Clinical Trials & Research Archives

Health Affairs Disability & Health Virtual Symposium

October 3, 2022 @ 1:00 pm – 4:30 pm

Virtual Event

Following the release of the Health Affairs October special issue, Willyanne DeCormier Plosky, Program Manager at the MRCT Center, presented recent research on eligibility criteria language and potential inappropriate exclusion of people with disabilities in clinical research. She joined other experts to take a comprehensive, scholarly look at the relationship between Disability and health.

Watch webinar recording

Excluding People With Disabilities From Clinical Research: Eligibility Criteria Lack Clarity And Justification (Publication)

CenterWatch feature

National Public Radio feature

Boston 25 News feature

Deliverables

Projects

Comments related to 2005 PHS Policies on Research Misconduct

Public Comments

Comments provided on: October 31, 2022

Comments provide to: Office of Research Integrity, Department of Health and Human Services

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Supported decision-making can advance clinical research participation for people with disabilities

Publication

Published on: October 21, 2022

Published in: Nature Medicine

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Post Trial Responsibilities

What is Continued Access?

Continued access can be defined as the continued provision of the investigational medicine or continued maintenance of the investigational significant risk device for any clinical trial participant after participation in the trial. Some investigational interventions may require unique supportive care that should be considered by the sponsor, researcher, healthcare systems, or host country governments. Post-trial, continued access is a shared responsibility and should be determined before the trial begins.

Developed by the MRCT Center’s Post-trial Responsibilities: Continued Access Taskforce developed the following working definition

The PTR task force developed a revised set of principles with associated analysis and a framework of responsibilities for continued access to investigational medicines and a framework for significant risk (SR) devices after a clinical trial: scenarios that require further consideration.

Principles of Post-Trial Continued Access

Framework of Responsibilities: Investigational Medicines

Framework of Responsibilities: Investigational Significant Risk Devices – Scenarios for Further Consideration

Why is this work important?

Research participants deserve consideration of continued access to an investigational product to which they have received benefits as part of a clinical trial.

International ethical guidelines, including the Declaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS) discuss the responsibilities stakeholders have to provide continued access to investigational products. Notably, in 2024, paragraph 34 of the Declaration of Helsinki was revised to reflect the responsibilities that sponsors and researchers have to plan for post-trial provisions and the role research ethics committees play in approving exceptions.

Post-Trial Provisions

34. In advance of a clinical trial, post-trial provisions must be arranged by sponsors and researchers to be provided by themselves, healthcare systems, or governments for all participants who still need an intervention identified as beneficial and reasonably safe in the trial. Exceptions to this requirement must be approved by a research ethics committee. Specific information about post-trial provisions must be disclosed to participants as part of informed consent.

World Medical Association. (2024). WMA Declaration of Helsinki: Ethical principles for medical research involving human subjects

There is no guidance or instruction on fulfilling the responsibilities set forth in the Declaration of Helsinki and CIOMS. To fill this gap, the MRCT Center convened a group of experts to develop and put forth actionable and practical tools to help sponsors and researchers understand their ethical responsibilities and how to achieve them practically. We have developed a series of resources, including principles, frameworks, recommendations, and case studies.

WHAT ARE THE SHARED RESPONSIBILITIES OF CONTINUED ACCESS?

Principles

The MRCT Center’s Post-Trial Responsibilities: Continued Access to an Investigational Product outlines a principled and practical approach to identify the shared ethical responsibilities that can, in turn, guide action to provide continued access to an investigational product at the conclusion of a patient’s participation in a clinical trial.

The foundation of the MRCT Center’s work is grounded in 12 principles. The principles, accompanied by an analysis, should be read as a whole.

