renal cell carcinoma, colorectal cancer, and melanoma. 70 , 71 , 72 The high remission rate of ALK inhibitors for ALK-driven NSCLC, ALCL, and IMT unlocked the “single-target to single-drug” model in the epoch dominated by chemotherapy, which was the most typical pattern of basket trials.

Considering the clinical bottleneck of poor response to conventional treatment as an opportunity, the basket trial identified the qualitative and quantitative proliferation-driven ability of the molecular phenotype in different tumor species and extended its application to pan-cancer. In contrast to traditional targeted therapy that focuses on the targets in one specific disease, basket trials pay more attention to the commonalities of targets in pan-cancer. The off-label attempt of basket trials brings hope to patients faced with the treatment dilemma. In addition, basket trials may provide initial proof-of-principle evidence for the clinical treatment potential of newly discovered disease-driven targets, especially for uncommon or orphan gene alternations. 73 Moreover, the emergence of basket trials has made it possible to conduct drug development for low-frequency gene alternations that have been previously unexamined. For example, in 2018, a basket trial first demonstrated that larotrectinib had a remarkable and durable antitumor activity among patients with tropomyosin receptor kinase (TRK) fusion-positive cancer, regardless of the histology and age. 74 Furthermore, a basket trial also allows for the initial screening of potential efficacy of a regimen to target specific alterations across multiple tumor types in order to guide subsequent disease-specific traditional trials. In a basket trial for vemerafinib in BRAF V600E-mutated pan-cancer, the results showed that vemerafinib showed activity in NSCLC and other histologies, but not in colorectal cancer. 75 A follow-up conventional trial was then conducted separately in an NSCLC cohort with a large sample size. 76 Finally, a basket trial can yield vital data to support a new standard regimen for rare cancers with specific targets. A basket trial reported in 2015 was the first to elucidate the efficacy of anti-BRAF therapy in patients with Erdheim-Chester disease and Langerhans cell histiocytosis and BRAF V600E. 75 Previously, these two types of cancers lacked a standard recommendation, whereas this basket trial established a standard regimen for these diseases. Depending on a high enrollment efficiency across tumor anatomical species, the basket trial has been recognized by the FDA as an effective pathway for approving rare antitumor therapies. 77 In the past 6 years, pan-cancer indications for pembrolizumab, larotrectinib, entrectinib, selpercatinib, dorstarlimab-gxly, envafolimab, serplulimab, dabrafenib, and trametinib have been approved in succession, 72 , 74 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 indicating that basket trials are ushering in great opportunities.

Although basket trials are less common in nononcology fields, the concept of basket trials has also been applied to other nononcology diseases, including Alzheimer’s disease, 89 , 90 vasculitides, 91 metabolic diseases, 92 , 93 and infectious diseases. 94 , 95 For example, basket trials have been used in the assessment of the effectiveness of interventions that focus on specific pathophysiological mechanisms in Alzheimer’s disease. It should be emphasized that the utilization of basket trials in the nononcology field is currently constrained, and additional investigation is required to investigate the particular advantages and challenges that pertain to these fields.

Umbrella trial design guided by molecular phenotypes of a certain disease

Due to shared genetic alterations across different cancer types, the basket trial design was developed with the core theme of “treating different diseases with the same treatment”. In contrast, the umbrella trial design was developed with the core theme of “treating the same disease with different treatments” due to the different molecular phenotypes of a certain disease. 16 Thus, the umbrella trial was designed to evaluate multiple interventions within a particular disease in a single trial. The principle of the umbrella trial design stems from a deep understanding of disease heterogeneity, including genomic heterogeneity and clinical phenotypic diversity. 15 , 20 For example, lung cancer was initially treated as a whole, but with varying outcomes. The treatment outcomes of lung cancer were then significantly improved by using different treatment approaches when lung cancers were categorized into different subtypes that included adenocarcinoma, squamous cell carcinoma, and small cell lung cancer. In the era of precision medicine, various gene mutations associated with lung adenocarcinoma, such as EGFR, ALK, MET, and ROS1, have been observed, and remarkable efficacy improvements by administering targeted therapies based on specific gene mutations have been achieved. 96 , 97 Previously, a single traditional trial targeting a specific genetic phenotype or clinical characteristic was conducted, which was time-consuming and hindered the rapid clinical application of effective drugs or interventions. Umbrella trials have effectively addressed this issue.

Although the AACR formally proposed the “umbrella trial” concept in 2014, this trial design had been employed for a long time prior to this event. In 2006, the biomarker-integrated approaches of targeted therapy for lung cancer elimination (BATTLE) trial was initiated, which was a landmark umbrella trial in the field of precision oncology. The BATTLE trial was designed to evaluate multiple targeted therapies simultaneously in patients with NSCLC based on individual specific molecular profiles. 98 All patients with NSCLC were assigned into four subgroups: KRAS/BRAF mutation, VEGF/VEGFR2 overexpression, RXR/CyclinD1 overexpression/CCND1 amplification, as well as EGFR alteration) to test the efficacy of the specific targeted therapy. BATTLE was the first umbrella trial to identify which treatments were most effective for specific genetic subgroups using a biomarker-driven approach. The successful implementation of early umbrella trials showcased the efficiency of this trial design in the era of precision medicine, subsequently leading to the initiation of numerous similar design trials. 99 , 100 , 101 , 102 These trials showed the potential of umbrella trial designs to enhance the efficiency and effectiveness of clinical trials in the pursuit of precision medicine and to improve cancer treatments.

With advancements in precision medicine, there was a growing recognition that a one-size-fits-all strategy may not be suitable for all patients with a certain disease. The umbrella trial is a model that embodies the concepts of precision medicine and epitomizes the efficient implementation of precision medicine. 20 , 103 , 104 Umbrella trials allow for the assessment of personalized treatment strategies by considering the specific characteristics or biomarkers of each patient. Additionally, as a valuable trial design, the umbrella trial design also addresses several issues in conventional trials. First, the diversity of diseases, also called heterogeneity, is under consideration in umbrella trials. An increasing number of diseases have been shown with significant heterogeneity, including different disease subtypes and molecular phenotypes. Typically, patients with a certain disease are enrolled into the arm that is most appropriate for their specific characteristics under a prespecified treatment arm design. Each arm is evaluated separately, and the trial may have a hierarchical statistical analysis plan to compare the effectiveness of different interventions against a common control group or standard-of-care. Second, the efficiency and resource optimization of clinical trials in precision medicine are improved. Umbrella trials provide a highly efficient method to evaluate multiple interventions simultaneously in a single trial. By incorporating multiple treatment options, investigators can collect comparative efficacy data rapidly and without the requirement for separate trials for each intervention. In addition, in traditional trials, it is expensive and time-consuming to perform individual trials for each intervention. In contrast, umbrella trials allow for the shared utilization of infrastructure, resources, and patient populations, resulting in cost and time efficiencies. Moreover, new effective biomarker-guided therapy regimens can be discovered using umbrella trials for one specific disease and can then be expanded to other types of diseases using basket trials, thus achieving the maximization and optimization of precision medicine.

In addition to basket or umbrella trial designs alone, the exploration of the combination of basket trials with umbrella trials has been an ongoing area of interest in precision medicine. The pooled objective of integrating these two trial designs is to develop a more comprehensive and personalized approach to select the optimal treatment. By incorporating the basket trial concept within an umbrella trial framework, investigators can assess multiple regimens simultaneously across different tumor types and genetic alterations. The MATCH conducted by the National Cancer Institute (NCI) was a notable trial design that integrated basket and umbrella trial designs; patients with refractory cancer were assigned to different subgroups according to the specific molecular alteration. 105 , 106 Since 2015, NCI-MATCH has been in progress, with the primary objective of assessing a tumor-agnostic approach in the selection of treatments based on genetic alteration. To date, there are nearly 37 molecular subgroups in the NCI-MATCH trial, which is considered the largest umbrella trial worldwide. In 2022, FDA grants accelerated the approval of dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with the BRAF V600E mutation, which was supported by data from the NCI-MATCH trial. 86 Nevertheless, it is crucial to note that this combination design is still the subject of ongoing trials led by governmental institutions, and further studies are required to fully understand and maximize its value in precision medicine.

Platform trial design guided by the dynamic perspective of precision medicine

Both basket and umbrella trials are revolutionary innovations for the accelerated development of precision therapeutic drugs and the advancement of precision medicine. Basket and umbrella trials have significantly accelerated drug development or drug indication approvals, but they rely on drugs (or interventions) that are limited to a certain time point, resulting in lack of dynamic adaptation to the latest evidence. In the era of precision medicine, the importance of a dynamic perspective is increasingly emphasized in view of disease evolution and the rapid emergence of novel drugs (or interventions), thus giving rise to new clinical trial designs called platform trials. A platform trial is a flexible and adaptive clinical trial design that allows for the simultaneous evaluation of multiple interventions or treatment strategies against a single control arm for a specific disease within a unified framework. 23 , 24 Within the prespecified protocol, it is possible to add interventions that show promise or remove ones with insufficient evidence of activity over time, enabling ongoing evaluation and optimization based on innovative and emerging scientific knowledge or advancements in treatment strategies. 107

The primary advantages of platform trials are flexibility, adaptability, and the capacity to dynamically adjust trial designs based on accumulating evidence throughout the trial. For example, the STAMPEDE trial, initiated in 2005, was the first multi-arm platform trial conducted in high-risk localized or metastatic prostate cancer. 108 The last patient for the STAMPEDE trial was recruited on March 31, 2023, marking the official completion of the largest platform trial, which enrolled nearly 12,000 participants and lasted for 18 years. A notable feature of the STAMPEDE trial was its adaptive design. Although only six arms were included in STAMPEDE when it was initiated in 2005, nearly 11 interventions had been investigated when the trial was closed in 2023. This trial generated significant research findings that resulted in treatment-changing guidelines for patients with advanced prostate cancer. For instance, the STAMPEDE trial demonstrated the benefits of adding docetaxel chemotherapy, abiraterone acetate, and androgen deprivation therapy (ADT) to the standard-of-care for improving overall survival, all of which were then cited into the guidelines for prostate cancer as the recommended stand-of-care. 109 , 110 , 111 Moreover, platform trials often incorporate a biomarker-guided approach in which patients are stratified according to specific molecular genotype or genetic alteration. This feature enables the evaluation of interventions in selected patient populations, eventually leading to personalized treatment approaches. For example, the GBM-AGILE is a novel multi-arm platform trial designed to evaluate a therapy based on biomarker status, including the EGFR alteration and the MGMT promoter methylation status, among patients with glioblastoma. 112

A platform trial design exhibits several advantages for clinical investigation in precision medicine. 113 , 114 , 115 First, similar to umbrella trial design, the platform trial design offers clinical investigation efficiency by assessing multiple interventions simultaneously within a single trial. This design accelerates the research process as well as reduces the duplication of efforts, eventually optimizing resource utilization. Second, platform trials facilitate rapid learning and informed decision-making by continuously monitoring and analyzing interim data of the trial and external emerging evidence. This allows for the timely adjustment of treatment strategies, interventions, and trial processes. Third, platform trials offer improvements in statistical power. Platform trials require larger sample sizes because they evaluate multiple interventions, which can enhance the accuracy for estimating treatment effects and enable the detection of smaller but clinically significant differences. Finally, platform trials promote collaboration and data sharing among researchers and clinicians. For example, 165 researchers e STAMPEDE trial. In addition, the standardization of data collection methods and data transparency in single trials could further improve trial quality and facilitate the rapid approval of research protocols. In summary, the above features render platform trials an innovative and effective approach for clinical trials in precision medicine.

Development: excavating therapeutic potential according to new biomarker-guided clinical trial design

The clinical popularization of NGS has revealed an abundance of potential therapeutic targets. However, it is unknown whether targeted therapy can achieve clinical benefits. The new clinical trial design guided by biomarkers efficiently explores the therapeutic potential of emerging gene-variation data. Based on the logic of drug-target relationships, tumor molecular typing, and dynamic changes, this paper summarizes the development achievements of basket, umbrella, and platform clinical trials.

Basket trials unearthing the pan-cancer therapy of existing drugs based on the drug-target relationship

Based on the drug-target relationship, basket theory provides “targets search drugs” and “drugs identify targets” as two methodology models, extending drug indications for confirmed proliferation-driven targets and potential targets for proven effective drugs across different tumor species.

Targets search drugs

The “targets search drugs” mode of basket theory focuses on targets with confirmed pan-cancer independent proliferation-driven ability, such as receptor tyrosine kinase families (e.g., EGFR, HER2, MET, and FGFR) and their downstream MAPK/PI3K pathway trunk signals (KRAS, BRAF, MEK, PI3K, AKT, and mTOR), and CDK4/6. Therefore, as long as potentially beneficial cancer species are identified, researchers can directly search for the corresponding drugs after detecting the targets (Fig. 3 ).

figure 3

The efficacy and approval status of common targeted drugs in different tumor species. The number represents the ORR of drugs in different tumor species, with red indicating high response rates and blue indicating low response rates. The pentagram represents that the drug indication in a certain tumor species has been approved by FDA

The “targets search single-drug” mode is undoubtedly the most classic pan-cancer treatment of the basket trial. By visually demonstrating the response rate and potential beneficial cancer species of common targeted drugs, we aim to assist cancer-related researchers in conducting large-scale clinical verification or new basket trials.

EGFR: EGFR is the most extensive proliferation-driven target in epithelial cancers, and its driving value extends from the first-line therapy for lung, colorectal, head and neck, and pancreatic cancers to cancers with squamous characteristics (head and neck carcinoma, cervical cancer, and Chinese esophageal cancer) and female reproductive system cancers (ovarian and breast cancers). Combined chemotherapy with EGFR-TKI prolongs the progression-free survival (PFS) of patients with NSCLC to almost 3 years. 116 , 117 In addition, EGFR monoclonal antibody combined with chemotherapy has been approved as a first-line treatment for advanced colorectal cancer with KRAS wild-type, pancreatic, and head and neck cancers. Furthermore, in tumors with squamous characteristics, such as head and neck carcinoma, cervical, and Chinese esophageal cancers, the ORR of EGFR inhibition therapy combined with radiotherapy and chemotherapy is up to ~90%, showing improved survival compared to radiotherapy and chemotherapy alone. 118 , 119 , 120 , 121 Similarly, the ORR of EGFR inhibition combined with chemotherapy for female reproductive system tumors, such as ovarian and breast cancers, also exceeds 50%. 122 , 123

HER2: As the second-ranked molecule in the EGF receptor family, HER2 is recognized as a proliferation-driven target with overexpression (IHC2 + /3 + ) across multiple cancer types. Supporting the survival benefits for patients with breast and gastric cancers, anti-HER2 therapy has also achieved gratifying remission rates for lung, 124 , 125 , 126 , 127 digestive tract tumors (esophageal, gastric, and colorectal cancers), 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 digestive gland tumors (gallbladder and pancreatic cancers), 136 , 137 and genitourinary tumors (breast, prostate, urothelial, and endometrial cancers). 138 , 139 , 140 , 141

MET: MET, belonging to the HGF receptor family, was originally found in the form of a MET exon 14 skipping mutation in chemotherapy-insensitive tumors, such as liver cancer and renal cell carcinoma with poor prognosis, which could be reversed by MET inhibition therapy. 142 , 143 , 144 Considering the transformative potential of MET in epithelial cells, MET inhibition has been validated in epithelial-derived tumors such as lung cancer and digestive tract tumors (gastric and colorectal cancers). 145 , 146 , 147 , 148 , 149 , 150 , 151

FGFR: In addition to the evolution of tumor cells, fibrotic matrix remodeling mediated by FGFR activation leads to resistance. FGFR inhibition has been approved for FGFR2 amplification or mutation in urinary tumor and cholangiocarcinoma. 152 , 153 Therefore, potentially beneficial tumor types may be those anatomical sites with a high degree of fibrosis caused by long-term chronic inflammatory stimulation, including pancreatic, lung, endometrial, and breast cancers, as well as head and neck squamous cell carcinoma. 153

MAPK: The MAPK pathway, represented by RAS/RAF/MEK, has high evolutionary conservation and performs generalized functions, such as cell growth, differentiation, apoptosis, and migration by virtue of the widely expressed Ser/Thr kinase, which is the foundation of pan-cancer therapy. MAPK is the main downstream and compensatory activation pathway for ERGR, HER2, MET, and FGFR. Therefore, the tumor types that are likely to see the greatest benefit from KRAS, BRAF, and MEK-targeted therapy are similar to those of RTK families, mainly concentrated in lung and digestive system tumors. 83 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 BRAF and MEK have also been approved as characteristic signals for BRAF-mutated solid tumors.

PI3K: PI3K/Akt/mTOR is another pan-cancer proliferation-driven pathway, and the downstream hub molecule mTOR has been functionally validated in most solid tumors. In addition, PI3K and Akt, which are characteristic resistance signals of breast cancer, are expanding the therapeutic potential of breast cancer to reproductive system tumors. 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170

CDK4/6: CDK4/6 inhibitor reverses the dilemma of endocrine resistance in breast cancer by alternating activation of CyclinD1 and ER. 171 , 172 The CCND1 encoding CyclinD1 is a target gene of ER, and CyclinD1 can bind to ER to promote downstream gene expression of ER through a non-CDK-dependent pathway. 173 According to interactions with hormone dependent pathways, CDK4/6 inhibitors are widely proven effective in reproductive system tumors. 174 , 175 , 176 , 177 , 178 , 179 , 180

With the prolongation of survival and evolution of tumors under therapeutic stress, the proliferative signal network is intricate and ever-changing. Therefore, the low signal-blocking intensity and breadth of monotherapy will undoubtedly lead to a poor response or resistance.

According to multidrug synergy, the “targets search multi-drug” of basket trial is proposed to increase efficacy and delay drug resistance. On account of the inhibition of universal driving targets such as PD-1, MEK, and EGFR, the combined drugs design simultaneously cover tumor characteristics to ensure powerful and comprehensive signal blocking, achieving “high efficacy and slow resistance” across different tumor species.

PD-1 inhibitor-based therapy: PD-1 inhibitors improve the feasibility of the combination regimen for the universal mechanism among different tumor types. The phosphorylated intracellular structure of PD-1 mediates the dephosphorylation of downstream protein kinases Syk and PI3K, and further inhibits the activation of the AKT and ERK pathways, which can downregulate the expression of T-cell activation genes. 181 , 182

The “omnipotent combination” of PD-1 inhibitors and multitarget TKIs is representative of the pan-cancer combined drug design, which shifts from posterior- to first-line stemming from their broad-spectrum antitumor activity. 183 Multitarget TKIs promote vascular normalization to increase immune cell infiltration and improve the hypoxic microenvironment, thereby exerting synergistic efficiency enhancement. Moreover, multitarget TKI work quickly but are easily resistant, whereas PD-1 inhibitors take effect slowly but are unlikely to be resistant once effective. Therefore, this combination can cover the entire treatment process and achieve rapid and continuous remission. Specifically, apatinib inhibited PD-L1 expression in macrophages by targeting VEGFR2/STAT3 to reduce immune escape. 184 , 185 , 186 , 187 , 188 Conversely, PD-L1 inhibitors can interact with VEGFR2 to block angiogenesis that is activated by the FAK/AKT pathway. 189 , 190 Similarly, anlotinib reprograms the immunosuppressive microenvironment and increases immune cell infiltration to potentiate the therapeutic effect of PD-1 blockade. 191 , 192 Apatinib combined with camrelizumab and anlotinib combined with cedilimumab have been validated in most solid tumors. 157 , 183 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 Similar omnipotent combined drug design include lenvatinib with pembrolizumab and sulfatinib with toripalimab.

