NCHR Comments on The E6(R3) Guideline for Good Clinical Practice and International Council for Harmonisation Draft Guidance

September 5, 2023

We appreciate the opportunity to comment on the proposed guidance: “E6(R3) Guideline for Good Clinical Practice; International Council for Harmonisation (ICH); Draft Guidance for Industry; Availability.”

The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

NCHR supports the ICH’s objective of attaining global regulatory harmonization to ensure that safe, effective, and high-quality medicines are developed worldwide. We agree that Good Clinical Practice guidelines will help streamline regulatory expectations across the globe while also promoting worldwide safety and accessibility of medicines.  However, it is essential that global regulatory harmonization does not weaken the FDA’s reputation as the gold standard, and does not further undermine harmonization among HHS agencies’ standards.

NCHR agrees with incorporating stakeholder engagement to help improve study feasibility and protocol design. Nevertheless, stakeholder engagement is only effective when stakeholders are unbiased and knowledgeable about research design and feasibility. In addition, we recommend strengthening this approach by emphasizing early engagement of stakeholders (i.e., during protocol development) and maintaining engagement throughout the study coordination and planning process. We also recommend using committees comprised of patients and caregivers with relevant experience to review protocols and provide insight to increase study adherence and minimize participant burden. Further, in regard to patients and caregivers we strongly recommend strengthening the language in the guidance to better reflect their centrality to the clinical trial being performed. Specifically, we ask that the ICH include “clinically meaningful benefit to patients” to the statement: “The quality and amount of the information generated in a clinical trial should be sufficient to provide confidence in the trial’s results as providing a clinically meaningful benefit to patients and support good decision making.”

NCHR strongly agrees with the draft guidance in acknowledging that diverse study populations are necessary to ensure that trial results are relevant to a broad range of patients. We recommend outlining explicit strategies and requirements for clinical trials in terms of recruiting and enrolling diverse study populations and how to apply such a framework on a global scale. For example, the U.S. has more racial and ethnic diversity than many other countries, and is unique in having a national health coverage that is specific to people over 65 and people with disabilities. NCHR encourages adding requirements for using diverse study sites to ensure access for patients from diverse communities. Often, clinical trials include the youngest, healthiest sick patients, in order to reduce the confounding impact of co-morbidities and maximize the chances that the results will indicate benefits rather than harm.

There is a great need for increased representation of older patients, people of color, and women in order to show that benefits do outweigh risks for medical products. NCHR recommends adding requirements for using diverse study sites, as this will further help increase the accessibility of the study to patients from diverse communities. Further, we strongly recommend using stakeholder committees comprised of patients and caregivers with experience that lends itself to promoting understanding and awareness that helps to increase patient diversity, including racial/ethnic diversity; age; sex; and patients who have been harmed by medical products as well as those seeking new medical treatments. We also urge that the ICH Expert Working Group to add “from diverse communities and positive and negative medical experiences” to the section on 3.1 on Trial Design: “Sponsors should consider inputs from a wide variety of stakeholders, for example, healthcare professionals and patients from diverse communities and positive and negative medical experiences, to support the development plan and clinical trial protocols as described in ICH E8(R1) and when developing the informed consent material and any other participant-facing information.”

In addition, NCHR supports the draft guidance in requiring periodic review of scientific knowledge and methodology so that the trial may be optimized to reflect current scientific understanding and clinical practices. However, to make this requirement meaningful, NCHR strongly urges using explicit language with strict timeframes for review, rather than allowing review process to occur as “appropriate.” We also recommend explicit standards for provider oversight: providers should be required to report incidents that may have an impact on participant safety or trial results rather than being compelled to do so by ethics and regulatory committees. We are concerned that in general, given the conflicts of interest of sponsors, implementing policies that rely heavily on sponsor oversight may compromise ethical standards and participant safety. We therefore strongly urge that the ICH adds language that would require more transparent and unbiased oversight by ethical or stakeholder committees as well as the investigators conducting the trials.

In conclusion, we appreciate the opportunity to comment and support the efforts of the ICH to provide guidance in conducting responsible, high-quality, clinical trials with a global perspective. However, we strongly urge more explicit, clarifying wording to strengthen the draft guidance. Specifically, we emphasize a need to 1) incorporate diverse stakeholder engagement that includes diversity in race/ethnicity; age, sex, and patients who have been harmed by medical interventions, 2) explicit plans for recruiting and enrolling diverse study populations within clinical trials, 3) establish a clear timeframe for necessary scientific review, 4) strictly require providers and investigators to report trial incidents rather than rely on ethics and regulatory committees, and 5) incorporate trial oversight committees that are more objective than sponsors to safeguard study participants.