Research participants deserve consideration of continued access to a beneficial investigational product.
The responsibilities of post-trial, continued access of an investigational product to a trial participant (patient) after completion of a clinical trial are shared among all stakeholders: sponsor, investigator, site, healthcare provider, healthcare system, and the participant.
Provision of continued access is a bounded and limited responsibility of any one stakeholder.
The responsibility to provide continued access to the investigational product is generally not influenced by whether the sponsor is a for-profit, not-for-profit, governmental agency, or sponsor-investigator, and whether the trial is conducted in a well- or low-resourced setting.
Provision of continued access must not inadvertently advantage some and harm others.
The plan to offer or not to offer continued access to an investigational product should be determined before a trial begins and appropriately communicated to investigators, ethics committees, and participants.
If there is evidence of benefit exceeding risk in the trial population, and importantly in settings of unmet medical need, individual participants should be evaluated for continued access.
Generally, the informed consent document should include language related to continued access to the investigational product.
If continued access to an investigational product is offered, medical care, infrastructure, and long-term maintenance specifically necessary for the appropriate provision of the investigational product should be considered.
Continued access to an investigational product should always be provided under mechanisms that satisfy local regulatory requirements for investigational products.
The sponsor is responsible for continuously assessing whether there is an ongoing unmet medical need for the investigational product during the clinical trial and product development program.
For the health and safety of an individual participant, responsible transition from the investigational product to other appropriate care may be, and is often, necessary. The responsible transition of the participant to the marketed product following regulatory approval should also be anticipated and planned.

Principles of Post-trial Continued Access

Post-Trial Responsibilities: A Shared Responsibility of Continued Access

This image illustrates the shared responsibility of continued access throughout product development in an ideal situation, from planning to marketing to product availability. The work of the task force focused on challenging scenarios when this ideal situation does not happen.

WHAT INVESTIGATIONAL INTERVENTIONS SHOULD BE CONSIDERED FOR CONTINUED ACCESS?

What should sponsors consider when deciding whether or not to provide continued access?

The sponsor should apply interdependent criteria to determine whether continued access will be offered tostudy participants.

The MRCT Center has defined a set of interdependent criteria related to the study program that may lead to continued access, which may include but are not limited to:

INTERDEPENDENT CRITERIA

Program Level:

Impact of discontinuation: The disease or condition under study is serious or life-threatening, and the research participant could be adversely impacted if access to the product were discontinued.
Medical need: The investigational product addresses an unmet medical need in that no suitable therapeutic alternatives are available.
No Access/Not Accessible: A physician cannot yet prescribe the product for the condition being studied.
Research viability: The provision of continued access to the investigational product will not affect the viability of the research or the ability to complete the trial or other trials.
Benefit/risk assessment: A positive overall study population benefit/risk assessment based on data analysis from first interpretable results or full study results.

Individual Participant Level:

In addition, the following criteria should be considered at completion of the trial:

The eligible participant has completed the clinical trial protocol as intended.
There is demonstrable evidence of benefit exceeding risk for an individual participant as determined by the investigator, in discussion with the participant and informed by the participant.

HOW DO YOU PLAN FOR CONTINUED ACCESS?

Sponsors and Researchers generally agree upon the criteria used to determine post-trial, continued access, the regulatory milestones, and the mechanisms used to provide continued access. The timing between a pivotal trial of an investigational product and its regulatory approval is variable, as is the timing to commercial milestones such as market availability and reimbursement. It is in these windows that decisions about the provision of continued access must be made. There are, however, complex decisions that require further analysis.

Regulatory Milestones:

Study planning
Ongoing clinical trials
Bridging the gap while awaiting a regulatory decision
Transition I: The investigational product is not approved
Transition II: The regulatory authority approves the investigational product

The Framework of Responsibility: Scenarios that Require Further Consideration is a list of considerations that organizations can utilize to make equitable and fair decisions related to continued access to an investigational medicine or significant-risk (SR) device. These frameworks were designed for organizations developing investigational products and can be utilized to develop policy or guidance.

Timeline of the MRCT Center’s Work on Post-Trial Responsibilities: Continued access

In November 2017, the MRCT Center published the Post-Trial Responsibilities: Continued Access to Investigational Medicines Guidance Document and Toolkit. This original framework outlined a case-based, principled, stakeholder approach to evaluate and guide the ethical responsibilities related to providing continued access to investigational medicine at the conclusion of a patient’s participation in a clinical trial. These resources have been used to develop policies and procedures at many global research organizations.