The PD-1, BRAF, and MEK inhibitor combined drug design blocks the synergistic enhancement of the oncogenic pathway and immune response in characteristic BRAF mutant tumors, including NSCLC, colorectal cancer, thyroid cancer, and melanoma. BRAF combined with MEK inhibitors has been approved for use in BRAF mutant solid tumors. BRAF upregulates PD-L1 expression by C-Jun via the MAPK/JNK pathway, which can be reversed by MEK inhibition. 167 , 207 BRAF also upregulates PD-L1 expression through non-MAPK pathways, such as by activating IL-1 or LEF-1 transcription. 208 , 209 Furthermore, BRAF responds to immunotherapy by inducing an IFN-γ-dominant immune microenvironment. 210 Mutually, PD-1 inhibition reverses the exhaustion of CD8 + T cells induced by BRAF and MEK inhibitors. 167 PD-1 inhibition suppresses the RAS/RAF/MAPK cascade by preventing SHP2 recruitment. 211 , 212 The persistent immune response induced by PD-1 inhibition can also monitor reactivation of drug resistance pathways, including MAPK. 213 Therefore, PD-1, BRAF, and MEK inhibitor combined therapies have been confirmed to be effective in BRAF-mutated colorectal cancer and melanoma. 211 , 214 , 215 , 216

The PD-1 and KRAS inhibitor combined drug design also blocks the synergistic effect of the driving signal and immune escape in characteristic KRAS mutant tumors, including lung cancer and digestive tumors such as gastric cancer, colorectal cancer, and pancreatic cancer. KRAS upregulates PD-L1 expression by activating MEK/ERK, TGF-β/EMT, or YAP/TAZ transcriptional activators in lung cancer. 217 , 218 , 219 , 220 Similarly, KRAS-driven pancreatic cancer is accompanied by PD-L1 overexpression caused by the deletion of the transcriptional suppressor TGIF1. 217 The PD-1 and KRAS inhibitor basket has been demonstrated to be effective in KRAS mutant lung cancer and colorectal cancer. 221

MEK inhibitor-based therapy: The MEK inhibitor-based therapy enhanced the blocking intensity of the MAPK pathway and predictably suppressed the alternative activation pathway to delay the occurrence of resistance, thereby improving the outcome of BRAF/KRAS mutant solid tumors that depend on the MAPK pathway.

The BRAF and MEK inhibitor combined design improves the efficacy of BRAF mutant tumors by blocking upstream and downstream signals. BRAF is a pan-cancer driver mutation with an incidence of 50% in melanoma and thyroid cancer and 10% in colorectal cancer. 29 BRAF mutant tumors are MEK-dependent. Highly active mutants directly phosphorylate MEK through monomers or dimers, whereas low-activity mutants activate MEK through endogenous CRAF or RAS. 222 , 223 , 224 Furthermore, resistance to BRAF inhibitors is also related to MAPK reactivation. 225 , 226 , 227 , 228 However, the BRAF inhibitor vemurafenib or the MEK inhibitor trametinib alone failed in the cross-tumor exploration of BRAF V600E-mutated melanoma to other solid tumors. 229 , 230 , 231 , 232 The failure of monotherapy suggests the necessity of increasing the blocking intensity of the MAPK pathway to accommodate differences across tumor species. Further trials have demonstrated that the combination of dabrafenib and trametinib, targeting both BRAF and downstream MEK, is effective in melanoma after BRAF inhibitor resistance. 233 Similar combinations include vemurafenib with cobimetinib and encorafenib with binimetinib. 234 , 235 The latter combination has also been validated in BRAF V600E mutant lung cancer and colorectal cancer. 158 , 236 Moreover, the combined drug basket not only enhances the blocking intensity of the MAPK pathway but also magnifies its pro-apoptotic activity. BFAF inhibitors induce the ER stress response and upregulate the pro-apoptotic protein PUMA through the PERK pathway. MEK inhibitors can also mediate the expression of the pro-apoptotic protein BIM and the activation of the apoptosis mitochondrial pathway. 237 As expected, the overall response rates of BRAF V600E solid tumors in the phase II ROAR (including cholangiocarcinoma, glioma, and thyroid cancer) basket trial and the NCI-MATCH sub-regimen are both around 80%. 83 , 84 , 85 , 86 Subsequently, dabrafenib and trametinib baskets were approved in BRAF V600E mutant solid tumors, representing a defining change for the multidrug basket based on MEK inhibitors.

The EGFR, BRAF, and MEK inhibitor combined drug design blocks the downstream, upstream, and alternative activation signals to overcome the resistance of BRAF mutant tumors after combined treatment. BRAF mutant colorectal cancer has a high level of EGFR phosphorylation, which may induce the reactivation of ERK through EGFR-mediated RAS and CRAF activation to resist vemurafenib. 228 , 238 However, a phase 2 basket trial of vemurafenib combined with cetuximab for treating BRAF V600E mutant non-melanoma cancer failed. 75 Resistance may be attributed to MAPK reactivation and could not be reversed by adding chemotherapy. 157 , 239 Furthermore, NRG1 derived from stromal cells can resist dabrafenib and trametinib through EGFR signal transduction. 238 , 240 In other words, the combined inhibition of BRAF and EGFR leads to MEK-activated resistance, whereas combined inhibition of BRAF and MEK leads to EGFR-activated resistance. The failure of these clinical trials suggests the necessity of combined blocking of upstream, downstream, and alternative activation signals. Finally, encorafenib, binimetinib, and cetuximab basket were shown to prolong OS in patients with BRAF mutant colorectal cancer compared to standard treatment, which opens up new ideas for comprehensively blocking signal networks. 241

The SHP2 and MEK inhibitor combined drug design has been shown to improve the efficacy of refractory KRAS-driven solid tumors by jointly blocking downstream and key node signals. SHP2 is not only the universal node of the MAPK pathway activated by different RTKs but is also the convergence node of many signaling pathways, including JAK/STAT, PI3K/AKT/mTOR, and PD-1/PD-L1. RAS-GTP-dependent carcinogenic KRAS mutation and amplification causes the full activation of upstream RTKs to converge to the RAS signal in pancreatic cancer, lung cancer, and melanoma cells. 242 , 243 , 244 , 245 , 246 , 247 KRAS mutations also mediate acquired resistance to MEK inhibitors in NSCLC and thyroid cancers. 248 , 249 , 250 SHP2 inhibitors can suppress the activation of KRAS mutants with GTP activity, and prevent SOS/RAS/MEK/ERK from responding to RTK reactivation induced by MEK inhibitors. The SHP2 inhibitor SHP099 combined with the MEK inhibitor trametinib has been shown to be effective in pancreatic, lung, and ovarian cancers with KRAS mutations and in triple-negative breast and gastric cancers with RAS amplification. 244 , 245

EGFR inhibitor-based therapy: The EGFR inhibitor-based therapy blocks the same level of signal crosstalk to inhibit growth factor signal-dependent epithelial tumor proliferation. EGFR is the most significant proliferation-driven signal in epithelial tumors, with strong cross-tumor conservation. HER2, FGFR, MET, and VEGFR are the major alternative bypass signals that mediate resistance. Therefore, the foresighted combined inhibition of EGFR and accessory signals can improve the reduction rate and delay resistance of “dual signal addiction” tumors.

The EGFR and HER2 inhibitor combined drug design delays the resistance of EGFR/HER2-driven solid tumors due to the alternative activation signal within the ERBB family. ERBB2 mutations and amplification bypass activate downstream signals leading to EGFR inhibitor/antibody resistance to lung, colorectal, head and neck, and bladder cancers. HER2/HER3 dimerization activates the PI3K/AKT and ERK pathways to promote tumor growth in head and neck tumors after anti-EGFR therapy. 251 , 252 HER2 D16 mutation promotes lung cancer resistance to osimertinib through an Src-independent pathway. 253 HER2 L755S and R784G mutations are associated with anti-EGFR resistance in colorectal cancer. 254 Bladder cancer cells resistant to cetuximab have high levels of ERBB2 phosphorylation and respond well to pan-HER inhibitors. 255 Similarly, EGFR activation is the primary mechanism of anti-HER2 resistance in breast cancer and gastrointestinal tumors. ERBB mutations are present in 7% of HER2+ breast cancer cohorts and are resistant to HER2 inhibitors. 256 Herceptin-resistant breast cancer cells show higher levels of EGFR phosphorylation and EGFR/HER2 heterodimers, with sensitivity to erlotinib and gefitinib. 257 , 258 Overexpression of EGFR is observed in 26% of patients with HER2+ gastric cancer. 259 Gastroesophageal cancer with co-amplified EGFR/HER2 is trastuzumab-resistant but sensitive to the pan-HER inhibitor afatinib. 260 Lapatinib, may add therapeutic value in combination with trastuzumab through increased membrane HER2 levels and enhanced ADCC activity in breast cancer. 261 , 262 Similarly, trastuzumab combined with lapatinib achieves regression of HER2-amplified gastrointestinal tumors by blocking HER3/EGFR reactivation. 263 The activity of BIBW2292, AZD8931, AST1306, TAK-285, epertinib, and other EGFR/HER2 tyrosinase inhibitors in solid tumors indirectly confirms their interdependent proliferation-driven activity. 264 , 265 , 266 , 267 , 268 , 269

The EGFR and FGFR inhibitor combined drug design prevents resistance from bypass activation in EGFR/FGFR dual-signal addictive tumors such as lung cancer, head and neck squamous cell carcinoma, hepatobiliary carcinoma, and esophageal cancer. The high expression/fusion of FGFR1 increases tumorigenicity and resistance to EGFR-TKI in EGFR mutant lung adenocarcinoma cells, which can be reversed by the dual inhibition of EGFR and FGFR. 270 , 271 The combination of EGFR and FGFR inhibitors reverses EGFR resistance mediated by downstream PIK3CA activation in skin squamous cell carcinoma. 272 Interactively, EGFR-dependent signal transduction induces resistance to FGFR inhibitors in head and neck squamous cell carcinoma cells with high expression of FGFR1 and cholangiocarcinoma cells with FGFR2 fusion. 273 , 274 The inhibition of FGFR by lenvatinib results in the feedback activation of the EGFR–PAK2–ERK5 signal axis, which can be blocked by EGFR and EGFR inhibitors combined therapy. 275 The combination of the FGFR inhibitor and gefitinib significantly decreased the levels of p-AKT and p-ERK1/2, inducing strong apoptosis and decreasing the ability of clone formation in esophageal squamous cell carcinoma. 276

The EGFR and MET inhibitor combined drug design blocks MET co-activation through ligand-dependent or -independent pathways in EGFR-addicted tumors, including lung cancer, gastroesophageal cancer, colorectal cancer, and head and neck tumors. MET inhibition induces TGF-α to activate EGFR, resulting in bypass resistance in the abovementioned tumors. 277 , 278 , 279 Conversely, EGFR inhibitors also induce HGF overexpression to bind to MET receptors that activate MAPK. 280 Interestingly, TGF-α/HGF could activate MET/EGFR in both ligand-dependent and -independent manner. 281 , 282 Therefore, inhibition of MET or EGFR alone is insufficient in MET/EGFR co-activated tumors. In MET amplification and EGFR mutation with T790M-negative NSCLC, the ORR of savolitinib combined with osimertinib is 64%, 283 while the combination of tepotinib and gefitinib extends the OS to 24.2 months. 284 Similarly, patients with NSCLC with EGFR mutant and high expression of MET treated with MET monoclonal antibody plus erlotinib exhibit a median PFS that is increased by 15.3 months compared to treatment with erlotinib alone. 285 Moreover, combined treatment of MET inhibitor and cetuximab causes further tumor regression in patients with MET-positive colorectal cancer after anti-EGFR therapy. 147 The bispecific antibody avantumab effectively downregulates the level of EGFR/MET activation and increases the immune directional antitumor activity induced by γ-IFN secretion. 286 The ORR of avantumab reaches 40% in NSCLC with EGFR exon 20ins after platinum chemotherapy, and its potency in other tumors, such as gastroesophageal adenocarcinoma, is still being elucidated. 151 , 287

The EGFR and VEGF inhibitor combined drug design blocks the energy loop enhanced by the cross-linking of epithelial proliferation and angiogenesis activation signals in EGFR-addicted tumors. Bevacizumab induces intracellular accumulation and activation of EGFR in colon cancer cells and tumor-associated endothelial cells, which can be attenuated by erlotinib, regardless of RAS status. 288 Similarly, EGFR resistance in lung cancer may be related to increased VEGF expression in tumor and stromal cells. 289 VEGF expression is regulated by EGFR signaling in a hypoxia-independent manner and remains high after resistance to EGFR inhibitors in EGFR-mutant lung cancers. 160 The combination of bevacizumab and erlotinib basket has been validated in solid tumors, such as NSCLC, cholangiocarcinoma, liver cancer, breast cancer, head and neck carcinoma, glioblastoma, and anaplastic glioma. 290 , 291 , 292 , 293 , 294 Other dural EGFR/VEGF inhibition therapy have also been proven effective, such as erlotinib plus cabozantinib in NSCLC, pazopanib plus cetuximab in head and neck squamous cell carcinoma, sorafenib plus cetuximab in colorectal cancer, pazopanib plus cetuximab in head and neck squamous cell carcinoma, and vandetanib in liver and thyroid cancer. 295 , 296 , 297 , 298 , 299

The NCI and National Clinical Trials Network developed NCI-ComboMATCH in 2023, followed by a biomarker-guided study of NCI-MATCH, in order to address biomarker-guided drug synergies to increase efficacy. 300 The therapeutic regime was supported by valid preclinical in vivo experimental evidence, consistent with the underlying logic of our proposed combined therapy. Further, ComboMATCH has both histology-specific and histology-agnostic arms, which reflects the comprehensiveness and inclusiveness of the new clinical design, including basket and umbrella trials. The publication of the ComboMATCH plan also manifested the recognition of the “targets search multidrug” model in basket trials by international institutions.

Drugs identify targets

The “drugs identify targets” mode of basket trials establishes therapeutic potential by identifying new targets of confirmed effective drugs across different tumor types. The detection of unknown gene variations by using NGS is the foundation for target expansion. Meanwhile, the pan-cancer application permission of the basket trial accelerates the verification of the therapeutic value of new targets. For example, PARP inhibitors expanded potential effective targets from BRCA2 to homologous recombination deficiency (HRD) and DNA repair-related genes.

From BRCA mutation to HRD and then to DNA damage repair-associated genes, PRAP inhibitors enlarge the pool of potential targets based on the generalizations of commonalities between individual cases. PARP can repair DNA single-strand breaks via the BER pathway. PARP inhibitors block BER, sequentially resulting in single-strand break accumulation, shortened replication forks, and formation of double-strand breaks. If BRCA mutations lead to HRD simultaneously, double-strand breaks mediated by PARP inhibitors will lead to cell death owing to their inability to be repaired. Olaparib and other PARP inhibitors have been approved for the treatment of advanced ovarian, breast, prostate, and pancreatic cancers with BRCA mutation. 301 , 302 , 303 , 304 , 305 , 306 , 307 Unlike the “target search drug” mode, PARP inhibitors do not directly block the activation signal but anchor HRD to expand potential targets. Clinical studies have confirmed that PARP inhibitors offer clinical benefits to the above four cancers with other HRD-related genes (RAD51, ATM, and PABL2) and HRD without germline BRCA mutations. 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 Clinicians have demonstrated that other DNA damage repair-related genes, such as SLFN11, indicate better efficacy of PARP inhibitors combined with temozolomide in small cell lung cancer (SCLC) and Ewing’s sarcoma. 316 , 317 , 318

The basket trial has successfully opened up new opportunities for single-drug or multidrug therapies of rare tumors, which typically present challenges such as enrollment difficulties in traditional randomized trials. However, the trial type also has limitations. For example, replacing tumor tissue types with proliferation-driven molecular characteristics as treatment classification criteria is not always effective. Further, the gene-mutation spectrum of tumors is usually related to the site of tumor origin. Therefore, how to eliminate or master the negative impact of tumor tissue types on targeted therapy is a challenge and a major future research direction for basket trial design.

The internal logic of the success of the basket trial for tumors is that tumors have definite driving gene variations. In non-tumor diseases, if similar situations exist, patients may also benefit from a basket trial in the paradigm of “same drug for different diseases.” In neurodegenerative diseases such as Alzheimer’s disease, the biggest obstacle to performing a basket trial is the lack of sufficient biomarkers for most molecular pathologies besides Ab and tau. However, because both AD and certain non-AD neurodegenerative syndromes are strongly linked to underlying tau pathology, it is possible to combine populations such as AD, PSP, and corticobasal syndrome (CBS) in a single clinical trial of a tau-targeted intervention. 89 Studies of drugs for infectious diseases or metastatic disease caused by the same pathogenic factor can also be done on the basket trial. 93 In these studies, different stages of the disease were treated as different cohorts. 94 When the concept of the basket trial extends to the research field of animal experiments, it can quickly help identify biomarkers. 92

Umbrella trial exploring tumor molecular-subtype-driven therapy

Umbrella trials allow the rapid validation of the effectiveness of multiple therapies or intervention for a certain disease, overcoming the limitation of traditional trial designs that only recruit patients who share common characteristics. These trials maximize the inclusion of individuals in the implementation of precision medicine, aiming to find the most suitable and personalized treatment strategies for each patient. Thus, it is essential for the application of an umbrella trial design to accurately and thoroughly identify the molecular biological feature of a specific disease, especially for precision-oncology research. Previously, numerous umbrella trials in the field of oncology have revealed many potential therapeutic strategies for cancer without a highly effective regimen.

There is currently no approved targeted therapy for squamous cell lung cancer. Despite The Cancer Genome Atlas (TCGA) project and other similar works detecting a high number of somatic gene mutations in squamous cell lung cancer, these molecular alternations occur at a relatively low frequency (5–20%), posing a significant challenge in rapid recruitment and efficient research if using traditional clinical trial design. 100 Thus, the Lung-MAP (Lung Cancer Master Protocol) has emerged, which is a well-known umbrella trial for patients with squamous NSCLC that started in 2014. 100 By incorporating multiple treatment options, investigators could simultaneously evaluate the biomarker-guided therapies more rapidly and without the need for separate trials for each regimen. This trial initially consisted of five arms, each investigating the efficacy and safety of a corresponding different approach. The first subgroup included patients without actionable molecular alterations of interest, who were assigned to receive durvalumab. Four additional subgroups were biomarker-driven and investigated targeted therapies including the PI3K inhibitor (taselisib) for PIK3CA alteration, CDK4/CDK6 inhibitor (palbociclib) for CDK4/CCND1/CCND2/CCND3 amplification, FGFR inhibitor (AZD4547) for EGFR1/2/3 alteration, and rilotumab and erlotinib for MET mutation (this arm was closed owing to toxicity). 319 The Lung-MAP is a comprehensive umbrella trial that evaluates multiple targeted therapies and treatment approaches for squamous NSCLC patients. It utilizes biomarker-driven designs to match patients to specific interventions based on their molecular characteristics, ultimately improving treatment outcomes and advancing personalized medicine in lung cancer. Owing to the good design of Lung-MAP, this trial was expanded to include all of the histologic types of NSCLC in 2019 using a new screening protocol. The overarching aim of novel Lung-MAP is to evaluate multiple therapies and biomarkers in a single master protocol, facilitating personalized treatment approaches for patients with NSCLC.

Another important example is triple-negative breast cancer (TNBC). Although TNBC accounts for about 10–20% of all of the newly diagnosed breast cancers, patients with this type of breast cancer are prone to visceral metastasis. TNBC also comes with the highest risk of recurrence and the poorest survival rate of all breast cancers. Owing to lack of common breast cancer-associated targets such as the estrogen receptor, progesterone receptor, and HER2 expression, biomarker-guided treatment for patients with TNBC has been challenging. To address this issue, investigators have proposed the “Fudan Classification” based on multi-omics profiling of TNBC. In this classification system, patients with TNBC are categorized into four different subtypes: luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). 320 Subsequently, the FUTURE trial using an umbrella design was initiated, in which previously heavily treated patients with TNBC were enrolled in four arms and received corresponding biomarker-guided therapy based on the FUDAN classification. The FUTURE trial found that the progression-free survival almost doubled compared with conventional chemotherapy. 320 , 321 , 322 Therefore, the FUTURE trial has provided precision treatment options for patients with TNBC. This umbrella trial design has also offered a novel method for the efficient exploration of personalized treatment strategies.

The K-Umbrella trial for gastric cancer was carried out later, in which patients with gastric cancer were divided into three biomarker-guided therapy arms based on molecular subtyping (arm 1: EGFR IHC2+ or 3 + ; arm 2: PTEN loss/ineffectiveness; arm 3: immune-related biomarker enrichment including PD-L1 positive, microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR), or EBV-related), as well as a control arm, with none of the abovementioned biomarkers. 323 Similarly, the K-Umbrella trial aimed to simultaneously assess the efficacy improvement of three biomarker-based regimens. Even though this umbrella trial did not reach the study endpoint, it initiated the precedent of umbrella trials in a gastric cancer cohort. In addition, multiple umbrella trials are also being conducted to assess biomarker-guided therapy for ovarian cancer, urothelial cancer, and other diseases. 324 , 325 The results of the above various umbrella trials allow us to realize the importance of accurate molecular profiling to achieve biomarker-based strategies in the era of precision medicine.

At present, tumor molecular profiling has become a focal point of research investment in line with precision medicine strategies. As the first comprehensive catalog of cancer-associated genomic alterations, TCGA has allowed researchers to explore genomic changes that may contribute to oncogenic phenotypes. The method uses genomic signatures to classify cancer at a molecular level, which has greatly enhanced the accuracy of selecting biomarker-guided therapies, thereby further improving the success rate of umbrella trials. Moreover, researchers can further establish tumor molecular profiling based on the vast amount of emerging omics data from advancements in next-generation sequencing and multi-omics technologies.

Lung cancer

The discovery of the common driver-gene therapeutic value, such as EGFR, ALK, and ROS1 in lung cancer, marked the initial exploration of umbrella trials based on molecular subtyping. The integration of comprehensive transcriptomic and epigenetic analysis, along with clinical-pathological data, has uncovered more intricate gene-network events and potential classifications. This advancement offers guidance for patients with lung cancer who do not harbor the defined driver genes. One novel classification has been proposed for this type of lung cancer, in which lung cancer is divided into three subtypes: Proximal-Proliferative (PP), characterized by KRAS mutations combined with STK11 inactivation; Proximal-Inflammatory (PI), characterized by NF1 and TP53 co-mutations; and Terminal Respiratory Unit (TRU), characterized by a high frequency of EGFR mutations. 326 Similarly, the response to immunotherapy in KRAS mutant lung cancer is also closely linked to molecular subtyping. Different subtypes have shown significantly varying ORRs to PD-1 inhibitors: KL subtype (KRAS mutation with STK11/LKB1 co-mutations) had a rate of 7.4%, KP subtype (KRAS mutation with TP53 co-mutations) had a rate of 35.7%, and K-only (KRAS mutation alone) had a rate of 28.6%. 327 All of these novel molecular subtypes have provided the possibility of conducting umbrella trials in common driver-gene-negative lung cancer, similarly to the FUTURE trial in TNBC.

Colorectal cancer

Colorectal cancer is another paradigm in the field of precision oncology. However, the previous biomarker-guided therapy for this cancer has been used for reverse selection of colorectal patients who are not responsive to targeted agents. For example, patients with colorectal cancer with the RAS/RAF-mutation could not obtain a clinical benefit from an anti-EGFR therapy should be treated with an anti-VEGF-targeted therapy. 328 This molecular classification seems to be insufficient to support the application of a biomarker-guided therapy in the era of precision medicine. Thus, a more novel classification has been proposed. In 2015, the Colorectal Cancer Subtyping Consortium provided the clearest classification system for colorectal cancer to date. 329 The consortium identified four molecular subtypes (CMS): the CMS1-MSI immune subtype, CMS2-Classic subtype, CMS3-Metabolic subtype, and CMS4-Mesenchymal subtype. Each subtype has distinct characteristics and potential benefits from specific biomarker-guided treatments. CMS1 has the characteristics of immune cell infiltration and the highest potential benefit from immunotherapy. CMS2 is primarily characterized by downstream targets of the WNT signaling pathway (APC gene) and high-frequency mutations in the p53 gene, which may benefit from treatments aimed at restoring the p53 function. CMS3 is the only subtype of the four with a high frequency of KRAS gene mutations, and RAS gene mutations have prognostic implications in colorectal cancer, predicting resistance to the anti-EGFR therapy in metastatic colorectal cancer. CMS4 is characterized by upregulation of EMT and stromal infiltration, which may be sensitive to therapy targeting WNT2. These classifications were developed in a preclinical setting, but further umbrella trials could explore biomarker-based therapy in accordance with molecular profiling.

Breast cancer

The most well-known molecular subtypes of breast cancer are Luminal A, Luminal B, HER2 overexpression, and TNBC, which have been widely used in clinical practice. 330 In addition to these subtypes, as mentioned above, a novel molecular classification for TNBC, called “Fudan classification,” was developed based on clinical, genomic, and transcriptomic data. 320 Despite hormone receptor-positive, HER2-negative breast cancer being the most prevalent form of breast cancer, the problem of resistance to endocrine therapy remains unresolved, highlighting the urgent need for accurate molecular classification to guide biomarker-based precision treatments. Based on the comprehensive omics data, investigators have classified HR + /HER2- breast cancer into four distinct subtypes: canonical luminal, immunogenic, proliferative, and receptor tyrosine kinase (RTK)-driven. 331 Specific biomarker-guided treatment strategies would be developed based on the biological characteristics of each subtype. For example, the immunogenic subtype, which exhibits abundant immune cells, may produce a clinical benefit from an immune checkpoint inhibitor.

Gastric cancer

The failure of the K-Umbrella trial emphasizes the crucial importance of accurate and precise molecular classification for the successful implementation of an umbrella trial. Recently, multiple molecular-subtyping strategies for gastric cancer were proposed. TCGA proposed four subtypes of gastric cancer in 2014: genomic stability, chromosomal instability (CIN), microsatellite instability (MSI), and Epstein–Barr virus-positive. 332 Unfortunately, the treatment-guided value of these molecular profiling types remains uncertain owing to the lack of adequate clinical data. In 2015, the Asian Cancer Research Group (ACRG) categorized gastric cancer into four subtypes, namely, MSI-H, MSS/TP53 + , MSS/TP53–, and MSS/EMT subtype, using gene-expression profiles, whole-genome-copy number-variation arrays, and targeted gene sequencing. 333 The prognosis analysis demonstrated that patients with the MSI-H subtype exhibited the most favorable survival rate. In addition, gastric cancer has been classified into two groups using a predictive stratification based on genes related to immune function (GZMB and WARS) and intestinal epithelium (CDX1): one that would benefit from adjuvant chemotherapy and one that would not. 334 Of course, this also requires the use of an umbrella trial design to effectively explore whether these novel preclinical molecular subtypes could guide clinical practice in the era of Precision Pro.

Biliary tract cancer

Biliary tract cancer is a highly heterogeneous malignant tumor at the genomic and epigenetic levels. With the development of gene-sequencing technology, multiple biomarkers that could guide targeted therapy or immunotherapy have been discovered, such as FGFR2 alteration, IDH1/2 mutation, NTRK fusion, RET fusion, BRAF V600E mutation, HER2 alteration, MSI-H/dMMR, and high tumor-mutation burden (TMB). 74 , 335 , 336 , 337 , 338 As the traditional histopathological classification has exceeded the demands of precision medicine, a traditional “one-size-fits-all” trial also could not effectively assess the potential of a therapy target to the above molecular alterations. With the implementation of a new trial design for the umbrella trial, several biomarker-guided therapy approaches have been incorporated into clinical guidelines for cholangiocarcinoma. For instance, using the philosophy of an umbrella trial design, the FIGHT-202 trial aimed to explore the FGFR inhibitor in cholangiocarcinoma with FGFR gene alteration, including two genetic subpopulations: FGFR2 fusion or rearrangement and other FGF/FGFR alterations. 339 In 2020 ASCO, an umbrella trial was designed to explore multiple biomarker-based therapy-target MET amplification, HER2 amplification, IDH1 mutation, and FGFR fusion among 46 patients with refractory biliary tract tumors, which yielded 26.1% of the ORR, with a median progression-free survival of 5 months. 340 Except for these molecular events, there are several potential druggable genetic alterations in ongoing trials, such as EGFR, PI3K, and BRAF. 341 Moreover, the molecular subtyping of cholangiocarcinoma has advanced into the field of multiple omics. For example, biliary tract cancer is now classified into five subtypes based on the tumor microenvironment, namely, immune classical, inflammatory stromal, hepatic stem-like, tumor classical, and desert-like. 342 Each subtype has distinct characteristics, which can potentially guide trial design in a future umbrella trial.

Ovarian cancer

Biomarker-based therapy based on molecular heterogeneity has clearly emerged as a direction for precision treatment in ovarian cancer. Precision molecular subtyping forms the foundation for achieving individualized treatment for ovarian cancer. In 2011, TCGA categorized high-grade serous ovarian cancer into four subtypes based on gene content, namely, immunoreactive subtype, characterized by CXCL11/CXCL10/CXCR3 expression; proliferation subtype, characterized by HMGA2/SOX11/MCM2/PCNA overexpression with MUC1/MUC16 low-expression; differentiated subtype, characterized by MUC16/MUC1with SLP1-positive; and mesenchymal subtype, characterized by a HOX/stromal high-expression marker. 343 The survival analysis showed that patients with the immunoreactive and mesenchymal subtypes had the best and worst prognosis, respectively. Further, Tan et al. reported a novel classification scheme to address the heterogeneity of epithelial ovarian cancer based on the gene-expression patterns of 1538 cases. Five subtypes, namely, epithelial-A, epithelial-B, mesenchymal, stem-like-A, and stem-like-B, exhibited biologically distinct characteristics and prognoses, as well as sensitivity to drugs. 344 This molecular subtyping offers new insights into the development of biomarker-guided personalized therapy for ovarian cancer using the umbrella trial design.

Prostate cancer

Although precision medicine for prostate cancer started comparatively late, prostate cancer has also entered its era of precision medicine. The PROfound trial, released in 2020, is the first phase III clinical trial to explore biomarker-based therapy based on molecular subtyping in the field of prostate cancer. 303 The PROfound trial has become a milestone in precision medicine for prostate cancer, leading to the approval of a PARP inhibitor (Olaparib) for advanced metastatic castration-resistant prostate cancer patients with BRCA mutations. The molecular subtyping of prostate cancer is mainly based on factors including transcriptomics, genomics, and proteomics. The molecular classification analysis based on this multi-omics information can help identify the gene-expression profile, activation status of oncogenes, DNA repair deficiencies, as well as protein expression, thus guiding the selection of biomarker-based therapies. For instance, BRCA1/2 gene mutations contribute to high sensitivity to PARP inhibitors. 345 Moreover, PTEN gene loss is associated with the potential efficacy of PI3K/AKT/mTOR pathway inhibitors. 346 Patients with the androgen-receptor variant may obtain a clinical benefit from androgen-receptor antagonists or CYP17 inhibitors. 346 Similarly, therapy targeting the prostate-specific membrane antigen (PSMA), a prostate cancer-specific protein, is being tested in an ongoing trial. Owing to the high degree of genetic variation in metastatic castration-resistant prostate cancer, ~90% of patients harbor gene mutations with clinical significance. 347 Therefore, using umbrella trial designs to evaluate the efficacy of multiple biomarker-guided therapies simultaneously is expected to become an effective approach for exploring precision treatment in prostate cancer.

Cervical cancer

The development of precision medicine in cervical cancer seems relatively slow, which can be attributed partly to the lack of an accurate understanding of the molecular subtype in cervical cancer. The accurate molecular classification can lay the foundation for therapeutic stratification of cervical cancer. Researchers have also made many attempts to explore the molecular subtyping of cervical cancer. For example, Li et al. reported a molecular stratification based on the data of single-cell transcriptomics and further identified four different molecular subtypes: hypoxia (S-H subtype), proliferation (S-P subtype), differentiation (S-D subtype), and immunoactive (S-I subtype). 348 Moreover, patients with the S-H subtype, the S-I subtype exhibited the worst and best prognosis, respectively. In addition, different molecular subtypes presented various infiltrations of immune cells, especially for CD8 + T cells, suggesting immunotherapeutic potential of the immunoactive subtype. Currently, there is no standardized molecular subtyping for cervical cancer supported by relevant clinical trials. Cervical cancer exhibits a lot of genetic molecular alternations with unknown treatment values. The umbrella trials can help rapidly and effectively identify molecular alterations with significant treatment value.

In addition, molecular classification exploration is being conducted for many cancers, and an umbrella trial is an effective method for identifying a biomarker-guided therapy. Similarly, with the development of precise molecular-subtype exploration of the nononcology disease, the umbrella trial design would play a huge role in the precision treatment of these diseases.

Platform trial screening of an optimal treatment in a long-term dynamic model

As a dynamic umbrella trial design, the platform trial is another new trial design that has revolutionized clinical research and drug development. The platform trial has broken from the traditional clinical trial model, using an adaptive clinical trial model designed to improve trial efficiency by minimizing the number of participants and shortening the time required to evaluate an experimental invention. Compared with umbrella trials, the standards for experimental intervention or controls are dynamically changing, resulting in a more effective way to screen out optimal treatment in a long-term dynamic model. Therefore, during the long process, the efficacy differences between different subgroups are dynamically quantified to ensure that the included patients receive the best treatment. The first platform trial, STAMPEDE, provides multiple standard treatment options for advanced prostate cancer. 108 Subsequently, several platform trials have emerged in the field of precision oncology, although the number of this type of trial remains relatively small. 112 , 349

The I-SPY 2 trial is widely regarded as another pioneer of tumor platform trials, which is designed to evaluate a neoadjuvant therapy in breast cancer, primarily to explore the effectiveness of different biomarkers and corresponding experimental drugs. First, a new patient with breast cancer is classified into one of 10 molecular subtypes. 349 Then, I-SPY 2 trial’s adaptive randomization design enables this participant to be assigned randomly to a study arm. Initially, five experimental drugs can be efficiently, independently evaluated in parallel compared with the control, with a pathological complete response rate as the primary endpoint. During the course of the I-SPY 2 trial, the efficacy of each experimental drug is evaluated in a timely manner, and the study protocol can be adjusted based on the emerging evidence. For example, an experimental drug is considered successful if it achieves a predetermined level of effectiveness in one or more molecular subtypes. However, if it reaches a maximum number of participants without demonstrating any effectiveness, it may be terminated owing to futility. Throughout the trial, new experimental agents can enter into the trial by following a protocol amendment.

The I-SPY 2 trial provides several neoadjuvant regimens for different molecular subtypes of breast cancer in a single trial. In triple-negative breast cancer, the combination of veliparib-carboplatin and standard chemotherapy can result in significantly higher rates of a pathological complete response than standard therapy alone. 350 Among patients with HER2-positive, HR-negative breast cancer, the I-SPY 2 trial revealed that neratinib added to standard chemotherapy was more likely to achieve a pathological complete response than standard chemotherapy with trastuzumab. 351 In HER2-negative breast cancer, the combination of durvalumab and olaparib added to standard neoadjuvant chemotherapy showed superior efficacy to standard neoadjuvant chemotherapy, especially in a highly sensitive subset of patients with high-risk HR-positive/HER2-negative breast cancer. 352 Moreover, MK-2206 (Akt inhibitor) combined with standard neoadjuvant therapy resulted in higher estimated rates of a complete pathological response in patients with HR-negative and HER2-positive breast cancer. 353 The success of I-SPY 2 trial has highlighted the efficiency of umbrella trials in the field of precision medicine, specifically when exploring the use of molecular-biomarker-guided therapy.

The groundbreaking I-SPY 2 trial of neoadjuvant treatment for locally advanced breast cancer has established a new benchmark for the efficiency of phase II clinical trials. I-SPY 2 trial has several unique and novel aspects. First, it has an adaptive randomization method. The experimental drug group with a higher effective data receives more random patients. Second, it has a shared standard treatment control group. The shared standard treatment group avoids multiple enrollments of control group patients, improving the efficiency of the trial. Third, it employs the Bayesian decision method. If the experimental drug has a high Bayesian predictive probability of success in subsequent phase III clinical trials based on I-SPY 2, regimens will be moved from this trial and will enter the phase III trial. If the predictive success probability of the experimental regimen in phase III is low, this group will be stopped directly and withdrawn owing to futility. Fourth, the trial offers a dynamic adjustment of a trial protocol. According to the latest evidence, researchers have the capacity to promptly adjust the plan by increasing or reducing experimental regimens. I-SPY 2 trial continues to have a major influence on the development of next-generation trial designs in oncology and beyond.

Beyond oncology, platform trials are especially suitable for sudden public health emergencies that require effective treatment, like COVID-19, owing to the high efficiency of recruiting patients compared with conventional trials. 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 , 365 , 366 In addition, platform trials can incorporate adaptive components whereby specific trial parameters may be altered during the course of the study if planned in advance. This kind of “rolling platform” can move on to test new drugs without stopping the trial or seamlessly including multiple stages of development. 367 This is also good news for some diseases lacking effective treatment drugs, such as Alzheimer’s disease. For example, DIAN-TU is a platform trial that simultaneously evaluated solanezumab and gantenerumab in Alzheimer’s disease. 368

Direction: precision Pro, dynamic precision, and intelligent precision clinical trial design

In the past decade, since the master protocol-based novel clinical trial design was proposed, precision medicine has developed rapidly. New-drug efficacy verification has shifted from empiricism to biomarker-guided trials. Owing to the efficient and flexible design of the basket, umbrella, and platform trials, researchers have transformed generous drug targets into treatment opportunities. However, with the gradual exploration of simple targets and molecular typing, the dividend period of the current trial design methodology for research innovation has passed. The precision medicine era 1.0 of biomarker-guided new clinical trial design is also drawing to an end.

How to further thoroughly and precisely explore the therapeutic guidance value of bursting biomarkers is the most important proposition of clinical trial design in the era of precision medicine 2.0. The deep mining of genetic-variation data from multiple dimensions represents a necessary path for innovative new clinical design in the next decade. Moreover, to improve the therapeutic efficacy, both biological rationality and practical feasibility should be considered in the trial-design stage. Therefore, we propose that Precision Pro, Dynamic Precision, and Intelligent Precision be used to instruct new biomarker-guided clinical trial design in the precision medicine era 2.0.

Precision Pro

Precision Pro refers to a treatment concept that explores optimal regimen closer to the essential biological mechanisms than current precision medicine. The Precision Pro concept re-evaluates characteristics of biological processes and involved molecules from multiple dimensions based on existing clinical and biological data. The Precision Pro concept will lead the second wave of new biomarker-guided clinical trials.

From a single target to multiple targets

Currently, most clinical trials focus on a single correspondence between the driving mutations and drugs. However, a comprehensive analysis found that genetic characteristics other than driving mutations were also related to curative efficacy and prognosis. Considering the impact of background gene features, including the TMB and TP53, 369 , 370 on driving mutations, the combined targets improve the representativeness of the target to biological behavior and enhances its compatibility with differences in clinicopathological characteristics (Fig. 4a ).

figure 4

The molecular signaling pattern of the Precision Pro and Dynamic Precision. a The key signal transduction signaling with therapeutic potential from transmembrane to intracellular and nuclear. The combined application of TP53 and TMB accurately characterize the biological behavior of targets. The TP53 mutation and TMB serve as immunogenic backgrounds, presented in the form of extensive activation of oncogenes and nonsense mutations, respectively. The extensive genetic variations lead to the plenty production of tumor antigens and predict immunotherapy responses. The HDAC and EZH2 are the main epigenetic regulatory targets in nucleus with wide-ranging but relatively concentrated biological functions. The EGFR and HER2, FGFR, VEGR, MET are the main proliferation-driven transmembrane signals. The MAPK, JAK/STAT3, PI3K/AKT are the main intracellular proliferative signaling cascade pathways. The PD-1/PD-L1 is currently the most widely used immune checkpoint. b The signaling pattern transformation in Dynamic Precision. HER2 clearance occurs after initial anti-HER2 therapy, presented as protein inactivation and disappearance of original gene mutations. The genetic profiles and biologic characteristics of tumors change greatly after neuroendocrine transformation

TMB combined with driver mutation: TMB, representing tumor immunogenicity, has been proven to predict the efficacy of immunotherapy for 27 tumor types. 79 , 371 TMB, as a marker of new antigen and clone formation, can also assist in identifying tumor proliferation-advantageous clones.