In 2022, the MRCT Center initiated the “PTR Taskforce” to update and add to the original resources. Utilization identified that the ethical principles and main consensus points remained valid. However, additional work was needed to advise on the practical application of the work. Throughout 2023 and the early months of 2024, the MRCT Center met monthly with the PTR task force to identify and develop updated tools and resources. The PTR task force developed a revised set of principles with associated analysis and a framework of responsibilities for continued access to investigational medicines. At the beginning of 2024, the work pivoted to the challenges of continued maintenance of investigational significant-risk (SR) devices after a clinical trial. The MRCT Center, working with device experts, developed a device-specific framework of responsibilities reflecting the unique challenges of post-trial continued access to and maintenance of SR devices. This work was released in April 2025.

ONGOING & FUTURE WORK

In 2025 and 2026, the MRCT Center will focus on the challenges of continued access in lower- and middle-income countries. This work started in November of 2024 during a hybrid meeting of involved parties. Additional future work will focus on post-trial, continued access in Investigator-Initiated Trials (IITs) and analyzing the role of the Research Ethics Committee in assessing post-trial continued access to an investigational product.

Leadership:

Sarah White, MPH. Executive Director, MRCT Center

Karla Childers, BA, MSJ, MSBE. Co-Lead, Head of Bioethics-based Science & Technology Policy, Johnson & Johnson

Barbara Bierer, MD. Faculty Director, MRCT Center

Kayleigh To, MPH. Project Manager, MRCT Center

Task Force:

Dave Borasky, CIP, MPH. Vice President, Compliance Review Solutions, WCG IRB

Anthony Edmonds, MS. Senior Director, Global Medical Patient Access, Takeda

Sean Daly, Senior Director, Clinical Operations, Oncology, Takeda

Brandy Ellis, MBA, Participant/Patient Advocate

Christine Grady, MSN, PhD. Chief, Bioethics Head, Section on Human Subjects Research, NIH

Erika Hamilton, MD. Director of Breast Cancer and Gynecologic Cancer Research, Sarah Cannon Research Institute, ASCO

Donald Harvey, PharmD, FCCP, FHOPA, FASCO. Professor, Emory University School of Medicine, ASCO

Anna Kang, MPH, Principal Bioethics Leader, Roche-Genetech

Benjamin Rotz, Associate Vice President – Global Medical Policy, Strategy, and Operations, Eli Lilly and Company

Marjolein Willemen, MSc, PharmD, PhD. Medical Policy and External Collaborations Lead Novartis

Crispin Woolston, PhD. Global Head of Science Policy, Sanofi

Teri Pollastro, Participant/Patient Advocate

Device Experts:

Joy Domingo, MD. Medical Safety Officer, Johnson & Johnson

Elazer Edelman, SM, MD, PhD. Director, Center for Clinical Translational Research (CCTR), Edward J. Poitras Professor in Medical Engineering and Science Professor, Medicine, MIT, BWH & Harvard Medical School

Saskia Hendriks, MD, PhD. Neuroethics Consultant, NIH

Richard Kuntz, MD. Formerly Chief Medical and Scientific Officer, Medtronic

Gabe Lázaro-Muñoz, PhD, JD. Assistant Professor, Harvard Medical School

Bruce Rosengard, MD, FACS, FRCS. Vice President of External Innovation, Johnson & Johnson

Paul Underwood, MD, FACC, FSCAI, RAC. President, Cardio MedSci.

The original project (2015-2017) was co-chaired by:

Carmen Aldinger, PhD, MPH, PMP. Project Manager, MRCT Center

Luann Van Campen, PhD, MA. Senior Advisor and Head of Bioethics, Eli Lilly & Company

Barbara E. Bierer, MD. Faculty Director, MRCT Center

Resources: Post-trial Responsibilities: Continued Access

Promoting Global Clinical Research in Children

Promoting Global Clinical Research in Children

The development and administration of safe and effective therapeutic products for children is critical to the health of a population. Global innovations in pediatric drug development are essential to mitigate the myriad of practical challenges of executing multinational clinical trials, address regulatory challenges of working across jurisdictions, and ensure consideration of ethical approaches to enrolling children in research.

Medicines—including drugs, biologics, and devices—must be more frequently, rigorously, and carefully evaluated for safety and efficacy in the global pediatric population. This vision depends, in part, on identifying and overcoming existing barriers to conducting multi-regional pediatric trials, and then motivating their enrollment, conduct, and completion. Pediatric patients deserve, as all patients do, therapeutic products for which adequate safety and efficacy data have been rigorously collected.

Our commitment to advancing global pediatric clinical trials remains steadfast through the identification of challenges and the development of solutions to critical barriers, and our foci continue to evolve to meet the ever-changing needs of the pediatric clinical trial landscape. To harmonize approaches globally, the MRCT Center initially convened a multistakeholder workgroup in 2019 representing academia, industry, regulators, non-profits, trial networks, patients, and advocates.

With significant progress made to date, we continue to explore key aspects of pediatric product development and clinical trials, share findings through an array of freely available and widely disseminated materials, and advance integral international collaborations. Our resources and materials include theIncluding Young People in Research toolkit, currently under revision with a release anticipated in early 2026, Guiding Principles, and a curated selection of pediatric-focused webinars, complete with recordings and summaries.

Our interactive webpage summarizes the work to date and links to key deliverables. Our current work focuses on pediatric platform trials—studies evaluating multiple investigational products simultaneously. An October 2024 workshop, attended by 80 global experts, identified gaps and strategies in three disease areas: major depressive disorder, oncology, and multidrug-resistant tuberculosis. In July 2025, the MRCT Center co-hosted a follow-on workshop focused on pediatric oncology to develop an implementation framework for academic–industry platform studies to support regulatory requirements (PIPs, iPSPs) and potential marketing authorization. That work continues with the finalization of a comprehensive toolkit that will support academic/industry collaborations for pediatric oncology platform trials, slated for release and dissemination in mid-2026.

Part 1: The Challenges

The MRCT Center’s Promoting Global Clinical Research in Children project sought to examine the ethical, regulatory, privacy, and confidentiality concerns that impede the conduct of global clinical trials in children, with a particular emphasis on ex-US countries and low- and middle-income countries (LMICs). Understanding the challenges encountered in conducting global pediatric clinical trials informed the direction of the work and the development of the project products.

The health of a population is reliant on the development and administration of safe and effective therapeutic products for children. Because children often face diseases that do not affect adults and metabolize and respond to treatments differently than adults, data from clinical research and/or health care involving adults cannot reliably and consistently be extrapolated to pediatric populations. Therefore, ensuring that children have access to safe and effective medicines is generally contingent upon the conduct of trials that enroll children. The incidence of many pediatric-specific conditions in children, however, is low, and the pool of potential pediatric research participants is often small and geographically dispersed. Thus, it is often necessary to conduct multisite and multinational pediatric studies to secure sufficient enrollment for study completion. Given the dearth of relevant data and the challenges of working across jurisdictions, the pressing need to overcome existing barriers to multinational pediatric research remains. Further, regulatory complexities render approval of product for children challenging, and once approved, access to and payment for medicines to pediatric populations must be enabled to ensure the availability of approved products to those who need them.

Associated Assets:

Part 2: Principles to Guide the Work

The array of starting tenets offered to guide the work with children and teenagers in support of the belief that children should be protected in and through research. Children should only be enrolled in research that follows established ethical principles. All ethical principles relevant to the conduct of clinical research in the general population also apply to pediatric clinical research. National health authorities should regulate pediatric clinical research in accordance with internationally accepted ethical principles (e.g., CIOMS). Children’s rights, as stated, for example, in ~~the~~ ~~UN Convention on the Rights of the Child~~, must be respected within the clinical research context. Evidence of potential for clinical benefit to the enrolled children must justify the risks of participation, especially when those risks are significantly greater than those encountered in everyday life. Additionally, children should only be enrolled in research that has scientific and social value related to the health of children or diseases that originate in childhood. The burdens of research participation should be minimized, and efforts to accommodate the needs of children and their families and caregivers should be undertaken to minimize harm and disruption. Importantly, throughout the research process, children are entitled to have a voice in making decisions to the extent their capacity allows. Taken in its entirety, these starting principles undergird the project foci.