Strong driver-mutated (such as EGFR, ALK, ROS1, MET, and RET) tumors have monoclonal growth advantages across tumor species, which suppress new mutations and clones, resulting in low TMB. 372 , 373 The suppressive ability reflected by TMB positively correlated with single-drug basket therapy. Compared to those with high TMB, lung cancer patients with EGFR mutations and low TMB show a longer OS following treatment with EGFR-TKI. 126 Similarly, patients with colorectal cancer with low TMB showed better efficacy when treated with EGFR monoclonal antibodies. 374 , 375 Therefore, low TMB combined targets indicate that the signaling pathway activated by a strong driver mutation is the dominant factor in tumor proliferation.

Vulnerable driver-mutated tumors (e.g., BRAF, HER2, KRAS, and PI3KCA) require more mutations to gain survival advantages. The high TMB produced by nonsense mutations may dominate proliferation, exceeding that of driver mutations, indicating the benefits of immunotherapy. 372 A high TMB has been shown to be associated with a low clinical benefit of EGFR/BRAF blocking therapy in patients with advanced colorectal with BRAF mutation. 375 Moreover, lung cancer and melanoma with high TMB and BRAF mutations respond better to immune checkpoint blockade (ICB) therapy. 376 , 377 , 378 Similarly, high TMB is an independent prognostic factor for KRAS mutant lung cancer and colorectal cancer treated with ICB. 376 , 379 , 380 , 381 Furthermore, HER2 mutations are often associated with higher TMB in lung, breast, gastric, and colorectal cancers, all of which could benefit from ICB therapy. 382 , 383 , 384 , 385 , 386 , 387 Anti-HER2 combined with PD-1 inhibitors has synergistic antitumor activity in both first- and posterior-line treatment of HER2-positive gastroesophageal adenocarcinoma. 388 , 389 Therefore, although polyclonal proliferation driven by a high TMB responds poorly to single drugs, a higher level of antigen presentation tends to benefit from immunotherapy.

In summary, TMB condenses complex background genetic features into a single number, which is in accordance with the underlying logic of master protocol-based clinical trials. As a routine detection project for NGS, TMB has enormous potential for combined target applications.

TP53 combined with driver mutation: TP53 is a pan-cancer unfavorable prognostic gene that is mutated in 48.3% of solid tumors. 390 TP53 and RAS mutations usually coexist in NSCLC, colorectal cancer, gastric cancer, pancreatic cancer, cholangiocarcinoma, and ampullary cancer, leading to increased invasiveness and shorter OS. 391 , 392 , 393 , 394 , 395 , 396 , 397 , 398 , 399 , 400 , 401 However, TP53 wild-type can weaken the negative effect of RAS mutations on OS in lung and colorectal cancers. 391 , 397 Accordingly, TP53 deletion may be more dominant than the driving mutation; thus, ignoring its combined predictive value may lead to a poor response.

TP53 combined with driver mutations exposes the weaknesses of strong tendency mutations, which can be exploited in immunotherapy. Although the extensive oncogenicity of TP53 and KRAS co-mutations enhances the proliferation and invasiveness of lung cancer and digestive system tumors, it also leads to higher immunogenicity and makes it easier to be recognized by immune cells. TP53 mutant lung cancer loses the binding constraint of BTG2 to RAS (G12V), resulting in a substantial increase in RAS proliferative activity. 402 , 403 KRAS/TP53 co-mutation activates the Wnt/β-catenin pathway, leading to the separation of E-cadherin and β-catenin, thereby losing cell adhesion, and promoting invasion and metastasis in pancreatic ductal adenocarcinoma and gastric cancer. 404 , 405 , 406 Similarly, TP53 deletion facilitates RhoA–ROCK pathway-dependent cell invasion and lymphatic metastasis in KRAS-mutated colorectal cancer. 407 , 408 Fortunately, the widely oncogene expression activated by TP53/KRAS co-mutation also leads to the upregulation of immunogenic markers, such as TMB, PD-1, and MHC-I, and immunomodulatory factors, such as type I and type II interferons, indicating the potential benefits of immunotherapy. 409 Clinical research has demonstrated that PD-L1 is upregulated in KRAS/TP53 co-mutated lung cancer and gastroesophageal adenocarcinoma, 410 , 411 leading to better survival benefits with ICB therapy.

The discovery of the predictive value of high-frequency TP53 deletion in combined targets not only expands the potential beneficiaries but also avoids the poor efficacy of single-driver target suppression. Meanwhile, aiming functional enriched targets, such as TP53 and KRAS, further magnifies their proliferative advantages and reveals the weaknesses of immunogenic exposures behind their strengths. According to reverse thinking, the combined targets providing a unique approach for clinical trials to solve the bottleneck problem.

In clinical trial design, researchers should fully evaluate the sequencing data results and the biological implications of the enrolled patients. The accurate interpretation of biological-related data beyond therapeutic targets assists in precise treatment decision-making.

From the mutation to the mutation subtype

The salvageable structural p53 mutation subtype is screened by Arsenic trioxide from over 800 p53 mutations, which typically represents the “from the mutation to the mutation subtype” concept of Precision Pro. Although the mutation frequency of TP53 in advanced solid tumors is 48.3%, no drug targeting this mutation has been approved for 40 years. 390 The failure of the eprenetapopt non-selective targeting of p53 mutation in the transition from phase II to III manifests the limitations of pan-target therapy. 412 Essentially, the mechanism by which p53 mutations lead to functional loss varies, but includes unfoldable structural mutants, DNA-binding mutants with DNA-binding amino acid variation, and nonsense mutants. 413 Arsenic trioxide, an approved therapeutic drug for acute promyelocytic leukemia, causes unfoldable p53 structural mutations to fold and restore its tumor inhibition function in the balance of denaturation and renaturation by releasing arsenic atoms and covalently bonding DNA-binding sites and β-sandwich domain in p53. 413 , 414 Based on the logic of “from mutation itself to mutation subtype”, researchers have evaluated more than 800 TP53 mutants and found that 390 of them could be rescued by arsenic trioxide, of which 33 restored activities similar to the wild-type. 414 The “PANDA” (P53 AND As) pan-cancer basket trial is currently being conducted to further verify the therapeutic value of arsenic trioxide in solid tumors with TP53 structural mutations. Similarly, the activator PC14586 selectively binds to the gaps in TP53 Y220C mutations to regain transcriptional activity, attaining an ORR of 24.2% in solid tumors. 415 From the failure of general pan-targeting to the success of specific targeting of p53 mutates, the discovery of unknown structural variation through the “from mutation itself to mutation subtype” mode clarifies the beneficiaries of p53 inhibitors.

Similarly, the therapeutic potential exploration of pemigatinib among patients with cholangiocarcinoma in FIGHT-202 trial demonstrated the logic rationality of “ From the mutation to the mutation subtype ”. 339 The different responses of FGFR subtypes to pemigatinib suggested varying drug responses in different molecular subtypes, even within the same gene alteration.

Therefore, the determination of mutation subtypes among enrolled patients should be based on understanding the biological nature of the different mutation subtypes of the targeted gene. Overly strict screening can lead to slow enrollment efficiency, while excessively broad filtering can reduce the overall effectiveness of the treatment.

From transmembrane signaling to nuclear signaling

In the era of precision medicine 1.0, new biomarker-guided clinical trials widely block transmembrane signals and downstream intracellular cascade reaction signals. From the perspective of stress selection, there is less intervention in intranuclear signaling, which maintains a relatively high therapeutic sensitivity. Moreover, nuclear signals, represented by epigenetic targets, are the starting point of the central rule, determining the biological phenotype executed by the vast majority of functional proteins. Research has found that the tumor microenvironment is also closely related to epigenetics. Moreover, epigenetic antitumor drugs have a wide range of immune regulatory effects. In summary, exploring the efficacy of nuclear signal regulation is an important direction for new clinical trial design guided by the Precision Pro concept.

The epigenetic drug therapy regulates the expression of multiple genes in nucleus to manipulate the tumor phenotype by targeting an HDAC or EZH2 gene-expression switch, initiating exploration of nuclear signal targeting (Fig. 4a ). The complex drug resistance in the posterior line requires high-intensity combination rather than simple specific targeted therapy. HDAC inhibitors neutralize the positive charge of histone lysine by inhibiting its deacetylation, reducing its electrostatic attraction to negatively charged DNA, removing the entanglement between DNA and histones, and finally regulating the expression of multiple genes. 416 EZH2 inhibitors relieve transcriptional inhibition of multiple genes by blocking PRC2 deposition mediated by the EZH2-mediated H3K27me3 complex. 417 HDAC and EZH2 inhibitors can form the complex posterior-line state of tumors by reversing drug resistance, immune activation, and biological process enhancement through multi-gene regulation.

HDAC/EZH2 inhibitors reverse drug resistance by regulating the expression of multiple drug resistance-related pathway genes. HDAC inhibitors reverse endocrine drug resistance in breast cancer by reactivating ERα and aromatase expression. 418 HDAC inhibitors also attenuate bypass-activated resistance to EGFR or MEK inhibitors by reducing the nuclear output of redundant tyrosine kinases in head and neck and colorectal cancers. 419 , 420 Similarly, EZH2 inhibitors reverse chemoresistance by modulating local chromatin condensation and gene silencing, mediated by the downregulation of SLFN11 in SCLC. 421 EZH2 downregulates MEIS1 transcription to maintain the integrity of DNA damage repair function, resulting in resistance to oxaliplatin in colorectal cancer, which can be reversed by EZH2 inhibitors. 254 , 422 EZH2 inhibitors also reverse platinum resistance by downregulating the EZH2-mediated tumor suppressor DAB2IP in ovarian cancer. 423 EZH2 induces tamoxifen resistance in breast cancer cells by silencing the expression of the ERα cofactor GREB1. 424 EZH2 also inhibits RTK phosphorylation and overcomes alternatively activated sunitinib resistance in renal clear-cell carcinoma. 425 Moreover, EZH2 downregulates the regulatory subunit of PP2A, PPP2R2B, resulting in sustained phosphorylation of the PP2A targets p70S6K and 4EBP1 to mediate anti-HER2 drug resistance in breast cancer. 426

HDAC/EZH2 inhibitors enhance the efficacy of immunotherapy by upregulating the expression of inflammatory factors and immune-activating genes to reshape the proinflammatory tumor microenvironment. HDAC inhibitors stimulate the antitumor immune response by increasing the expression of proinflammatory chemokines and immunogenic cell death, thereby inducing proinflammatory tumor microenvironment in solid tumors such as triple-negative breast cancer, colorectal cancer, and adrenocortical carcinoma. 427 , 428 , 429 , 430 EZH2 inhibitors decrease histone H3K27me3 modification on the β2-microglobulin promoter, leading to upregulation of MHC-I expression in head and neck squamous cell carcinoma and upregulation of MHC-II expression and immune cell infiltration in urothelial carcinoma. 431 , 432 EZH2 inhibitors upregulate the NK cell-related genes MIP-1α, ICAM1, ICAM2, and CD86; activate NK cells in muscle-infiltrating bladder cancer; and upregulate the transcriptional level of the NKG2D ligand, which enhances the eradication of hepatoma cells by NK cells. 433 , 434

HDAC inhibitors solve the therapeutic problems of undrugable targets by inducing cell death. HDAC inhibitors initiate the process of gene transcription of oxidative stress and apoptosis to treat undrugable targets, such as MYC, RAS, and NF1, in glioma, breast cancer, non-small cell lung cancer, and thyroid cancer. 435 , 436 , 437 , 438

EZH2 inhibitors inhibit invasion-related pathways to reduce distant metastasis and improve disease control rates. EZH2 triggers SMAD3 methylation to promote the interaction between SMAD3 and its cell membrane locator, maintaining SMAD3 phosphorylation of TGFβ receptors and facilitating breast cancer metastasis. 439 EZH2 also induces ribosomal synthesis overactivation and ribosomal DNA instability by silencing PHACTR2-AS1 to accelerate breast cancer metastasis. 440 EZH2 induces methylation of lysine K362 in ERG, which is beneficial for DNA binding and increases ERG transcriptional activity, thereby enhancing the invasiveness of ERG fusion prostate cancer. 441 , 442 EZH2 silences primary cilia genes and activates the Wnt pathway to promote melanoma metastasis. 443

Clinical studies have confirmed that the EZH2 inhibitor tazemetostat has a good disease control rate in patients with epithelioid sarcoma and malignant pleural mesothelioma. 444 , 445 HDAC inhibitors have also been shown to be effective in solid tumors, such as hormone-resistant melanoma, prostate, endometrial, and breast cancers. 446 , 447 , 448 , 449 New clinical trials are expected to accelerate the clinical applications of epigenetic drugs. However, owing to the widespread impact of nuclear signaling on biological functions, serious side effects may occur. Therefore, in clinical trial design, a comprehensive evaluation should be conducted from the aspects of clinical drug accessibility, biological feasibility, and safety. Simultaneously, close monitoring of patients should be carried out.

From pan-cancer to relative specific cancer

As mentioned earlier, the “omnipotent combination” of PD-1 inhibitors and multitarget TKIs is representative of the pan-cancer drug combination. However, the “omnipotent combination” is not universally powerful for each cancer species. Clarifying the cancer relative specificity of combined therapy, especially the “omnipotent combination”, is an important mission assigned by precision oncology to new clinical trials design.

PD-1 expression specificity: PD-1 inhibitors, as a type of immunotherapy, stem from a universal biological mechanism and should be widely effective in pan-cancer therapies. However, the response rate to PD-1 inhibitors in advanced solid tumors is ~20%. 450 , 451 , 452 Distinct PD-1 inhibitors were not significantly different because they share a similar mechanism. Successive studies have demonstrated that differences in efficacy may be attributed to varied immune characteristics represented by PD-1/PD-L1 expression across distinct anatomical tumor sites.

According to the distribution difference of PD-L1 on the surface of tumor cells and immune cells, the potential immune benefit tumors can be divided into tumor cell proportion score (TPS)-inclined and combined positive score (CPS)-inclined types. The TPS-inclined type includes NSCLC, melanoma, and renal cell carcinoma. 192 , 451 , 453 , 454 Patients with positive tumor PD-L1 expression (TPS type) had a higher remission rate and were positively correlated with tumor quantity. 192 , 454 , 455 , 456 , 457 However, further studies have shown that PD-1 is not only expressed in tumor cells, but also in tumor-infiltrating immune cells. The total level of PD-L1 expression in tumors and infiltrating immune cells (CPS type) is more sensitive than TPS in predicting the efficacy of PD-1. 453 , 458 Clinical studies have confirmed the survival benefits of PD-1 inhibitors in CPS-inclined tumors, such as head and neck squamous cell carcinoma and esophageal, gastric, triple-negative breast, urothelial, cervical, and ovarian cancers. 191 , 459 , 460 , 461 , 462 , 463 , 464 , 465 , 466

Multi-target TKI specificity : Different cancer species show different responses in the clinical application of multitarget TKIs because of their different target spectra coverage. To optimize the selection of drugs in clinical practice, we divided multitarget TKIs in the “omnipotent combination” into six categories, namely, pan-cancer-prone (anlotinib and apatinib), neuroendocrine cancer-prone (sulfatinib), chemotherapy insensitivity prone (lenvatinib), renal cancer-prone (sunitinib, axitinib, and cabozantinib), gastrointestinal cancer-prone (fruquintinib and regorafinib), and liver cancer-prone (sorafenib and regorafenib), presenting with IC 50 values for different targets (Fig. 5 ). 467 , 468 , 469 , 470 , 471 , 472 , 473 , 474 , 475 , 476

figure 5

The inhibition power of common multitarget TKIs on different targets. The IC 50 (nM) for different targets in different tumor types of multitarget TKIs are shown. The application preference of multitarget TKIs in multi-cancer with common characteristics has been summarized

The high-intensity blockade of VEGFR2 by the pan-cancer-prone TKIs, apatinib and anlotinib, empowers them with stronger cross-tumor differential compatibility. As mentioned for the combined drug basket, both anlotinib and apatinib can be used in the pan-cancer combined drug basket.

The chemotherapy-insensitive cancer-prone TKI lenvatinib tends to comprehensively inhibit various growth factors, including VEGFR/FGFR/PDGFR, which may dominate proliferation in chemotherapy-insensitive tumors. 477 , 478 , 479 Lenvatinib combined with the PD-1 inhibitor pembrolizumab has been shown to be effective in metastatic liver cancer, renal cell carcinoma, melanoma, endometrial cancer, and gastric cancer. 480 , 481 , 482 , 483 , 484

The neuroendocrine cancer-prone TKI sulfatinib monotherapy with a disease control rate of up to 90% in neuroendocrine tumors (NET) perfectly interprets its rationale for tumor specificity. 485 Sulfatinib also reduces the progression risk of pancreatic and extrapancreatic NET by 51% and 67%, respectively. 486 , 487 Furthermore, sulfatinib inhibits tumor invasion of myeloid-derived suppressor cells (MDSCs) by specifically targeting CSF-1R, reducing the number or changing the phenotype of tumor-associated macrophages, upregulating the ratio of CD8 + /CD4 + T cells, thereby improving the combined immunotherapy efficacy. 488 , 489 , 490 , 491 The combination of sulfatinib and the PD-1 inhibitor treprinumab has an efficacy of 24% in advanced solid tumors (neuroendocrine cancer and gastrointestinal tumors with high neuroendocrine differentiation), in which standard treatment failed. 492

Renal cancer-prone TKIs have clear therapeutic effects in renal cell carcinoma, and research on soft tissue sarcoma can draw on work related to renal cancer because of their similar pathological type. In addition to the inhibition of VEGFR2, sunitinib, axitinib, and cabozantinib also inhibit tumor proliferation by blocking the MEK/ERK and SAPK/JNK pathways and inhibiting the autophosphorylation of KIT, RET, and FLT3, which are usually activated in these two types of tumors. 493 , 494 , 495 , 496 The efficacy of sunitinib, axitinib, and cabozantinib combined with PD-1 inhibitors has been confirmed in renal cell carcinoma and soft tissue sarcoma. 390 , 497 , 498 , 499 , 500 , 501 , 502 , 503 , 504

Gastrointestinal cancer-prone TKIs, such as fruquintinib and regorafinib, combined with PD-1 inhibitors, have been proven to be effective in gastric and colorectal cancers. 505 , 506 , 507 , 508 The therapeutic value of fruquintinib may have been underestimated in the past.

The liver cancer-prone TKIs Sorafenib and Regorafenib have been widely used to treat liver cancer. This clinical preference may be related to the rich blood supply to the liver, although the specific mechanism remains unclear. Sorafenib and PD-1 inhibition therapies improve the prognosis of patients with liver cancer. 509 The survival benefit of sorafenib is positively correlated with the level of IFN-γ + /CD8 + T cells, whereas PD-1 inhibition enhances the local concentration of antineoplastic drugs by increasing blood perfusion through CD8 + T-cell accumulation and IFN-γ production. 510 , 511 , 512 Similarly, regorafenib and PD-1 inhibitors are highly effective in the posterior-line treatment of liver cancer. 513

The pan-cancer clinical design does not mean that tumor species should not be screened. Instead, the inclusion criteria for tumor species should be formulated based on a comprehensive consideration of the biological behavior of the tumor species and the characteristics of the drug. The cancer relative specificity constantly changes with ongoing preclinical and post-clinical evidence. Therefore, the cancer relative specificity concept is more important than the results we have summarized.

Dynamic precision

Proliferation-dependent genetic characteristics of tumors constantly change dynamically under natural progression and therapeutic pressure. Accordingly, the drug-target relationship in new trial design should be considered with respect to variations in tumor characteristics. We focused on two types of dynamic target changes that have a considerable impact on the treatment strategy: from presence to absence, signifying the clearance of the driving target after treatment; and from absence to presence, signifying neuroendocrine transformation after treatment in non-neuroendocrine tumors (Fig. 4b ).