Associated Assets:

Part 3: Equitable Access

The larger body of project work supports the very basic premise that pediatric patients deserve equitable access to medicines. Children and their health needs are an important research priority, and this access includes safe and effective healthcare services, including vaccines, diagnostics, therapeutics, and disease prevention measures. There are ethical considerations to weigh, including that a child’s access to medicines (and healthcare) is often dependent on where that child lives. A product may be deemed safe and effective by a jurisdiction’s guiding regulatory body and the same jurisdiction’s health technology assessment body may determine that the product in question is not cost effective, thereby preventing access to that product. Children may take on the risks of participating in a clinical trial without benefit either to themselves or others if the interventional product is not available at the end of the trial to the population for whom it was intended. Investigators and sponsors have responsibilities to the child who has participated in research after the research has ended. This includes access to individual and overall research results, if desired, and post-trial access to the therapeutic intervention if found to benefit the child.

Associated Assets:

Part 4: Unique Ethical Dilemmas Around the World

Research with children presents a number of unique ethical dilemmas despite the premise that research involving children follows the same ethical foundation of research involving adults—respect for persons, beneficence, non-maleficence, and justice. For example, children’s decisions are generally subject to the authority and influence of parents, guardians, and/or other authorities, which can complicate how to best consider, discern, and honor children’s preferences during the process of the adult (parent/guardian) providing permission for the minor child’s participation. Assessment of potential risks and benefits is especially challenging in the context of pediatric research, given that the burdens of trial participation may vary with a child’s age, maturity level, medical condition, and situational factors. Finally, some research that may be permissible among adults following their informed consent may not be permissible among children who cannot give informed, autonomous consent, even though assent is desired if not required.

Part 5: Regulatory and Governance Complexities

There are significant differences in country-specific regulations and/or guidance internationally that give rise to regulatory complexities, including the fact that guidance is a recommendation rather than a requirement, rendering practice even more discordant. Such complexities include issues of exploitation and vulnerability, ambiguity around the definition of minimal risk, inconsistencies in the required timing of pediatric development plans, and confusion regarding what constitutes undue inducement and coercion. That some countries do not have regulations or guidance addressing pediatric research at all, and that existing regulations are not harmonized, renders multi-national pediatric research difficult, burdensome, and sometimes impossible. The COVID-19 pandemic served as a pointed reminder highlighting the need for consideration and inclusion of children, improved efficiencies, and global cooperation.

Related Assets:

Part 6: Role of HTA Bodies

The clinical trial enterprise is fueled by the desire to provide access to medicines for children worldwide, and different stakeholders have different remits that together impact access. Regulators are charged with assessing a medicinal product for safety and efficacy independent of price, while Health Technology Assessment (HTA) bodies are charged with assessing individual and societal value considering not only the cost but also available alternatives. In many countries, the assessments of the HTA authorities of pediatric medicines determine access. The perspectives of regulators, industry, academia, clinicians, patients and patient advocates, and HTA bodies were considered in an effort to develop a common understanding of the evidentiary requirements that HTA bodies need to render a comprehensive value assessment for pediatric populations. The work to promote understanding of the different roles and responsibilities for patients, parents and caregivers, investigators, and the public is ongoing.

Related Assets:

A scoping review of challenges in pediatric health technology assessments with a focus on pharmaceutical interventions; DOI: 10.1017/S0266462325103188

Part 7: Elevating the Voices of Young People

The Promoting Global Clinical Research in Children project sought to collaboratively identify and propose solutions to various regulatory, ethical, and operational challenges encountered in the conduct of international pediatric clinical trials. Of the many topic areas discussed over the course of the effort, a consistent thread of dialogue, almost irrespective of the starting point of any particular discussion, was the importance of soliciting, hearing, respecting, and responding to the pediatric patient voice. While not routinely solicited or included in product development or the clinical research enterprise, there are meaningful ways to engage patients including children, adolescents, and their families. We continue to learn how to make research stronger and build public trust by including the youth perspective in a thoughtful, systematic, and representative way. To that end, an array of deliverables focused on amplifying the voice of children and adolescents has been produced, with more forthcoming.

Related Assets:

Part 8: Pediatric Platform Trials

In an ongoing effort to speed access to safe and effective medicines for pediatric populations, the MRCT Center began exploring alternative, innovative clinical study designs such as platform trials. Such studies, which evaluate more than one investigational product simultaneously, may offer substantial efficiencies if companies were able to collaborate on a shared trial infrastructure.

We began this effort by hosting a 2-day workshop in 2024, Advancing Pediatric Platform Trials: Streamlining Development, Maximizing Impact, that explored how multi-sponsor pediatric platform trials can be leveraged to speed the delivery of innovative therapies to pediatric patient populations in association with adult approval. Three diseases that model different challenges—major depressive disorder (MDD), multi-drug-resistant tuberculosis (MDR-TB), and pediatric oncology—were used to ground the discussions in real-world settings and illustrate different challenges.

Discussants successfully identified knowledge gaps and practical challenges that impact pediatric platform trial planning and execution. Each of the three disease-specific breakout sessions over the two-day event proposed actionable strategies to address the identified barriers and challenges.

The work continued with a deeper exploration into academic/industry collaborations in pediatric oncology. In late 2025, the MRCT Center co-hosted a follow-on workshop, Advancing Childhood Cancer Academic-Industry Collaborative Platform Trials: A multistakeholder workshop. The aim was to develop an implementation framework for academic-industry collaborative platform studies that deliver data that could support a regulatory requirement (PIPs, iPSPs) and potentially marketing authorization applications, specifically focused on pediatric oncology medicines.

A comprehensive toolkit serving as a blueprint for conducting this work is in development, with a mid-2026 release planned.

Related Assets:

Objectives

To identify the challenges related to decision making for individual children that impede the conduct of transnational pediatric clinical trials, including issues related to assent, consent, and inclusion of the voice of young people.
To address the lack of consensus and awareness on key issues around benefit and risk considerations that create barriers to and inefficiencies in transnational research with children.
To define and address the operational barriers to conducting transnational pediatric trials and propose solutions, including the promotion of a model of global pediatric regulatory cooperation.

Key Milestones

October 2025: Published “A scoping review of challenges in pediatric health technology assessments with a focus on pharmaceutical interventions.”
July 2025: Co-hosted a 2-day workshop, Advancing Childhood Cancer Academic-Industry Collaborative Platform Trials workshop in Washington, DC.
May 2025: Released Podcast “Advancing Pediatric Platform Trials – A Conversation with Dr. Danny Benjamin“
April 2025: Released workshop report “Advancing Pediatric Platform Trials“
November 2024: Published Engaging children and adolescents in the design and conduct of paediatric research
October 2024: Successfully hosted a 2-day workshop, “Advancing Pediatric Platform Trials: Streamlining Development, Maximizing Impact,” in Washington, DC
January 2024: A comprehensive interactive overview of the Pediatrics project and key deliverables was released.
March 2023: Released the Including Young People in Research toolkit.
March 2023: Hosted the fifth in the 5-part webinar series, Informing the Future.
November 2022: Hosted the fourth in the 5-part webinar series, Facilitating Pediatric Medicines Development: Models of Global Cooperation
June 2022: Hosted the third in the 5-part webinar series, Assent and Consent in the Field: Culture, Context, and Respect
April 2022: Release of 3 additional pediatric educational brochures for young people contemplating participation in a clinical trial; these proudly carry the iCAN Seal of Approval
February 2022: Hosted the second in the 5-part webinar series, Time to Listen: Hearing from Young People in Clinical Research
October 2021: Hosted the first in the 5-part webinar series, Advancing international Pediatric Clinical Research: Informing the future form COVID-19 Lessons Learned.
July 2021: Panel discussion at DIA-Pediatric engagement in research: Young people have a voice
March 2021: Dissemination of “Biobank” comic book, a collaboration of Boston Children’s Hospital, Harvard Catalyst and Precision Link
February 2021: Project focus pivots to deliverable preparation
January 2021: Received an FDA R13 scientific conference grant to support a series of meetings, “Global Cooperation to Promote Clinical Research in Children” to be hosted virtually during 2021-2022
December 2020: Panel Discussion at MRCT Center Annual Meeting–Emerging Issues in Global Pediatric Clinical Trials: Perspectives on patient/family/caregiver engagement
November 2020: Released “Assent to Consent” flyer which earned the iCAN (International Children’s Advisory Network) “Seal of Approval”
January 2020: Core leadership team in-person meetings
October 2019: Project launch with first work group meeting of diverse stakeholders