Targets from presence to absence

HER2 clearance occurs in breast and gastric cancers with low target expression intensity but high anti-HER2 therapy intensity. After patients with HER2-positive early-stage breast cancer received T-DM1 or trastuzumab neoadjuvant therapy, the residual lesions in 8.3% of the patients became HER2-negative. 514 HER2 also changed from positive to negative in 8.6% of patients with advanced breast cancer with bone metastasis. 515 Similarly, in the T-ACT and GASTHER3 studies of advanced gastric cancer, 69% and 29.1% of patients treated with trastuzumab combined with chemotherapy became HER2-negative, respectively. 516 , 517

However, the HER2-ADC still had strong disease control ability after the HER2 status changed from positive to negative. In patients with early breast cancer whose HER2 turned negative after neoadjuvant therapy, the 3-year disease-free survival of patients treated with T-DM1 was 100%, whereas that of patients treated with trastuzumab was only 70.1%. 514 DS-8201 has also been approved for patients with breast cancer with low HER2 (IHC1 + ) expression based on DESTINY-Breast04 studies. 518 Similarly, in the DESTINY-Gastirc01 study of advanced gastric cancer, the disease control rate of DS-8201 in HER2-negative (HER2 IHC ≤ 1 + ) patients was as high as 71.5%, and the median duration of response was 12.5 months. 519

Target clearance after treatment is widespread in other tumor species and targets. For example, after first-line treatment of colon cancer, RAS and BRAF clearance occurred in 42.6% and 50% of patients with RAS and BRAF mutations, respectively. 520 In addition, the incidence of microsatellite instability (MSI) in colorectal cancer was higher in the early stages than in late stages. 521 Therefore, defining more characteristic tumor species and targets and further exploring treatment after target clearance is the future direction of dynamic precision clinical trial design. Furthermore, researchers should fully consider the potential impact of past treatments on the biological behavior of the tumor in a clinical trial design.

Targets from absence to presence

Neuroendocrine transformation characterized by presence of TP53 and RB1 variation is gradually becoming a common state of assimilation after multiline therapy. Profiting from the application of secondary biopsy after drug resistance, we observed the phenomenon of “neuroendocrine spectrum plasticity,” which means that non-neuroendocrine (non-NE) epithelial carcinoma changes to an invasive NE phenotype. 522 Neuroendocrine transformation is widely found in solid tumors, such as lung cancer, prostate cancer, breast cancer, gastrointestinal tumors, and head and neck carcinoma, but it has poor efficacy owing to the lack of specific targets. Although other types of neuroendocrine carcinoma (NEC) can follow the treatment paradigm of small cell lung cancer (SCLC) according to the basket concept of the same treatment for different tumors, the efficacy of etoposide and platinum regimens in gastroesophageal, colorectal, pancreatic, prostate, large-cell lung, and other neuroendocrine cancers is limited. 523 , 524 , 525 , 526

The entire gene-expression profile of tumors changes greatly after neuroendocrine transformation, along with the target feature changing from driving gene mutations to extensive gene variation. 527 Moreover, mutations with complex functions, such as NOTCH inactivation and TP53 and RB1 deletions, have been found to play an important role in the transformation of SCLC and extrapulmonary small cell carcinoma. 528 , 529 , 530 , 531 The extensive pattern of genetic variation in neuroendocrine cancer requires carpet-bombing therapy, based on immune checkpoint inhibitors combined with chemotherapy or anti-vascular targeting, to achieve long-term disease control. An etoposide and platinum regimen combined with ICB has been shown to achieve good efficacy and survival benefits in patients with advanced unresectable gastroenteropancreatic cancer, unidentified primary neuroendocrine neoplasms, and SCLC. 532 , 533 , 534 The ORR of toripalimab combined with sulfatinib in patients with advanced NEC was 33%. 492 Similarly, the ORR of atezolizumab combined with bevacizumab in pancreatic and extrapancreatic NET were 20% and 15%, respectively. 535

The transformation of tumors into a state of multidrug resistance after multiline therapeutic pressure is the main evolutionary path of pan-cancer species. In addition to treatment pressure, tumor natural evolution may also result in changes in targets. For example, the HER2-positive rate in both advanced colon cancer and breast cancer were higher than that in early stage. 536 , 537 , 538 Accordingly, identifying pan-cancer posterior-line homogeneity status and dealing with broad-spectrum biological effect drugs are meaningful directions for clinical trials in the era of precision oncology.

Intelligent precision

Innovative thinking based on underlying biological logic is the primary version of new clinical design in the era of precision medicine 2.0. However, with the emergence of bioinformatics data brought about by technological progress, there is a strong demand for tools with powerful and flexible analytical capabilities. Further, complex and heterogeneous data in new clinical trials have increased this demand. Therefore, we propose the advanced version of “Intelligent Precision” to integrate intelligent technology support with a new clinical trial design.

Artificial intelligence (AI) and machine-learning algorithms have significantly improved the width and depth of data mining that traditional thinking models cannot accomplish. The disease diagnosis classification abilities of AI algorithms such as deep convolutional neural networks based on image recognition have been proven to be effective in the field of diabetes and oncology. The diagnostic accuracy is comparable to that of clinicians. 539 , 540 The AI algorithms for disease progression modeling are also being developed to accurately characterize complexity and heterogeneity of neurological diseases, such as AD and Huntington’s disease. 541 , 542 , 543 The formulation of more precise biomarkers and molecular subtypes in a clinical trial design will further improve therapeutic efficacy. Furthermore, intelligent technology also enables continuous data collection, reducing the negative impact of subjective measurements on data validity and regional barrier pressure on long-term research follow-up such as platform trials. Intelligent-precision-guided technology support can optimize the design of new clinical trials by analyzing and interpreting omics data and dynamic monitoring of patients, thereby assisting in the design of more feasible and effective trial protocols.

Intelligent precision incorporates histological heterogeneity in a basket trial design through comprehensive analysis of pan-cancer data. The pan-cancer data analysis of AI can reveal the heterogeneity of biomarkers between different diseases and guide the design of precise treatment plans. Researchers proposed the “comboSC” AI algorithm to 119 tumor samples of 15 tumor types, demonstrating its widespread practicality and superior performance in optimizing combination therapy plans in different cancer types. 544

Intelligent precision identifies more accurate and diverse molecular subtype in an umbrella trial design through in-depth mining of multi-omics data. The analysis of genomic, transcriptome, and proteomic data by AI can fully reproduce the biological activity patterns from DNA to proteins. Researchers using spatial multi-omics techniques to analyze colon cancer samples have found that immune-exclusion (IEX) markers composed of DDR1, TGFBI, PAK4, and DPEP1 genes may become important predictors in the stratification of immunotherapy. 545 In addition to bio-omics, clinical imaging omics data can also be fully utilized in an umbrella trial. The immune-consensus molecular subtype CMS (imCMS) of colon cancer based on AI algorithms in image-omics accurately classifies TCGA samples that cannot be classified by RNA expression profiles, compensating for the limitations of bio-omics in patient classification. 546

Intelligent precision improves feasibility and patient compliance in long-term platform trial design through real-world data analysis. First, AI can efficiently estimate existing therapeutic efficacy data during platform trials (including successful and failed data) to verify the necessity of trial implementation. Second, in terms of patient recruitment, AI algorithms can search, analyze, and interpret big data such as electronic medical records, genetic testing omics data, and medical imaging data. Then, AI identifies potential clinical trial subjects and matches them with appropriate arms in platform trials, thereby significantly improving recruitment efficiency and reducing costs. Third, in terms of patient management, AI algorithms assist in continuously monitoring and managing patients through automated data collection in patient drug use, organ function, efficacy evaluation, adverse reactions, and other patient-centered data. Moreover, real-time and dynamic data monitoring further aligns with flexible designs represented by platform clinical trials, ensuring the accuracy of the verifying direction.

Based on a full understanding of underlying biological mechanisms, the Precision Pro, Dynamic Precision, and Intelligent Precision concept will assist clinicians and trial-related researchers develop full-scale precise therapeutic strategies (Fig. 6 ).

figure 6

The future direction of new clinical trial design in precision medicine: Precision Pro, Dynamic Precision, and Intelligent Precision

Conclusions and perspectives

In summary, the rapid development of high-throughput sequencing and multi-omics technology has created more possibilities for precision medicine. The new biomarker-guided clinical trial designs including basket, umbrella and platform trials have successfully transformed these possibilities into clinical benefits for patients. By sorting out the discovery and development of the new trial designs, trial-related researchers would be able to improve their understanding of this new methodology. However, with the gradual exploration of simple gene alterations and molecular typing, the innovation of trial methodology itself can no longer keep up with the individualized therapeutic demands. The cognition of the new biomarker-guided clinical trial design should not only focus on the primary idea of matching the targets, drugs, and diseases but also on the in-depth underlying biological logic of the origin and progression of diseases. The deep exploration of biomarker-related data will be full of opportunities for precision medicine in the next decade. We propose future direction for new clinical trials including Precision Pro, Dynamic Precision and Intelligent Precision. We look forward to jointly promoting clinical precision treatment from the perspectives of biological rationality and practical feasibility in the era of precision medicine.

The precise thinking model of biological mechanism-driven therapy will be the first principle in future clinical trial design. According to fully integrating theoretical innovation and intelligent technology to address the practical therapeutic demands of individual patients, the ability to control and manage disease precisely will be highly improved. The knowledge system construction based on new clinical trial design will assist researchers in grasping the decision occlusion and making a significant contribution to the rapid development of precision medicine era 2.0.

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Acknowledgements

This work was supported by Chinese National Natural Science Funding [grant number 82172710, 2021]; State Key Program for Chronic non-communicable Disease Prevention and Control of the Ministry of Science and Technology, China [grant number 2017YFC1309202, 2017]; Medical Innovation Research Project of Shanghai Science and Technology Commission (grant number 20Y11914400, 2020); Outstanding Discipline Leader Project in Public Health in Shanghai (grant number GWVI-11.2-XD22, 2023); Innovation Clinical Research Project of Shanghai Changzheng Hospital [grant number 2020YLCYJ-Z03, 2020; grant number 2023YJBF-FH05, 2023].

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Xiao-Peng Duan, Bao-Dong Qin, Xiao-Dong Jiao, Ke Liu, Zhan Wang & Yuan-Sheng Zang

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Z.Y.S. conceptualized the study and drafted and revised the manuscript. D.X.P., Q.B.D., J.X.D., L.K., and W.Z. drafted and checked the manuscript. D.X.P., Q.B.D., and J.X.D. drew the figures. All authors have read and approved the article.

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Duan, XP., Qin, BD., Jiao, XD. et al. New clinical trial design in precision medicine: discovery, development and direction. Sig Transduct Target Ther 9 , 57 (2024). https://doi.org/10.1038/s41392-024-01760-0

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Received : 30 November 2023

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DOI : https://doi.org/10.1038/s41392-024-01760-0

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From laboratory to patient: the journey of a centrally authorised medicine

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At its best, research training is an intentional and purposeful activity that is the product of a thoughtful analysis of the background, interests and needs of each trainee. This includes developing a mentoring plan that assesses the needs and goals of each student and postdoc, describes short- and long-term career objectives, and identifies professional development activities needed to reach them. The individual development plan (IDP) is a tool to help in this planning process and to facilitate communication between mentees and mentors. An IDP should be viewed as a dynamic document that is periodically reviewed and updated throughout an individual’s training. IDPs are of proven value at any stage, from the undergraduate to the postdoctoral level.

The concepts of mentoring plans and IDPs are not new, but recognition of their role and effectiveness in research training is fairly recent. NIGMS encourages the use of IDPs at all training levels. The use of IDPs is evaluated in the grant application review process, and must be described in NIH Research Performance Progress Reports ( NOT-OD-114-13​ ), for programs designed to provide training and professional development opportunities. Examples of IDPs can be found on the websites of these organizations:​

  • American Association for the Advancement of Science/Science Careers myIDP
  • American Chemical Society ChemIDP
  • American Psychological Association Resources for IDPs
  • Imagine PhD Career Exploration and Planning Tool for humanities and social sciences

clinical development plan in research

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clinical development plan in research

  • Health and social care
  • Research and innovation in health and social care
  • The Future of UK Clinical Research Delivery: 2022 to 2025 implementation plan
  • Department of Health & Social Care

The Future of Clinical Research Delivery: 2022 to 2025 implementation plan

Published 30 June 2022

clinical development plan in research

© Crown copyright 2022

This publication is licensed under the terms of the Open Government Licence v3.0 except where otherwise stated. To view this licence, visit nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: [email protected] .

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This publication is available at https://www.gov.uk/government/publications/the-future-of-uk-clinical-research-delivery-2022-to-2025-implementation-plan/the-future-of-clinical-research-delivery-2022-to-2025-implementation-plan

Ministerial foreword

In 2021 we, the UK and devolved governments, set out our vision for the future of clinical research delivery. Saving and Improving Lives: The Future of UK Clinical Research Delivery lays out our ambition to create a world-leading UK clinical research environment that is more efficient, more effective and more resilient, with research delivery embedded across the NHS. We also set out our plans for 2021 to 2022 , as the first steps in delivering on the vision.

A digitally enabled, pro-innovation and people-centred clinical research environment is key to realising our ambitions to make the UK a world-leading hub for life sciences that delivers improved health outcomes for our citizens and attracts investment from all over the world. We will harness the explosion in innovative technologies to benefit patient outcomes and make a tangible difference to people’s lives across the UK. Clinical research is crucial to these efforts, as the lynchpin to driving improvements in healthcare.

As we emerge from the shadow of the pandemic and look to the future, we will work together to ensure that the UK is seen to be one of the best places in the world to deliver cutting-edge clinical research. We are working hard both to recover research delivery in the NHS and to use this moment as a catalyst for transformation, building increased resilience and embedding innovative practice as we go. The cross-sector partnerships built through the UK Clinical Research Recovery, Resilience and Growth ( RRG ) programme provide the strong foundations we need to succeed, drawing on expertise and support from industry, academia, charities, patients and the public, regulators, funders and the NHS.

Our vision was clear on the importance of unleashing the true potential of clinical research across the UK, addressing long-standing health inequalities and improving the lives of us all. We, the UK and devolved governments, are excited to set out the next stages as we look to turn our vision into a reality and build a clinical research system of the future.

Lord Kamall of Edmonton in the London Borough of Enfield Parliamentary Under Secretary of State for Technology, Innovation and Life Sciences Department of Health and Social Care

Robin Swann Minister for Health Northern Ireland Executive

Eluned Morgan Minister for Health and Social Services Welsh Government

Humza Yousaf Cabinet Secretary for Health and Social Care Scottish Government

Executive summary

In March 2021, we published our bold and ambitious 10 year vision: Saving and Improving Lives: The Future of UK Clinical Research Delivery . This was followed in June 2021 by The Future of UK Clinical Research Delivery: 2021 to 2022 implementation plan setting out the steps we would take to progress the vision in 2021 to 2022.

This phase 2 plan summarises the progress that we have made so far and the actions that we will take over the next 3 years, from 2022 to 2025, ensuring we make the progress necessary to achieve our vision in full by 2031.

This plan has been developed by the cross-sector UK Clinical Research RRG Programme in consultation with stakeholders from across the clinical research ecosystem. Our plan is centred around the 5 overarching themes identified in the vision:

  • a sustainable and supported research workforce to ensure that healthcare staff of all backgrounds and roles are given the right support to deliver clinical research as an essential part of care
  • clinical research embedded in the NHS so that research is increasingly seen as an essential part of healthcare to generate evidence about effective diagnosis, treatment and prevention
  • people-centred research to make it easier for patients, service users and members of the public across the UK to access research and be involved in the design of research, and to have the opportunity to participate
  • streamlined, efficient and innovative research so that the UK is seen as one of the best places in the world to conduct cutting-edge clinical research, driving innovation in healthcare
  • research enabled by data and digital tools to ensure the best use of resources, leveraging the strength of UK health data assets to allow for more high-quality research to be delivered

We have made significant progress over the past year – a new combined review process has led to halving of approval times for new Clinical Trials of Investigational Medicinal Products (CTIMPs) since January 2022 compared to previous separate applications, streamlining the route through the regulatory journey for researchers, the world-leading £200 million data for research and development programme has been announced to invest in health data infrastructure in England with devolved administrations aligning and strengthening their infrastructure; and a new UK-wide professional accreditation scheme for Clinical Research Practitioners ( CRP ) has been launched to help double the size of this important workforce in the future.

However, the recovery of research delivery following the pandemic remains challenging. The Department for Health and Social Care (DHSC) and NHS England are taking firm action to address this, with the support of the devolved administrations, through the ‘Research Reset’ programme. We are committed not only to returning to pre-pandemic levels of performance, but to using this as an opportunity to reform and catalyse the transformation needed to create the flourishing, responsive and resilient system set out in our vision.

The phase 2 plan is aligned with funding confirmed through the government spending review for April 2022 to March 2025 and includes up to £150 million of additional funding from the National Institute for Health and Care Research ( NIHR ) and £25 million additional funding from RRG partners across the UK, complementing up to £200 million in England for the data for research and development programme announced in March 2022 and demonstrating the government’s ongoing commitment to delivering on the UK’s potential as a global life sciences superpower. This funding will enable RRG partners to:

  • recover the UK’s capacity to deliver research through DHSC and NHS England’s Research Reset programme, and aligned work in the devolved administrations, aiming for 80% of all open studies on the NIHR Clinical Research Network (CRN) portfolio to be delivering to time and target by June 2023
  • ensure we can recognise and support our expert workforce, and develop robust workforce plans, providing the basis for strategic investment in capacity development to support achievement of our vision in full
  • broaden responsibility and accountability for research across the NHS, and improve measurement, visibility and recognition of those supporting the delivery of clinical research studies
  • achieve a sector-wide, sustained shift in how studies are designed and delivered so that inclusive, practicable and accessible research is delivered with and for the people with the greatest need and in ways that enable us to tackle the greatest challenges facing the NHS
  • streamline processes, strengthen our regulatory environment and ensure faster approval, set-up and delivery of studies with more predictability and less variation, as well as make it easier to understand and access the UK’s clinical research offer, thereby utilising the unique opportunity to develop a more flexible and improved regulatory model for clinical research outside the EU and improving our attractiveness as a leading destination to conduct cutting edge and global multi-centre clinical studies
  • invest in the infrastructure and tools needed to implement people-centred, innovative data and digitally-enabled methods and increase partnership working across the health data ecosystem to ensure people across the whole of the UK can benefit from these approaches

The RRG programme will oversee the delivery of this plan, continuing to work in partnership with stakeholders across the sector and regularly revisiting the original vision to consider any further actions that will be needed to deliver it in full. In doing so, we will ensure that the NHS is able to tackle the healthcare challenges of the future and people across the UK and around the world will benefit from better health outcomes.

Further information about the RRG programme, including our delivery partners and governance , are available on the dedicated Recovery Resilience and Growth website . Detailed summaries of our progress to date and our future plans will be published on the site on an ongoing basis, providing a central point of information and updates about the programme and our progress towards achievement of the vision. You can also sign up to receive regular email updates on our progress.

UK-wide approach

Health policy is a devolved responsibility, where each of the UK administrations has distinct ownership over implementation. However, we are committed to delivering on a vision with a UK-wide reach and in pursuit of a common goal: to create a seamless and interoperable service across the UK to support clinical research delivery, shaping the future of healthcare and improving people’s lives.

We are therefore further strengthening a joined-up system, where sponsors of both commercial and non-commercial research can easily deliver studies across the UK and people can more easily participate. To ensure compatible and consistent ways of working across England, Scotland, Wales and Northern Ireland many commitments in this plan are focused on UK-wide implementation. Organisations such as MHRA ( Medicines and Healthcare products Regulatory Agency ) and systems such as IRAS ( Integrated Research Application System ) have a UK-wide reach and their actions will have impacts across the country. In some instances, actions are being led by a specific organisation on behalf of the UK, while others will be delivered through UK partnerships – recognising the different legislative and delivery contexts across the UK government and devolved administrations.

The needs of UK citizens and our health research system are broad and diverse. We are committed to maintaining a rich and balanced portfolio of studies in rare and common diseases, ranging from complex, intensive studies in small, highly targeted populations to pragmatic population health research in large cohorts, using a range of methodologies and methods as appropriate to the research questions.