Project Leadership & Staff

Barbara E. Bierer, MD. Faculty Director, MRCT Center
Steven Joffe, MD, MPH. Chief, Division of Medical Ethics, Perelman School of Medicine at the University of Pennsylvania
Dominik Karres, MD, CPM. Paediatric Medicines Office, Scientific Evidence Generation Department, European Medicines Agency
Robert “Skip” Nelson, MD, PhD. Senior Director, Pediatric Drug Development, Johnson & Johnson
Lisa Koppelman, MSW, LICSW, MPH. Program and Team Director, MRCT Center
Trevor Baker, MS. Program Manager, MRCT Center
Lauren Otterman, MBHL. Project Manager, MRCT Center

Project Resources

Protocol Ethics Toolkit and E-Learning

Protocol Ethics Toolkit and E-Learning

The moniker “Protocol Ethics” refers to addressing ethical issues in the design of clinical trials and documenting their rationale in a section of the study protocol easily understood by institutional review boards/research ethics committees. Study teams designing and developing clinical trial protocols may benefit from a systematic methodology to ensure that ethical issues have been considered, addressed, and documented appropriately.

Launched in August 2012, this project was driven to ensure that key ethical questions are addressed when navigating the process of designing protocols for multi-regional clinical trials. Released in November 2013, the resulting toolkit defined eleven essential elements that are recommended to be addressed in the design of multi-regional clinical trials. In November 2014, in collaboration with Global Health Network, an e-learning course was launched with the content of the toolkit, which has been utilized by learners around the world.

Given the evolution of clinical trial design and conduct, and the emergence of new considerations, the MRCT Center’s Protocol Ethics toolkit is currently under revision. It aims to ensure key ethical questions are systematically addressed during the design and conduct of multi-regional clinical trials to provide timely and relevant guidance when designing clinical trials.

OBJECTIVE

Increased clarity and transparency of ethics in study design and protocol

Key Milestones

December 2022: User statistics for e-learning course “Essential Elements of Ethics:” Since its launch, 13,645 e-learners from around the world have taken 332,997 modules and 130,521 certificates for completion of modules were issued
December 2019: User statistics for e-learning course “Essential Elements of Ethics:” Since its launch, 2,449 e-learners from around the world have taken 41,125 modules and 15,990 certificates for completion of modules were issued
December 2017: User statistics for e-learning course “Essential Elements of Ethics:” Since its launch, 1,375 e-learners from around the world have taken 22,048 modules and 625 certificates for completion of the entire course were issued
January 2016: Published “Incorporating ethical principles into clinical research protocols: a tool for protocol writers and ethics committees” in Journal of Medical Ethics
November 2014: Collaborated with the Global Health Network to disseminate this guidance as an e-learning resource.
November 2013: Launched the Protocol Ethics toolkit in conjunction with PRIMR – the toolkit includes a detailed points-to-consider document to guide the user towards drafting a standardized protocol ethics section
August 2012: A Workgroup of experts representing 18 stakeholder organizations started meeting twice a month to work on the protocol ethics initiatives.

Project Leadership & Staff

Barbara Bierer, MD. Faculty Director, MRCT Center
Carmen Aldinger, PhD, MPH, PMP, Sr. Administrative and Training Manager
Julia S. Etkin, MBE Candidate. Research Assistant II, MRCT Center

Project Resources

Post-Trial Responsibilities: Continued Access to Investigational Medicines and Devices

Meeting Summary / Sponsor Resource

Released on: October 13, 2022

Developed by: MRCT Center Bioethics Collaborative

View Article

Real World Evidence

Real World Evidence

Derived from data sources such as electronic health records, claims data, registries, and mobile devices, real world evidence (RWE) has the potential to bring innovative products to patients more quickly. Unlike randomized controlled trials (RCTs), which may not be representative of a general population due to strict inclusion and exclusion criteria, RWE may more closely identify how an investigational product will perform in a general population. To address the absence of widely accepted best practices for utilizing RWE, the MRCT Center collaborated with Duke-Margolis Center for Health Policy to define a framework to establish best practices for utilizing RWE for regulatory decision-making.

The MRCT Center also worked with OptumLabs to investigate sources of variability in RWE analysis as applied to replication (emulation) of RCTs. Conceptualized by the MRCT Center and OptumLabs, the Observational Patient Evidence for Regulatory Approval and uNderstanding Disease (OPERAND) Project aimed to understand the sources of variation in design, approach, methodologies, statistical analyses, and decision-making using real world evidence (RWE, specifically claims and EHR data) to emulate phase 3 clinical trials. First, RWE is used to replicate published clinical trials, using and analyzing data limited explicitly to the eligibility criteria of the trial. Later, the aperture of inclusion is broadened to determine any change in effect size by the broader population.