Our vision focuses specifically on the future of UK clinical research delivery. Other types of research, including social care and public health research, are vitally important to provide the evidence necessary to support policy making and service delivery in these areas. Many partners involved in the RRG programme support this broader programme of research activity and other work programmes are underway to enable their development. We expect that many of the improvements we make in the clinical research environment will have benefits for other kinds of research and will work across our organisations and with wider groups of stakeholders to ensure the lessons are shared.

Research reset

As we recover from the pandemic, clinical research delivery is facing unprecedented challenges and there is an urgent need to reset the UK’s research portfolio so we can build for a stronger future.

The number of studies in the NHS is now higher than ever before. This is accounted for by the additional COVID-19 studies, other research that has remained on the portfolio from before the pandemic and has been paused or delayed, together with new studies being funded and coming into the system. In addition, the number of studies in set up is now much higher than pre-pandemic, further increasing the workload for NHS R&D offices and research delivery teams. This is taking place in the context of the recovery of wider NHS services and resourcing the high number of studies is challenging. Throughout this, the resilience of the workforce has been remarkable.

Recovery of the UK’s capacity to deliver clinical research is essential if we are to deliver the ambitions set out in this phase 2 plan. Indeed, many of the challenges the vision seeks to address have been exacerbated by the pandemic, so Research Reset and reform go hand in hand.

Since summer 2020, all delivery partners across the sector have been working to restore the diverse and balanced portfolio of studies which were impacted due to the COVID-19 pandemic. While this has had some positive impact, it has not resulted in the restoration of activity across all studies that were underway before the pandemic. We are taking further action through the Research Reset programme to build back a thriving, sustainable and diverse research and development portfolio within the NHS.

Our objective in implementing Research Reset is to give as many studies as possible the chance of completing and yielding results, generating the evidence needed to improve care and sustain our health system. However, this will require closure of studies that are not viable in the current context to free delivery resources in the system for those studies that can deliver. Lessons must also be learned to reform and increase the resilience of our research system. As part of this we have asked funders and research sponsors to review their active studies to assess the viability of delivering these within the capacity available.

Our aim is for 80% of all open studies on the NIHR CRN portfolio to be delivering to time and target by June 2023. We will take an agile approach to the Research Reset programme, continuously assessing whether further action is required with the input of stakeholders across the sector including patients and the public.

The devolved governments support this approach and we are working together across the UK to ensure synergistic arrangements are in place to promote the smooth delivery of cross-border studies. Each devolved administration will also review possible new eligibility criteria for national delivery support to ensure deliverability within available resources is feasible.

A sustainable and supported research workforce

The UK clinical research workforce has been fundamental to our collective success to date and will be critical to the achievement of our vision in the future. Healthcare and research staff of all backgrounds must be offered rewarding, challenging and exciting careers within clinical research, so that the most talented people can be brought into clinical research, including research delivery and R&D management, as a life-long career. This will help to bolster the capacity of the clinical research system and support a motivated and sustainable workforce. Collectively, we can realise the potential of UK clinical research to improve outcomes for people across the country, sustain our NHS and improve the economy.

Progress over the past 12 months:

  • in England, to support the drive to recover the portfolio, DHSC provided over £30 million of additional funding via the NIHR Clinical Research Network (CRN) in the 2021 to 2022 financial year to increase research delivery capacity, especially in community settings and with a key focus on achieving flexibility and agility in the workforce. The Welsh Government provided £1.7 million to support additional capacity in order to achieve the recovery of non-COVID-19 research, including development of research capacity outside of hospital settings. £3 million of funding from the Department of Health in Northern Ireland has been provided to support the work of a Taskforce established to address clinical research recovery in Northern Ireland
  • the NIHR , working with the devolved administrations, launched a UK census for nurses and midwives working in clinical research in order to understand the true size of this workforce. Data was also sought on location, speciality and banding or grade. It was able to identify that there are at least 7,469 research nurses and midwives across the UK and Ireland working at every level and within all areas of healthcare. This census demonstrates the breadth and depth of nurse and midwife involvement in research across the healthcare sector
  • in June 2021, NIHR on behalf of the UK launched a new UK-wide professional accreditation scheme for Clinical Research Practitioners ( CRP ) as part of efforts to double the number of this important workforce over the next few years. Over 1,000 members have already signed up to the CRP directory
  • NIHR also launched the UK wide Associate Principal Investigator Scheme, which aims to make research a routine part of clinical training so doctors, nurses and allied health professions can become the principle investigators of the future. Over 1,000 health and care professionals had registered for the scheme by April 2022
  • in February 2022, Wales published a vision for research career pathways that outlines recommendations to improve support and encourage more health and social care professionals to embark on research careers

Phase 2 commitments

To continue this progress and build towards a sustainable and supported research workforce, we will ensure we can retain and recognise our expert staff and develop robust workforce plans to provide the basis for strategic investment in capacity development:

  • the RRG Programme will lead the development of a cross-sector research workforce plan to support implementation of our vision in full. Developed over 2022 to 2023, this plan will guide additional investment in our workforce from 2024
  • RRG  partners will ensure workforce plans developed by key healthcare organisations include research requirements, particularly noting the knowledge and skills needed across the wider workforce to deliver research as an essential part of high-quality care. This will include the NHS People Plan , coordinating with Health Education England and DHSC, and equivalent plans in the devolved administrations
  • NHS England, working with its partners is developing a comprehensive, long-term NHS workforce plan. This will include consideration of research requirements to support the delivery of high-quality care
  • Health Education and Improvement Wales, working closely with Welsh Government and the NHS, will develop plans to support and facilitate the nursing, midwifery, allied healthcare professionals and health sciences professions in embracing research as part of their roles and career pathways. Through the development of competency and skills frameworks, Health and Care Research Wales is working to support the inclusion of research delivery roles
  • NIHR will provide investment to support NHS R&D transformation, increase research capacity including nurses, midwives and allied healthcare professionals, and provide more opportunities for rewarding careers in research
  • the  RRG  partners will expand the package of training programmes for the research workforce including through the RCP- NIHR  Credentialing Scheme, the  NIHR  Associate PI scheme, the  NIHR  Nurse and Midwife Leaders Programme, an NHS England programme for executive nurses in Trusts and Integrated Care Systems (ICSs), and a research matron’s toolkit
  • NIHR  and the devolved administrations will invest in learning and support for researchers, so that they are equipped with the expertise and cultural competency to design and deliver people-centred studies to meet the needs of patients, service users and the public, including those from underserved communities and groups not traditionally served by research
  • in support for NHS R&D transformation, Wales will invest in a new Health and Care Research Wales Faculty, which will include increased investment in the NHS Research Time scheme to help develop the next generation of principal and chief investigators in the NHS alongside enhanced mentorship schemes

Clinical research delivery embedded in the NHS

Our aim is to create a step change in the delivery of clinical research in the NHS, so that research is increasingly seen as an essential part of healthcare. Making research an intrinsic part of clinical care means that patients and service users can expect to have access to the most cutting-edge treatments and technologies. We want the NHS to actively participate in generating evidence about effective diagnosis, prevention and treatment through research. By acknowledging the important role of the whole of the healthcare workforce in clinical research delivery, we can ensure everyone is empowered to get involved in research and further boost overall capacity for research in the NHS and wider health system. Measuring clinical research will also support NHS leaders to drive behaviour change and incentivise more engagement in research activity. Finally, ensuring clinical research is embedded within the NHS will be essential in giving the UK the capacity to grow in an increasingly competitive global market.

Progress in Phase 1:

the UK Research and Development (UKRD) and NHS R&D Forum, with NIHR , developed the ‘Best Patient Care, Clinical Research and You’ online guide that aims to help busy non-research staff become more aware of the impact of research in their trust

the General Medical Council (GMC) published its position statement Normalising Research - Promoting Research for all Doctors

the Allied Health Professions’ Research and Innovation Strategy was published, addressing the key areas which impact research and innovation across all health professions in England

the NHS Chief Nursing Officer (CNO) for England published the strategic plan for research for nurses. The plan aims to create a people-centred research environment that empowers nurses to lead, participate in and deliver clinical research that is fully embedded in practice and professional decision making

together with existing strategies in the devolved administrations, we are continuing the development of UK-wide support for the key professional groups

In order to more deeply embed clinical research in the NHS, we will take action to broaden responsibility and accountability for research across the NHS, and improve measurement, visibility and recognition of those supporting the delivery of clinical research studies. The role of healthcare leaders and professionals will be vital in this:

NHS England and the devolved administrations will each develop clear and tangible plans to work towards embedding responsibility and accountability for research in healthcare delivery

  • NHS England and the devolved administrations will use existing legal duties and planning frameworks to promote and facilitate research. Each administration will develop assurance frameworks and use existing channels such as annual reports and joint forward plans to help cement the importance of research as a core duty. In England this will include the implementation of the Health and Care Act . Integrated Care Boards (ICBs), NHS England and the Secretary of State for Health and Social Care will all have enhanced duties to report on how they are promoting and facilitating research. NHS England will also lead development of a research framework for ICBs to help them understand and fulfil the minimum expectations around research that the Health and Care Act sets. This will herald a significant shift in how research is considered within the NHS and drive a greater responsibility for more research activity across all sites. In Wales, we will explore opportunities provided through the development of the NHS Executive in Wales to strengthen the national oversight of NHS research
  • we will work across the UK administrations to introduce new metrics and measures to increase the visibility and recognition for undertaking and supporting clinical research across NHS organisations
  • NIHR , working in partnership with NHS England and the devolved governments, like the Scottish Health Research Register (SHARE), will continue to enhance the UK Be Part of Research platform through collaboration with other existing registries. National digital channels (for example the NHS App or NHS website) will feed into the Be Part of Research platform

The RRG programme will ensure strategic co-ordination of this work across the UK clinical research ecosystem, supporting progress and ensuring alignment of initiatives, as well as identifying key areas where we can go further in the next 3 years.

People-centred research 

The vision set out our ambition for more people-centred research, designed to make it easier for patients, service users and members of the public to access research of relevance to them and be involved in its design. To achieve this, delivery of research in community, primary care and virtual settings needs to increase, with delivery designed around the needs of the people participating in it. Alongside this, we will ensure we maintain our world-leading specialist research infrastructure, which provides opportunities for people to access early-phase studies, complex therapies and devices.

  • delivering studies such as PANORAMIC and IBS-RELIEVE has demonstrated the UK’s growing ability to harness technology and conduct studies virtually and in the community
  • HRA and MHRA, in collaboration with NHS Research Scotland, Health and Social Care Northern Ireland (the equivalent to the NHS in Northern Ireland), and Health and Social Care Research Wales, have published UK-wide guidance on the set up of interventional research to enable research to be delivered across organisational boundaries and to help take research to where people might find it easier to take part, for example using hub and spoke models
  • the NIHR led UK Working Group on Remote Trial Delivery published a report in June, which discussed the challenges and opportunities in remote trial delivery and provided guidance for researchers
  • the NIHR Race Equality Framework was piloted by industry. This self-assessment tool helps organisations to improve racial equality in health and care research
  • partners across the UK are working together to ensure patient and public involvement in research in a variety of ways including through regulation, ethics, payment for public contributors and development of new public engagement strategies. This includes the publication of a shared commitment to public involvement in research to ensure involvement is built into study design, delivery, and dissemination
  • in Northern Ireland the Clinical Research Recovery Resilience and Growth Taskforce implementation plan includes a patient and public engagement and involvement sub-group, which is focused on the development of patient and public centred priorities, and an innovation sub-group planning approaches to innovative and people-centred trial design
  • in Wales, the ‘Discover your Role’ programme is underway, with a co-created action plan to ensure that people are at the heart of new developments in research
  • the NHS Research Scotland patient and public involvement workshop series completed and reported in September 2021. Findings from the workshops and the Scottish Patient Public Involvement Survey are informing work to support greater visibility and connectivity, increased diversity and representation, and a review of the current mechanisms for pre-award funding
  • RRG partners have partnered with the International Standard Randomised Controlled Trial Number (ISRCTN) registry to make it easy for researchers to fulfil their transparency responsibilities. Trial registration is the first step to ensuring research transparency from the outset, and from 2022 the HRA began automatic registration of clinical research with ISRCTN , taking the burden away from research sponsors and researchers

Our aim will be to achieve a sector-wide, sustained shift in how studies are designed and delivered so that inclusive, practicable and accessible research is delivered with and for the people with the greatest need and in ways that enable us to tackle the greatest challenges facing the NHS. The UK’s ability to deliver diverse trials and studies will also give us a competitive advantage on the global stage, attracting researchers from around the world to base their studies here:

  • the HRA is leading a cross-sector project , co-produced with public contributors, to collect evidence about how high quality, people-centred clinical research is done well: finding out what matters most, what ‘good’ looks like and what might be making it difficult. It will make recommendations to help improve the way clinical research happens in the UK and disseminate information about actions and resources developed by partners
  • NIHR will invest in the development of skills and tools for innovative trial delivery, increasing the confidence and ability of our researchers to design and deliver studies in people-centred ways
  • NHS England will launch a toolkit that could be used by researchers across the UK to help them engage more effectively with selected underserved communities. NIHR will also promote increased use of the resources developed by the NIHR INCLUDE project project which enable researchers to increase inclusion of underserved communities in their research
  • NIHR and NHS Digital will develop mechanisms to monitor the diversity of people participating in NIHR Clinical Research Network portfolio studies in England in order that we can understand where improvement is needed and what action will be most effective.
  • in England, the NHS Accelerated Access Collaborative will invest in demand signalling (the process of identifying, prioritising and articulating the most important research questions) and horizon scanning (the process of identifying and better understanding emerging transformational technologies of potential benefit to the NHS and our communities) to improve identification of the most needed treatments and technologies and rapidly bring these into clinical use
  • in Scotland, SHIP is leading the new Scottish Health and Industry Partnership Demand Signalling Plan. This new framework will support identification and decision making around key strategic challenges and operational pressures to accelerate NHS Scotland Re-mobilisation, Recovery and Re-design, aligning with delivery of the NHS Recovery Plan 2021 to 2026, and the Life Science Vision healthcare missions
  • medical research charities play an important role in supporting people-centred research, utilising their contacts with patients and communities, and prioritising their needs when setting a research agenda. The Association of Medical Research Charities (AMRC) will be working with NIHR and NHS England to formalise this work – and will share findings once developed across the UK

The RRG programme will ensure strategic co-ordination of this work across the UK clinical research ecosystem, supporting progress and ensuring alignment of initiatives, as well as identifying key areas where we can go further within the next 3 years.

Work is also underway to improve access to research through digitised recruitment as detailed in the section on research delivery enabled by data and digital tools.

Streamlined, efficient and innovative research 

Facilitating research to happen quickly and predictably will not only bolster our economy and status as a life sciences superpower, but will also drive innovation, which translates into improved care. We have the opportunity to develop a more flexible and improved regulatory model for clinical research outside the EU in the best interests of patients and the public, and since the publication of the vision we have been building towards our aims of supporting a more streamlined, efficient, and effective clinical research environment.

Progress in phase 1:

  • in a new approach to licensing and regulation implemented by the MHRA, NICE, the All Wales Therapeutics and Toxicology Centre (AWTTC) and the Scottish Medicines Consortium (SMC), over 100 innovation passports have been issued through the Innovative Licensing and Access Pathway (ILAP), to robustly and safely support the path to market of the most innovative, transformative treatments
  • the combined review from the MHRA and the UK Research Ethics Service, in collaboration with the HRA facilitates speedier set up for clinical research trials by requiring applicants to only make a single application for both Clinical Trial Authorisation (CTA) and Research Ethics Committee (REC) approval. Since January 2022, all new Clinical Trials of Investigational Medicinal Products (CTIMPS) in the UK have been benefiting from the combined review, halving the approval time compared with separate applications over the period 2018 to 2021
  • the range of model UK contracts agreed with industry and the NHS has been expanded including the first UK-wide model Clinical Investigations Agreement (UK mCIA) for research in medical devices, and the first Model Confidentiality Disclosure Agreement (mCDA) for use by companies with potential NHS sites has also been launched
  • the MHRA ran a public consultation on proposals for legislative changes for clinical research. The proposals aim to promote patient and public involvement in clinical research, increase the diversity of participants, streamline clinical research approvals, enable innovation, and enhance clinical research transparency. The consultation sought the views of the wider public, clinical research participants, researchers, developers, manufacturers, sponsors, investigators, and healthcare professionals to help shape this important future legislation and over 2,000 responses were received
  • NHS England published refreshed guidance on Excess Treatment Costs (ETCs), expanding the framework to include studies where Clinical Commissioning Groups are the commissioner for the service where the study takes place and setting out the provider types which can utilise the national payment system in England. From April 2022 the provider thresholds for ETCs has been reduced, meaning that the number of providers who receive ETCs will increase

In our next phase of work, we will streamline processes, further strengthen our regulatory environment and ensure faster approval, set-up and delivery of studies with more predictability and less variation. Significant emphasis will be placed on reducing unwarranted variation in ways of working across sites and other research infrastructure, so that conducting clinical research in the UK is high quality, predictable and reliable. This will be particularly important for commercial contract research as speed and predictability is key to the UK’s competitiveness and our ability to attract global multi-centre research studies into the NHS.

The UK is globally recognised for its scientific expertise and dedicated research infrastructure. However, the devolved healthcare systems and competition between organisations has created a complex landscape which is difficult to navigate and creates barriers for researchers and companies. We will work across the UK clinical research system to ensure it is easier to understand and is attractive as a leading destination to conduct cutting edge clinical studies.

To improve research approvals and strengthen our regulatory frameworks:

  • a single UK approval service will replace HRA and HCRW Approval and equivalent process in Northern Ireland and Scotland, and site permission and confirmation processes across the UK
  • MHRA will work with HRA in continuing the development of IRAS to streamline health technology and medicines research, and HRA will explore whether it is viable to embed a fast-track ethics review as part of combined review
  • HRA will lead UK-wide work to further expand the suite of model agreements, including decentralised and other innovative delivery models as well as particular fields of innovative products such as Advanced Therapy Medicinal Products
  • following public consultation on proposals for legislative changes for clinical research, the MHRA is now carefully analysing the responses received, preparing a Government response and developing secondary legislation to improve and strengthen our clinical research legislation
  • MHRA will support risk-proportionate trial conduct and monitoring, including through Good Clinical Practice (GCP) guidance and pragmatic investigator guidance, and will work with HRA to develop guidance on use of in vitro diagnostics (IVDs) in clinical research
  • MHRA and HRA will also establish a comprehensive stakeholder reference group to assist with guidance generation on new legislation and ensure there is a common understanding of regulatory requirements that will enhance the UK’s international attractiveness as a place to conduct multinational trials

To improve study set-up:

  • learning lessons from delivering COVID-19 research, we will enhance our early feedback service offer via the NIHR CRN to support study design that is optimised for delivery and explore how we can further match research delivery demand to capacity across the UK
  • we will implement the UK-wide National Contract Value Review (NCVR), with the aim of expediting the costing elements of the contracting process across NHS Trusts to ensure costing does not delay study set-up. From 1 April 2022, the NCVR will begin to replace the current time-consuming process whereby each NHS organisation negotiates with each commercial sponsor for every study in order to agree bespoke contract value. The programme will be monitored throughout implementation to ensure lessons can be learnt and the process improved to ensure it achieves its aims. The existing single cost and contract review model in Scotland and across the NIHR Patient Recruitment Centres in England will integrate with NCVR as it develops, supporting more effective UK alignment and efficiency
  • the Experimental Cancer Medicine Centre (ECMC) Network, with support from MHRA and HRA, will complete their pilot to set up Phase I oncology trials within 80 days of IRAS submission. Learning from this programme will be shared to enable improved set-up performance in other specialities
  • RRG programme partners will identify and establish mechanisms to achieve efficient costing and contracting across other parts of the health system, supporting and enabling an increase in decentralised study designs and research taking place in primary care and community settings.
  • DHSC and NHS England will lead a review of their current Excess Treatment Costs (ETC) process in England to review experiences of the policy and t explore how best we can support non-commercial research in the NHS

To make the UK offer easier to navigate:

  • understand UK capabilities to deliver their study at all stages of the protocol development and delivery pathway
  • connect with the right part of the system to help them at the right time
  • access the network of expertise and resources available to create a package of support to deliver studies efficiently
  • MHRA, NICE, AWTTC and SMC will work with partners across the UK to develop ILAP as an effective route into the UK research system, particularly through the development of a support toolkit
  • the further development of IRAS will also provide navigation and signposting through the research journey, directing applicants to relevant guidance and advice. Through interfaces with other systems it will reduce burden and duplication

Research delivery enabled by data and digital tools

The UK’s health data offering is one of our global strengths due to our national health systems and cradle-to-grave healthcare records. Investing in data and digital tools, and making ethical use of them to support clinical research, for example by making it easier to recruit and follow-up participants, increases the efficiency and effectiveness of the clinical research process. These tools also increase the resilience and sustainability of the healthcare system and reduce the burden on the NHS workforce.

  • the data strategy for health and social care in England was published in June 2022
  • up to £200 million committed to support NHS-led health research (subject to business case) was announced on 2 March 2022 to invest in health data infrastructure to support research and development in England, with parallel activity in the devolved governments

the NHS-Galleri trial demonstrated the potential for the use of healthcare data to support rapid, large scale recruitment to and delivery of clinical studies in the NHS. The Accelerated Access Collaborative (AAC), led by NHS England, coordinated the design and set up of a 2 part, real-world demonstration project involving clinical data capture from NHS Digital and NIHR , and was a demonstrator for the ‘Find, Recruit and Follow-up’ service and NHS DigiTrials. The trial has already passed the halfway point in their recruitment of participants, with over 100,000 enrolled following the launch in autumn 2021

  • each delivery partner funded as part of year one of the ‘Find Recruit and Follow-up’ service launched Minimum Viable Products (MVPs) of their services including: NHS DigiTrials, which has successfully facilitated 28 active trials through its service with a further 8 in application and 12 in pre-application; NIHR CRN launched its early stage ‘concierge’ service, with 2 companies and 4 data service providers as early users; and HRA, which agreed an approach to review by the Confidentiality Advisory Group which will enable more efficient study set up in future. In addition, the MHRA Clinical Practice Research Datalink (CPRD) has launched SPRINT (Speedy Recruitment into Trials ), a data-enabled research service that facilitates rapid feasibility and patient recruitment into industry sponsored phase 2 to 4 trials across the UK
  • making use of real-world data (RWD) in and for clinical research is now a reality, supported by MHRA’s published guidance . This is the start of a series of guidelines to provide general points to consider for sponsors planning to conduct clinical research using RWD to support regulatory decision making

The next 3 years will see a revolution in how we use data across the health system. We will go further in utilising innovative data-driven methods and digital tools to transform the way we design, manage and deliver people-centred clinical research studies across the whole of the UK. We will achieve this by increasing the use of data and digital tools in recruitment and follow up, and by improving access to data via Trusted Research Environments (TREs: a type of Secure Data Environment, secure spaces where approved researchers can access rich, linked datasets) and through increased partnership working across the UK health data ecosystem.

We are very clear that the opportunity to use health data must be done in a way which is secure and trusted by members of the public, so governance and oversight processes must be both as efficient as possible and transparent, robust and trustworthy. Public trust and understanding of how data is being used to support research continues to be critical in developing appropriate activities. We will be working together to consider how to implement recommendations from the Goldacre Review , and ensuring that all work is supported by comprehensive public involvement and engagement activity.

To improve study planning, recruitment and follow-up:

  • the Find, Recruit and Follow-up service will work across the 4 administrations to consider how activity can be expanded to include SAIL, Scottish Health Research Register, data infrastructure in Northern Ireland, NIHR BioResource and other key national data infrastructure, increasing opportunities for people to quickly and easily access research of relevance to them
  • NHS DigiTrials and CPRD (via MHRA) will enable a significant increase in the scale of identification of people who match the eligibility criteria for specific studies in order that they can be given the opportunity to participate in research. They will also support increased use of routine healthcare data to streamline reporting of follow-up data, increasing predictability and releasing delivery capacity in the NHS
  • in England, the Data for R&D Programme will invest in health data infrastructure for research and development, supported by comprehensive PPI and engagement throughout the programme, including embedded within its governance
  • NIHR will invest in data and digital platforms such as Be Part of Research and NIHR BioResource, and provide the tools and support necessary to deliver virtual and decentralised studies. Increased interoperability between regulatory, NHS and NIHR platforms will enable further streamlining of processes for researchers
  • in Wales, a digital recruitment programme will be developed through partnership between Health and Care Research Wales, SAIL Databank and the NHS Wales National Data Resource programme, to develop services that utilise data resources to drive research delivery. An Expert Working Group has been established to guide on the development of this ‘data for research’ programme. A pilot service has been funded to use SAIL data to provide rapid intelligence to aid placement of research trials in Wales to support most effective recruitment
  • in Scotland, scoping work and stakeholder engagement is informing plans for developments to support increased use of NHS data and digital technology to accelerate clinical trial delivery, and for further development of the Scottish Health Research Register (SHARE) to support recruitment to health research studies. We will continue to support the already established regional NHS Scotland controlled data safe havens (Trusted Research Environments) and their collaboration with the newly established Research Data Scotland to support use of data in research. We will also look for opportunities to support research and innovation as part of the forthcoming Scottish Government Data Strategy for Health and Social Care
  • in Northern Ireland, the RRG Taskforce data and digital sub-group will lead work to prepare the NI data infrastructure to support digitally-enabled trials and participate in UK-wide initiatives such as the ‘Find, Recruit and Follow-up’ service.

To improve access to data and TREs:

  • over the next 3 years NHS England will build upon foundational investments made in 2021 and 2022 in an interoperable network of TREs. At a national level, we will expand the scale, scope and capacity of the NHS Digital TRE to enable more users to have timely and secure access to a range of national datasets. At a regional level, we will develop a small network of regional ‘Sub National TREs’ in England, each covering a population of more than 5 million citizens and enabling access to near real time, multimodal data particularly amenable to the development of AI algorithms
  • the Data for R&D Programme within NHS England will expand the ability for researchers to access a range of rich linked genomic datasets, creating linkages across the various health data systems so that genomic data can be used to support innovation and patients and service users can benefit from the provision of innovative genomic healthcare. The Genome UK Implementation Coordination Group Data Working Group will lead work looking to link genomic datasets from across the UK, and federate these where appropriate, as set out in the Genome UK: shared commitments for UK-wide implementation 2022 to 2025
  • in Scotland, we will continue to support the already established regional NHS controlled TREs and their collaboration with the newly established Research Data Scotland to support use of data in research
  • in Wales, we will continue to invest and grow the internationally recognised expertise and TRE available via the SAIL Databank, offering national population coverage and secure access to billions of person-based records
  • in Northern Ireland, the Honest Broker Service and the more recently established Northern Ireland TRE will be supported to further develop secure access to data for research. This will sit alongside a sustained public dialogue and progression of the enactment of secondary uses legislation to facilitate data access for research in Northern Ireland.

Connecting these developments into a coherent UK offer will bring added benefit, therefore to unite plans:

  • the RRG programme will ensure strategic co-ordination of this work across the UK clinical research ecosystem, supporting progress and ensuring alignment of initiatives, as well as identifying key areas where we can go further within the next 3 years to take steps towards fully realising our overarching vision
  • an RRG data and digital subgroup will be established to enhance collaboration across the sector and ensure people across the whole of the UK benefit from research delivered using data and/or digitally-enabled approaches

Governance, detailed plans and ongoing updates

The UK Clinical Research RRG programme will oversee the delivery of this plan, continuing to work in partnership with stakeholders across the sector and regularly revisit the original vision to consider any further actions needed to deliver on the 10 year vision. In doing so, we will ensure that the NHS is able to tackle the healthcare challenges of the future enabling people across the UK and around the world to benefit from better health outcomes.

Given the scope of the work and the fast pace of change in clinical research, we will keep the specifics of this plan under review via the RRG programme and adapt delivery as needed. This flexibility will allow us to meet emerging challenges and ensure that the outcomes are aligned to the most pressing issues to realise our shared ambitions.

Progress will be measured by the RRG Programme Board and the Ministerially-chaired Oversight Group, ensuring we are delivering on the commitments set out in this plan and that they are having the intended impact on the UK clinical research system. Specific measures for success will be published on the RRG website later in 2022.

We will publish a Phase 3 plan in 2025 to 2026 to align with the next government spending review period. The Phase 3 plan will showcase our progress and lay out the next steps needed to ensure the vision is delivered.

Achievement of our plan will require action across the whole sector, but by building on the foundations of collaboration and partnership that we have created through RRG programme we can collectively work through current challenges and see this vision become a reality.

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  • Published: 01 March 2024

GMP-manufactured CRISPR/Cas9 technology as an advantageous tool to support cancer immunotherapy

  • M Caforio 1   na1 ,
  • S Iacovelli 2   na1 ,
  • C Quintarelli 1 ,
  • F Locatelli 1 , 3 &
  • Valentina Folgiero   ORCID: orcid.org/0000-0002-9838-1520 1 , 4  

Journal of Experimental & Clinical Cancer Research volume  43 , Article number:  66 ( 2024 ) Cite this article

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CRISPR/Cas9 system to treat human-related diseases has achieved significant results and, even if its potential application in cancer research is improving, the application of this approach in clinical practice is still a nascent technology.

CRISPR/Cas9 technology is not yet used as a single therapy to treat tumors but it can be combined with traditional treatment strategies to provide personalized gene therapy for patients. The combination with chemotherapy, radiation and immunotherapy has been proven to be a powerful means of screening, identifying, validating and correcting tumor targets. Recently, CRISPR/Cas9 technology and CAR T-cell therapies have been integrated to open novel opportunities for the production of more efficient CAR T-cells for all patients. GMP-compatible equipment and reagents are already available for several clinical-grade systems at present, creating the basis and framework for the accelerated development of novel treatment methods.

Here we will provide a comprehensive collection of the actual GMP-grade CRISPR/Cas9-mediated approaches used to support cancer therapy highlighting how this technology is opening new opportunities for treating tumors.

The incidence and mortality of cancer still remains the principal health issue worldwide. Despite countless progress, much still needs to be done to improve the outcomes of those patients without a valid therapeutic alternative. The Advanced Therapy Medicinal Products (ATMP) oriented to a precision and individualized treatment for the patients have opened a new era for cancer treatment. In this scenario, the genome editing offers a powerful tool for the development of new strategies for treating cancer.

Good Manufacturing Practice (GMP) guidelines

ATMPs offer a new powerful opportunity for treating, and in some instances, curing diseases (such as cancer) for which there are often no other available treatments. While this has offered an important new therapeutic tool, it has also raised the need to produce drugs following regulations, modalities, and quality standards that ensure safety for patients. In fact, ATMPs are characterized by a very different modalities, use different cell types and, mostly, for the different manufacturing protocols. In particular, ATMP production is a complex manufacturing process and the procedures are still evolving to meet these unique needs. In this regards GMP [ 1 ] are the mandatory guidelines governing ATMPs manufacturing. Noteworthy, GMP compliance is mandatory for all products intended for the market and those used for clinical trials.

These guidelines describe the minimum quality standard that a medicines manufacturer must follow to ensure that products are consistently produced and controlled. These are designed to minimize the risks involved in any pharmaceutical production which cannot be avoided or eliminated even testing the final product [ 2 ]. Furthermore it is very important to note that the guidelines do not intend to place any restrains on the development of new concepts of new technologies, rather intend to ensure the quality, safety, efficacy and traceability of the product. In fact, any alternative approaches may be implemented by the manufacturers, the important thing is to demonstrate that the alternative approach can meet the same quality standard. Based on the previous considerations, it is important to make the appropriate assessments of the technologies that are being developed and employed for the ATMPs production, before moving from research scale to clinical or commercial manufacturing. For this reason, it is essential to have a very good process development phase. The main goal of process development is to reach a very robust manufacturing process with high efficiency, cost containment, maintenance of quality and safety standards, and overall risk reduction as additional key objectives. To this end, several preclinical studies have already been developed for ready clinical translation [ 3 , 4 , 5 ].

CRISPR/Cas9 technology mechanism of action

Discovered for the first time in 1987 as a defense mechanism in prokaryotes [ 6 ]Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) has greatly improved the field of precise genome editing. The CRISPR system relies on RNA ‘guides’ that drives the site-specific binding of CRISPR-associated (Cas) proteins for mediating DNA or RNA cleavage [ 7 ]. The CRISPR system includes three principal types (I, II and III) and 12 subtypes [ 8 ]. The type II relies on a single Cas protein, Cas9, to target a specific sequence of DNA. For this reason, the CRISPR/Cas9 has become the most widely adopted genome editing tool [ 9 ]. The requirements for recognizing and cut a specific DNA sequence, once paired with a guide RNA (gRNA), are as follows: 1) a site-specific complementarity between a 20-nucleotides (nt) targeting sequence, called the protospacer, that is a part of the CRISPR RNA (crRNA), which together with the transacting crRNA (tracrRNA) generated a single guide RNA (sgRNA), which recruits the Cas9 nuclease to specific DNA sequences, 2) an NGG protospacer adjacent motif (PAM) sequence located at the 3´ of the targeting crRNA/protospacer sequence. It has been observed that, without the PAM sequence, the Cas9 nuclease cannot cleave the target sequence, also if fully complementary to the sgRNA [ 10 ].

Once these two criteria are met, the DNA sequence could be targeted and cut by the Cas9/sgRNA system. The design of a specific sgRNA guide sequence allows the detection of double-strand breaks (DSBs) sites where [ 11 ] Cas9 binds and cleaves the target DNA sequences, complementary to the crRNA. DSBs, located at approximately − 3 nucleotides before the PAM sequence, are introduced in the target sequence and then the endogenous DNA DSB repair mechanisms rebuild the breaks. The DNA repair machinery is initiated via two most common pathways: non-homologous end joining (NHEJ), which is the predominant repair pathway in most mammalian cells; the less-frequent homology-directed repair (HDR). The NHEJ frequently results in genomic insertions or deletions (indels) which can introduce frameshift mutations that can result in truncated and/or non-functional proteins. Whereas the HDR uses the donor DNA template to precisely repair DSBs for gene modification [ 12 , 13 ]. In the genome editing procedure, it is possible to design a DNA template, with high homology to the specific target gene locus, containing the aimed genetic change. The procedure of the genome editing could be very challenging because the efficiency of HDR-mediated gene insertion is significantly lower than NHEJ-mediated INDEL formation [ 14 ]. Hence, the editing outcomes are the result of the interaction between these two different repair pathways. Furthermore, the CRISPR/Cas9 system can accurately modify the DNA sequences by generating multiple DSBs at specific sites in the genome and, using multiple guide RNAs, it can achieve a multiple genome editing of the target sequence [ 9 ]. Because CRISPR/Cas9 system is more effective and easier to perform compared to the other gene editing technologies, such as zinc-finger nucleases (ZFNs) and transcription activator like effector nucleases (TALENs) [ 15 , 16 ], it can be advantageously applied in the clinical trials that incorporate gene editing for cancer treatment.

The CRISPR/Cas9 system is mostly employed in ex vivo strategies to perform gene editing in cells that are then reinfused into the patient. The most commons delivery technologies for gene editing are broadly classified as viral, such as lentivirus, retrovirus, adenovirus and adeno-associated virus, or non-viral vectors, such as electroporation, nanoparticles and cell squeezing (Fig.  1 ).

figure 1

CRISPR/Cas9 mechanism of action. Cas9 and sgRNA vehiculation to edit the nuclear target sequence by nanoparticles when assembled to form RNP complex (left); delivery of the elements as single plasmids of expression through lipo-assisted transfection reagent or by electroporation (center); Viral transduction of Cas9 and sgRNA carrying vector (right). DNA repair machinery (NHEJ, HDR) is activated when the nucleus is reached by the CRISPR/Cas9 system

CRISPR/Cas9 clinical applications

The first clinical application of CRISPR/Cas9 system was performed by Lu et al. in 2016, when they carried out in human phase I clinical trial of CRISPR/Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer [ 17 , 18 ]. Rising from this study, many other clinical trials that use CRISPR/Cas9 in cancer treatment or using gene edited CAR T-cells or Tumor Infiltrating Lymphocytes (TIL) cells have been established (Table  1 ). Considering this new and powerful opportunity for cancer treatment, it is very important to develop safe and efficient delivery CRISPR/Cas9 system vectors to target the tissues and cells. To be used in clinical trials it is mandatory that these strategies for CRISPR delivery are manufactured following GMP procedures.

In a very interesting study, Palmer DC et al. [ 3 ] developed a clinical scale and GMP-compliant manufacturing process for highly efficient and precise CRISPR/Cas9 CISH knockout (KO) in human T cells and TIL. In several clinical trials the genome editing of the biological component of the study is associated to chemotherapy. Based on the study of Palmer and colleagues, a phase I/II trial has been started for patients with metastatic gastrointestinal epithelial cancer (NCT04426669), in which Cyclophosphamide, Fludarabine and Aldesleukin are administered combined with TIL in which the gene encoding CISH has been inactivated using the CRISPR/Cas9 System. To be administered to the patients the TIL production and the gene editing procedure need to be performed in a GMP grade environment with a quality system that guarantees the final release of genetically modified cells. Another interesting application for CRISPR/Ca 9 system is in the cancer immunotherapy with CAR T-cells. It has been demonstrated that PD-1 deficient CAR T-cells have an improved antitumor activity in vitro [ 19 ] while a previous study and clinical trials (NCT02808442 and NCT02746952), performed using TALEN as gene editing system, have showed how disrupting genes encoding T cell receptor (TCR) α and β chains in the infused CAR T-cell product can prevent graft-versus-host disease (GVHD) appears [ 20 ]. Based on these results several other clinical trials have been established. In the phase I study for patients with mesothelin positive multiple solid tumors (NCT03545815), a CRISPR/Cas9 mediated gene knock-out of PD-1 and endogenous TCR for CAR T-cells is performed. Following a similar strategy, a phase I trial to assess the safety and feasibility of administering pre-manufactured allogeneic T cells from healthy donors expressing CD19.CAR T-cells lacking expression of HLA class I, HLA class II molecules and endogenous TCR through CRISPR/Cas9 mediated genome-editing of beta-2 microglobulin (β2M), CIITA and T cell receptor alpha chain, respectively (Table  1 , NCT05037669).

All of these studies showed the fundamental GMP grade manufacturing role for producing a CRISPR/Cas9 gene edited cell product for clinical trials. In fact several studies are now performed for developing production process for improving clinical scale manufacturing of genetically modified cells for clinical trials [ 4 , 21 ]. In this review we will provide a comprehensive collection of the actual GMP-grade CRISPR/Cas9-mediated approaches used to support cancer therapy, highlighting how this technology is opening new opportunities for treating tumors.

CRISPR/Cas9 gene-editing of immune check-points

Immunotherapy is a novel approach to fight the growth and invasion of tumor cells by inducing the stimulation of the immune system [ 22 ]. It involves cytokine therapy, oncolytic virus therapy, dendritic cell (DC) therapy, cancer vaccine, adoptive cellular immunotherapy (ACT), immune checkpoint blockade, and antibody-drug conjugate (ADC). Additionally, CAR T-cells therapy has demonstrated high efficacy for hematological and recently for solid tumors [ 23 , 24 ].

Tumor immunity promotes tumor progression by modifying tumor biological features [ 25 ], selecting tumor cells adapted to the microenvironment [ 26 ] or creating a favorable tumor microenvironment [ 27 ]. Among the factors that play an important role in tumor immunity, immune checkpoints molecules such as PD-1 and CTLA4 deserve a special mention. Under physiological conditions, PD-1, expressed on T-cells, binds its physiological ligand, PD-L1, expressed on tumor cells. This interaction may impair the activity of T-cells and prevent further damage induced by cytotoxic effector molecules and autoimmunity.

In recent years immune checkpoint blockade became one of the most important therapeutic options for cancer. Several anti- PD-1/PD-L1 antibodies (Nivolumab, Pembrolizumab, and Atezolizumab) have shown significant advantages in certain malignancies such as melanoma, non-small-cell lung cancer (NSCLC) and urothelial carcinoma, and have been approved by the Food and Drug Administration [ 28 , 29 , 30 ]. However, specific side effects remain [ 31 , 32 ], and the overall survival rate is not significantly improved [ 33 ].