The OPERAND project convened a technical expert panel (TEP) comprising key stakeholders from industry, academia, and regulators, to consider the principles behind, the methodology to draw upon, and the appropriate utilization of, observational data in regulatory review and approval and comparative effectiveness research.

Brown University and Harvard Pilgrim Health Institute, were selected to replicate two trials:

(1) the ROCKET trial for atrial fibrillation, a multicenter, randomized, double-blind, double-dummy, event-driven trial that was conducted at 1178 participating sites in 45 countries) and
(2) the Lead-2 trial for Type 2 Diabetes control, a multi-center, randomized, double-blind, parallel assignment of 1091 participants conducted at 190 study sites across 4 continents).

The project helped validate the use of observational data to complement evidence from RCTs and used empirical data to understand methodologies and sources of variability.

Objectives

To develop empirical data to understand data quality – and the limitations of RWD – from various data sources (e.g., Claims, EHR) and the assumptions necessary to use such data for replication
To determine whether and how the addition of EHR to Claims data improves sensitivity and utility of data, and thus RWE utility
Following replication, to determine how RWE informs understanding of effectiveness for on-label indications in approved populations
To advance regulatory decision-making through RWE

key milestones

February 2021: Presentation about OPERAND at FDA/Duke Margolis virtual workshop Evaluating RWE from Observational Studies in Regulatory Decision-Making: Lessons Learned from Trial Replication Analyses
January 2021: With William Crown, co-authored Real-World Evidence: Understanding Sources of Variability Through Empirical Analysis, in Value in Health
December 2019: Duke-Margolis released Adding Real-World Evidence to a Totality of Evidence Approach for Evaluating Marketed Product Effectiveness
November 2019: Duke Margolis released Understanding the Need for Non-Interventional Studies Using Secondary Data to Generate Real-World Evidence for Regulatory Decision Making, and Demonstrating Their Credibility
September 2019: Duke-Margolis released Determining Real-World Data’s Fitness for Use and The Role of Reliability
June 2019: Grants announced for two academic institutions to replicate two clinical trials using real world data
August 2017: Launched Project OPERAND and held first conference call with the Technical Expert Panel (TEP)
March 2017: Started collaborating with Duke-Margolis Center for Health Policy to develop a framework for real world evidence for regulatory decision-making

Project leadership & Staff

Barbara Bierer, MD. Faculty Director, MRCT Center
William Crown, PhD. Chief Scientific Officer, Brandeis University (formerly Optum Labs)
Hayat Ahmed, MSc., Program Manager

Project Resources

Excluding People With Disabilities From Clinical Research: Eligibility Criteria Lack Clarity And Justification

Publication

Published on: October 3, 2022

Published in: Health Affairs

Abstract
The exclusion of people with disabilities from clinical research without appropriate justification is discriminatory, is counter to federal regulations and research guidelines, and limits study generalizability. This matter is understudied, and data on the disability status of trial participants are rarely collected or reported. We analyzed ninety-seven recent interventional protocols in four therapeutic areas registered on ClinicalTrials.gov. Eighty-five percent of protocols allowed broad investigator discretion to determine eligibility, whereas only 18 percent explicitly permitted people with disabilities to use forms of support (such as supported decision making or assistive devices) to facilitate study participation. Eligibility criteria affecting people with disabilities included exclusions for psychiatric (68 percent), substance use (62 percent), HIV or hepatitis (53 percent), cognitive or intellectual (42 percent), visual (34 percent), hearing (10 percent), mobility (9 percent), long-term care (6 percent), and speech and communication (3 percent) disability-related domains. Documented justification was provided for only 24 percent of these exclusions. We recommend greater scrutiny of study eligibility criteria, scientific or ethical justification of exclusions, and accessible study design.

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Diversity, Inclusion, and Equity in Clinical Research: Integrating Considerations for Diversity, Equity, and Inclusion (DEI) into a Recruitment Strategy Document

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Developed on: October 2022

Developed by: MRCT Center Diversity Workgroup

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