CRISPR/Cas9 is an RNA-guided endonuclease, which is widely used as a simple and fast method to modify the DNA of mammalian cells [ 34 ]. In primary T-cells, researchers have conducted several studies to test the effectiveness of CRISPR/Cas9 in vitro. Schumann and colleagues introduced prassembled sgRNA and Cas9 endonuclease into human CD4 + primary T-cells using electroporation. This delivery resulted in inducing site-specific mutations in CXCR4 and PD-1 genes [ 35 ]. Su S. and colleagues conveyed CRISPR/Cas9 system through electroporation in the peripheral CD8 + T-cells of cancer patients or healthy individuals. Disruption of PD-1 In T-cells increased immune responses against cancer antigens [ 36 , 37 ].

The knock-out of PD-1 in T-cell lymphocytes reduces the number of regulatory T-cells (Treg) or impairs Treg activity and recruits more effector cells. In addition, it can modulate the production of cytokines and activate caspases, inhibiting tumor proliferation in vivo and in vitro and improving survival [ 37 , 38 , 39 ].

In light of the recent pre-clinical results, CRISPR/Cas9 technology seems to be a good candidate to provide a powerful and effective protocol for editing genes that express checkpoint inhibitors, in particular PD-1, in a wide range of immune cells to block immune checkpoints [ 33 ].

Thus, in recent years, numerous clinical trials have been started with the aim to evaluate the potential of gene editing and to translate this knowledge into clinical settings [ 40 ].

All therapeutic drugs, including CRISPR/Cas9, during clinical trials must follow GMP procedures in order to minimize steps involved in any pharmaceutical production that cannot be eliminated through final product testing. Since immunotherapy obtained by the CRISPR/Cas9 system has not yet been deeply programmed in clinical practice, many clinical trials are in progress. In fact, in vitro, the combined effect of CRISPR/Cas9 with immunotherapies has been demonstrated such as the improvement of antibody performance [ 41 , 42 ], the modulation of TME and immune cell activity [ 43 , 44 , 45 , 46 ] and reprogramming MHC specificity (correcting MHC mismatches) [ 47 ].

But the main focus regards the editing of T-cells. Among the targets of CRISPR/Cas9, PD-1 is the most targeted checkpoint in T-cell. In particular, many clinical trials have focused their attention on the autologous origin T-cell, in which CRISPR/Cas9 system is used to deplete PD-1 (Fig.  2 ).

figure 2

CRISPR/Cas9-mediated editing of T-cell. Interaction between PD-1 receptor transcribed by T-cells and PD-L1 ligand expressed on cancer cells. Activation of PD1/PD-L1 checkpoint inhibits cytokine production and cytotoxic activity of T-cell (left). CRISPR/Cas9-mediated editing of the PD-1 sequence inhibits PD-1 expression allowing extracellular cytokines release and improving T-cell killing activity (right)

For example, in order to evaluate the safety of CRISPR/Cas9 technology, Lu et al. used the CRISPR/Cas9 method to obtain PD-1 depletion in T-cells from patients with non-small-cell lung cancer (NSCLC). The editing of autologous T-cell was followed by ex vivo reinfusion, hypothesizing that may ameliorate T-cell response. PD-1-edited T-cells were modified by co-transfection performing electroporation of Cas9 and sgRNA plasmids. Monitoring of T-cells modifications by next generation sequencing resulted in mutation frequency of off-target events of about 0.05% at 18 candidate sites. The authors conclude that clinical application of CRISPR/Cas9 gene-edited T-cells is generally safe and feasible and that this approach is clinically feasible (NCT02793856) [ 18 ].

The knockout of PD-1 performed using the CRISPR/Cas9 system is also used in Epstein-Barr virus cytotoxic lymphocytes (EBV-CTL) cells to treat patients affected by EBV positive advanced stage malignancies. Also in this case, the editing is obtained through CRISPR/Cas9-mediated PD-1 knockout in T-cells of autologous origin. The authors evaluate adverse events after each cycle by Common Terminology Criteria for adverse events as primary endpoint. Tumor and immunological markers are also evaluated as secondary endpoints to monitor the efficacy of the anti-tumor effect (NCT03044743) [ 48 ].

Among combination therapies involving PD-1 disruption in T-cells, an important study analyzes the safety and efficacy of a therapeutic vaccine in combination with the depletion of PD-1 carried out by the CRISPR/Cas9 system in the treatment of advanced prostate cancer. The therapeutic vaccine consists in a customized product involving the use of a recombinant fusion protein (PAP-GM-CSF) to stimulate the production of the antigen that would increase the immune system activity to kill tumor cells [ 49 ]. The strategy used by the authors was once again the engineering of patient’s T-cells through CRISPR/Cas9 technology to disrupt PD-1 gene. The therapeutic vaccine and PD-1 knockout T cells will be infused back to the patient in 3 times with a 2-week interval and the safety and efficacy effect will be evaluated at the end of the study (NCT03525652).

Another trial investigates the safety and effect of transcatheter arterial chemoembolization (TACE), a minimally invasive therapy that combines local delivery of chemotherapy with a procedure called embolization, in combination with engineered T-cells modified by CRISPR/Cas9 on PD-1 gene in patients with advanced hepatocellular carcinoma. TACE would block the blood supply of the tumor to achieve ischemic, hypoxic and necrotic effects (NCT04417764).

Among immune-checkpoint, the role of Cytokine-inducible SH2 domain-containing protein (CISH)has recently been deeply understood. CISH belongs to the suppressor of cytokine signaling (SOCS) family of negative feedback regulators that have been demonstrated a pivotal role in lymphoid cell function and development. Thus, it is a novel intra-cellular immune checkpoint and an important negative regulator of T-cell able to impair their activity [ 50 ].

Tumor Infiltrating Lymphocytes (TIL) have demonstrated efficacy in some malignancies, principally melanoma. Efficacy in most common solid tumors was shown through the selection of cancer neoantigen-specific TIL. Combined therapy with checkpoint inhibitor molecules has also been employed with the aim to increase the efficacy of the therapies with the autologous TILs. Since genetic engineering of T-cells performed by CRISPR/Cas9 that may ameliorate anti-tumor activity is now possible, researchers have improved and optimized a CRISPR/Cas9 based methodology to achieve precise and efficient editing in primary human T-cells without affecting cell function or viability, obtaining the inhibition of undruggable intracellular checkpoint. Thus, researchers are trying to edit the gene encoding this new intracellular checkpoint target, CISH, in TIL obtained from patients with metastatic cancers. Trials that regard the targeting of CISH in TIL through CRISPR/Cas9 involve Metastatic Gastrointestinal Cancers (NCT04426669) and NSCLC (NCT05566223). In these trials the safety and efficacy of genetically modified T-cell selected for anti-tumor activity for solid tumors are evaluated in the setting of novel target that involved checkpoint inhibitor [ 51 ].

In the last years scientists have evaluated the possibility to use TALEN and CRISPR/Cas9 to treat human cervical intraepithelial neoplasia induced by Human Papillomavirus (HPV) without invasion. In fact, the infection of HPV is the main causative factor of cervical intraepithelial neoplasia (CIN) and cervical cancer. HPV vaccines strategy allows to target the two most important oncoproteins expressed by HPV16 and HPV18, E6 and E7, which are also constitutively expressed by cancer cells [ 52 , 53 ]. Numerous strategies have been applied to develop therapeutic vaccines using vectors, peptides/proteins, DNA and genome editing tools. Vector, peptide and protein vaccines are used in particular to treat HPV16 infection, whereas DNA vaccines and the vaccines that use genome editing tools are mostly polyvalent vaccines used for the treatment of both HPV16 and HPV18 and target E6 and E7 genes. The important roles of E6 and E7 playing in HPV-driven carcinogenesis make them attractive targets for therapeutic interventions. Furthermore some experimental studies demonstrated that using TALEN and CRISPR/Cas9 as genome editing tool may induce depletion of E6 and E7 genes, significantly decreasing the expression of E6/E7, inducing cell death and inhibiting cell lines growth [ 54 , 55 ].

The efficacy and safety of E6/E7 disruption induced by TALEN and CRISPR/Cas9 technology in treating HPV Persistency and HPV-related Cervical Intraepithelial Neoplasia is under evaluation of a specific clinical study (NCT03057912).

NTLA-5001 is an investigational CRISPR/Cas9-engineered T-cell receptor (TCR)-T cell therapy in development for the treatment of all genetic subtypes of acute myeloid leukemia (AML) using a WT1-targeting TCR. This study is conducted to evaluate the safety, tolerability, cellular kinetics (CK), activity, and pharmacodynamics (PD) of NTLA-5001 in participants with AML (NCT05066165).

CRISPR/Cas9 gene-editing of CAR T-cells

Over the last 30 years, adoptive T-cell transfer has become the major form of cancer immunotherapy, used, predominantly, in hematological malignancies. With this approach, tumor-specific cytotoxic T-cells are infused into patients, upon lympho-depleting chemotherapy [ 56 , 57 , 58 ]. The key potential advantage of this treatment strategy is the ability to reach privileged niches where conventional anticancer therapeutics have struggled to penetrate [ 59 ]. CAR T-cells usually identify cell surface antigens present in the natural state on the surface of tumor cells without the necessity of peptide processing or HLA expression for recognition [ 60 ]. The two most diffused safety-related problems, due to CAR T-cell administration, have been partially overcome. The first, concerning the targeted destruction of normal cells, is resolved through the identification of tumor-specific cell surface molecules to be targeted. The second concern, regarding the possible induction of a cytokine storm associated with anti-tumor response mediated by large numbers of activated T-cells is strongly overcome utilizing suicide genes such as inducible caspase-9 to halt deleterious responses [ 61 , 62 ]. The innovative principle of CAR T-cells is to couple the potency of a T-cell with the specificity of an antibody to selectively kill target cells. Modifications applied to subsequent generations of CAR T-cells achieved a very efficient product in which inhibitory domains were eliminated and co-stimulatory domains were introduced.

Engineering a patient’s own T-cells to selectively target and eliminate tumor cells has cured patients with untreatable hematological cancers [ 62 , 63 ] and the manufacturing of CAR T-cells under GMP is a focal point for this therapeutic modality [ 64 , 65 ]. The main challenges for CAR T-cell therapy concern solid tumors due to the difficulty to identify truly specific tumor antigens as targets, overcoming tumor antigen escape, improving CAR T-cells trafficking, infiltration and expansion at the tumor site as well as persistence and functions in a hostile tumor microenvironment (TME) [ 66 ]. Many clinical trials are on going testing CAR T-cells in brain tumors targeting several antigens such as Disialogangloside GD2, to test the promising data obtained at pre-clinical level [ 67 , 68 , 69 , 70 , 71 ].The same target resulted strongly valid in the NCT05573097 clinical trial against high-risk pediatric neuroblastoma showing a sustained anti-tumor effect [ 72 ].

Preparation of clinical-grade CAR T-cells for therapy begins with leukopheresis to obtain large numbers of peripheral blood mononuclear cells followed by cryopreservation of these cells. After being thawed, at the manufacturing facility, the cells are activated by CD3/CD28 stimulation for ex-vivo expansion [ 73 ].

Then, genetic modification of T-cell is carried out through transduction with a self-inactivating lentiviral or retroviral vector encoding the transgene of interest. The transgenic T-cells are expanded through different platform (GE bioreactors, G-Rex bioreactors) until sufficient numbers for treatment are obtained, around 300 million cells. Transduction efficiency is measured by flow cytometry and percent of killing activity is evaluated against tumor cell lines expressing the target antigen [ 74 ](Fig.  3 ).

figure 3

CRISPR/Cas9-mediated editing of CAR T-cell. Production of CAR T cell starting from patient for autologous infusion (black line) including apheresis from peripheral blood and cryo-conservation; thawing is followed by stimulation and lentiviral transduction for generation of CAR T-cells. The expansion is achieved by bioreactors and the requested number of CAR T-cells is ready for patient infusion. The process starting from healthy donor (red line) for allogenic CAR T cell production follows the same procedure until CAR transduction. CRISPR/Cas9 editing of HLA and TCR before CAR T-cells expansion generates universal CAR T-cells that can be infused into the patient

The use of virus in CAR T-cells production has showed some disadvantages including an increased risk of tumor development resulting from insertional mutagenesis [ 75 ].

Despite the success of CAR T-cells in treating hematological malignancies, challenges such as cytokine release syndrome (CRS) [ 76 ], T-cell exhaustion, tumor antigen masking [ 77 , 78 ] and durability and risk of GVHD remain [ 79 ].

For this reason, recently, CRISPR/Cas9 technology has been integrated with CAR-T cell-based treatment to open novel opportunities for the production of more efficient CAR-T cells for all patients [ 80 , 81 , 82 ].

Non-viral gene-editing systems can be delivered to primary T cells using electroporation, liposome or nanoparticle transfection methods [ 83 ]. The best tool that meets the three crucial criteria which are lack of immunogenicity, compatibility with GMP grade reagents and feasibility on a clinical scale is electroporation [ 84 ]. A non-viral protocol to generate gene-specific integrated T-cells was developed in 2021 by Jiqin Zhang et al. An anti-CD19 CAR sequence containing 4-1BB and CD3z was constructed and electroporated into T cells. Through this procedure, cell expansion was not impaired and cell viability was high. In addition, electroporation increased the ratio of CD8 + to CD + 4 T cells when compared to lentiviral transduction. Since blocking the PD1-PD-L1 axis has been demonstrate to improve CAR T-cells killing activity, the authors integrated an anti-CD19 sequence into the PD1 gene obtaining a robust clearance of tumor cells. Safety and efficacy assay, followed by GMP-procedures adaptation, was performed to carry out a phase I clinical trial (NCT04213469) in B-NHL patients and in relapsed/refractory B-cell malignancies (NCT04637763, CB010). Data obtained by the trial revealed that the development of non-viral gene-specific targeted CAR T-cells by CRISPR/Cas9 showed high efficiency against the tumor through a simplified manufacturing procedure with reduced preparation time and expenses.

Although autologous T-cells have shown promising results in many cases, there are many patients that cannot be treated in this way or for lymphocyte repertoire depletion due to myeloablative therapies, or for intrinsic defect of autologous T-cells. These limitations can be overcome by developing universal genetically engineered CAR T-cells derived from allogenic donor T-cells where TCR and HLA-I are silenced. CRISPR/Cas-9 can be used to knock-out β2M of donor CAR T-cells, a component that forms heterodimers with HLA-I and is requested for HLA-I surface expression, and to silence TCRα subunit constant (TRAC) or TCRβ gene (TCRB) to eliminate the recognition of alloantigen of the recipient. Although at a preclinical level, this study demonstrates that CRISPR/Cas9-mediated multiplex gene editing is applicable and a relay promising strategy [ 85 ]. Indeed, a recent phase I clinical trial (CARBON) shows how CTX-110, an anti CD19 CAR T-cell in which MHC I complex has been eliminated by CRISPR/Cas9 editing of TCRA and β2M administrated in patient with relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL) resulted highly efficient (NCT04035434).

Antigen-escape-mediated relapse is another limitation CAR T therapy and the use of multiantigen targeting could allow the optimization of the response. Yongxian Hu et al. proposed combined approach using universal CD19/CD22 dual targeting CAR T-cells in which TRAC and CD52 gene region is disrupted by using CRISPR/Cas9 technology. The phase I clinical trial (NCT04227015) in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia showed a safety profile and prominent anti-leukemia activity, especially for patients that were ineligible for autologous CAR T-cells administration [ 86 ]. Recently gene editing supported also allogenic “off-the-shelf” CAR T-cells targeting B-Cell Maturation Antigen (BCMA) in multiple myeloma (CTX-120) using CRISPR/Cas9 system to eliminate TCR and MHC class I, coupled with specific insertion of the CAR at the TRAC locus [ 87 ]. Results from animal models showed complete tumor regression and phase I study is ongoing in patients with refractory or relapsed multiple myeloma (NCT04244656). A valid study was performed in clear renal cell carcinoma through the development of allogenic CRISPR/Cas9-engineered CAR T-cells. It was designed to insert an anti-CD70 CAR cassette into the TRAC locus to disrupt TRAC, b2M and CD70 CTX-130). The results from phase I trial (NCT04438083) showed safety and encouraging antitumor activity [ 88 ].

Conclusions

The latest advancements in GMP procedures are allowing an efficient improviement of personalized medicine. In particular immunotherapy is strongly taking advantage of clinical manufacturing platforms to cure patients who are refractory to previous therapy or who relapse upon a first period of remission. CRISPR/Cas9 technology has become the most widely used gene-editing tool in cancer immunotherapy favoring differentiation and persistence of genetically modified T-cells. The discovery of cancer-selected markers remains one of the principle obstacles while the use of allogenic CRISPR/Cas9-modified CAR T-cells is overcoming the difficulties to treat relapsing cancer cells showing an antigen different from that expressed at the onset of the disease. CAR T-cells generated against multiple tumor targets are preventing relapsing events. The manufacturing processes still comprised procedures performed manually even if supported by semi-automated manner, which result in product variability and very high cost. The development of a more controlled and cost-effective manufacturing process remains the pivotal aim to ensure CAR T-cells therapy for all patients.

Abbreviations

Clustered Regularly Interspaced Short Palindromic Repeats

CRISPR Associated Protein 9

Chimeric Antigen Receptor

Good Manufacturing Practice

Advanced Therapy Medicinal Products

Transacting crRNA

Single Guide RNA

Protospacer Adjacent Motif

Double-Strand Breaks

Non-Homologous End Joining

Homology-Directed Repair

Insertions or Deletions

Zinc-Finger Nucleases

Transcription Activator Like Effector Nucleases

Program Cell Death 1

Tumor Infiltrating Lymphocytes

Cytokine-Inducible SH2 Domain-Containing Protein

T-Cell Receptor

Graft Versus Host Disease

Human Leukocyte Antigen

Beta-2 Microglobulin

Class II Trans Activator

Dendritic Cell

Adoptive Cellular Immunotherapy

Antibody-Drug Conjugate

Cytotoxic T-Lymphocyte Antigen 4

Program Cell Death Ligand-1

Non Small Cell Lung Cancer

Chemokine Receptor Type 4

T-Regulatory-Cell

Tumor Microenvironment

Major Histocompatibility Complex

Epstein-Barr Virus Cytotoxic Lymphocytes

Prostatic Acid Phosphatase-Granulocyte Macrophage-Colony Stimulating Factor

Transcatheter Arterial Chemoembolization

Suppressor of Cytokine Signaling

Human Papillomavirus

Cervical Intraepithelial Neoplasia

Acute Myeloid Leukemia

Wilms Tumor-Suppressor Gene-1

Cellular kinetics

Pharmacodynamics

Cytokine Release Syndrome

B-Lymphoma Non Hodgking

TCRα Subunit Constant

T Cell Receptorβ

Diffuse Large B-cell Lymphoma

b-Cell Maturation Antigen

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Acknowledgements

Figures were created with Biorender ( https://www.biorender.com/ ).

This work was supported by the Italian Ministry of Health with “Current Research” funds.

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Locatelli F and Folgiero V are co-last authors.

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U.O. Cellular and Genetic Therapy of Hematological Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

M Caforio, C Quintarelli, F Locatelli & Valentina Folgiero

U.O Officina Farmaceutica, Good Manufacturing Practice Facility, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

S Iacovelli

Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy

F Locatelli

IRCCS Bambino Gesù Children’s Hospital, Viale San Paolo 15, 00146, Rome, Italy

Valentina Folgiero

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MC, SI and VF conceived and wrote the manuscript; CQ intellectually contributed to the manuscript composition; FL provided intellectual input and critically revised the manuscript.

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Caforio, M., Iacovelli, S., Quintarelli, C. et al. GMP-manufactured CRISPR/Cas9 technology as an advantageous tool to support cancer immunotherapy. J Exp Clin Cancer Res 43 , 66 (2024). https://doi.org/10.1186/s13046-024-02993-1

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DOI : https://doi.org/10.1186/s13046-024-02993-1

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