TRIbune Fall 2019 - Harmonization and Contradictions Among Human Clinical Research Guidelines Regarding Consent of Participants
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Harmonization and Contradictions Among Human Clinical Research Guidelines Regarding Consent of Participants

September 2019



In recent years, the understanding of what it means to give "informed consent" to participate in a clinical trial has been under increased scrutiny by both the research community and the general public. As the number and complexity of clinical trials continues to grow, it has become increasingly difficult to determine the appropriate type and amount of protocol information to include in the informed consent process, to ethically recruit and enroll potential trial participants.

The development of checklists and instructions for writing clinical trial protocols and informed consent forms has been a fluid process spanning over several decades. To date, several guidances have been internationally agreed upon and are used by members of the scientific, medical, and ethical communities, as well as with the various levels of governments and community leadership. These documents form the ethical and moral base for medical research. However, considering the wide variety of the public and private entities involved, combined with the diversity of users, ranging across government legislators, clinicians, and scientists, to members of the general public - it is not surprising to find a large number of disparities in the understanding and interpretation of ethical guidance documents. Some of these topics will be explored here, along with an overview of some recent efforts made to come to a general consensus.

Some of the most widely used guidance documents for clinical research include:

  1. The World Medical Association's (WMA) Declaration of Helsinki (First Revision 1975; Seventh Revision, Oct. 2013)1
  2. The Council for International Organizations of Medical Sciences' (CIOMS) International Ethical Guidelines (2016)2
  3. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Efficacy Guideline E6(R2) Good Clinical Practice(Finalized Integrated Addendum, November 2016; published on the FDA Federal Register in March 2018)3
  4. The U.S. Federal Government's Title 21 Code of Federal Regulations Part 50, Protection of Human Subjects (May 1980)4
  5. The U. S. Health and Human Services' Code of Federal Regulations 45 CFR Part 46, Protection of Human Subjects [Jan. 2017 (Pre-2018) and Jan. 2019 (2018 Revised)]5,6

The Human Subjects Protection (HSP) team at TRI writes and reviews sample and site-specific informed consent forms and related documents, and ensures that they meet all applicable federal requirements, guidelines (such as those listed above), and other client-specific policies.

Working Towards Harmonization

Examples of Reconciled Terms
Progress has been made over the last few decades regarding some major areas of concern. For example, the concept of "community," has been incorporated by the aforementioned groups in HHS 45CFR465 sections x.101(f)5, x.114(b)(2)(i), and x.116(i & j)5; Helsinki General Principles Guideline 105.; and CIOMS Guideline 7, Community Engagement. This concept testifies to the need for ethically and legally respecting the norms, standards and traditions of groups, communities, or tribes of people.6,8

Similarly, the recognition of the need for more effective collection, handling, storage, and use of the large volumes of "biospecimens and private information" from the vast sea of clinical trials and other research has led to the development of more efficient systems and establishment of storage repositories for future use. This has also brought about changes in guidelines to increase the security of confidentiality of the trial participants that are graciously donating these valuable specimens for future research use. This can be found in 45 CFR 46.1165,6 basic and additional elements.

"The Revised Common Rule" (US 45 CFR Part 46, Subpart A)5,6
Subpart A of the HHS policy 45 CFR Part 46, "The Federal Policy for the Protection of Human Subjects," also known as the "Common Rule," was originally published in 1991. In early 2017, the HHS Secretary's Advisory Committee on Human Research Protections (SACHRP) charged the Subcommittee on Harmonization (SOH) to identify potential areas that could be updated to increase harmonization, consistency, clarity, simplification, and/or coordination among the agencies. During this time, there was backlash from the research community regarding numerous elements and vagueness of terms. After several meetings and time frames allowing for commenting opportunities by the scientific, medical, and public communities, agreement was reached in only some areas. On April 20, 2018, a Notice of Proposed Rule Making (NPRM) was made by the Office for Human Research Protections (OHRP) regarding the Federal Policy for the Protection of Human Subjects, to delay the general compliance date to the revised 2018 Requirements of the Common Rule from July 19, 2018 to January 21, 2019.

One change of particular note is that the importance of participant comprehension is now explicitly mandated by the revised Common Rule,5 which ensures that information is presented in a manner that facilitates understanding and decision-making by potential trial participants, thus improving safety and protection of the rights of these individuals.

During this delay period, however, three provisions aimed at decreasing the burdens on Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) became permitted (but not required) to be implemented on June 18, 2018. An IRB/IEC is an administrative body that protects the rights and welfare of human participants in research, and has the authority to approve, require modifications in, or disapprove research. Two areas of clinical trial informed consent forms that are still of specific concern are the new 'key information' section to be presented at the beginning of the consent form; and new elements regarding the collection of identifiable private information and biospecimens, along with the use of 'broad consent' for future use of biospecimens and health information. In late October 2017, new U.S. federal guidance templates for consent forms for clinical trials, as well as 'broad consent' for future use of biospecimens and health information, were provided by SACHRP. Additionally, the new website "About Research Participation" is now available as a public resource for understanding trials, and is available at SACHRP, however, continues to discuss these topics with researchers with the hope that they will be able to provide additional guidance by the end of 2019.

It should also be noted that ICH E6 (R2), Section 4.8.103 and federal regulation 21 CFR 50, Subpart B, sections 20 and 25,4 contain many of the same basic and additional elements of consent as 45 CFR 46.116,5 but they have not been revised to include the new elements and other changes as seen in the Common Rule updates.

Concepts That Have Not Yet Been Harmonized

In spite of the great efforts made by the groups as discussed above, understanding and interpretations of several key topics remain disparate – and sometimes contradictory – when compared across the guidance documents.6,7,8,10 Among these are the following subjects:

  1. Does the Control Arm of Research Studies Need to be the Best Proven Intervention?
  2. How Do We Define Who Makes Up a Vulnerable Group?
  3. Do We Need to have Post-Trial Provisions for Continued Care Measures?
  4. What Compensation is Available for Participating in Research and Research-related Injury?

Also, additional discussions between the research and regulatory communities are still needed to work out details for maintaining a trial participant's confidentiality, finding the balance between autonomy and beneficence, and making decisions regarding waivers of consent.

Perseverance Towards International Reconciliation of Guidances

Future meetings on the ethical and practical governance of medical research involving human subjects will include discussions on the topics listed above. Meetings which are already scheduled include those by SACHRP (Quarterly Meeting, October 16-17, 2019), the ICH [Global Meeting on ICH E6 (R1) Guideline on General Considerations for Clinical Trials, October 31, 2019], and the WMA (WMA General Assembly, October 23-26, 2019). The CIOMS currently has a special Working Group XI - Patient Involvement.


Through continuing efforts made by scientists, medical professionals, statisticians, regulators, and others involved in designing, carrying out, and overseeing clinical trial research, great strides have been made to secure the safety and well-being of participants. The TRI HSP Team, along with TRI's other regulatory professionals, are very proud to be a part of these efforts. But as discussed here, the challenges of performing clinical trials are becoming larger and more intricate. Advancements in preparation and storing of drugs, the use of medical devices, and implementation of information technologies are allowing researchers to carry out trials and analyze data for thousands of participants located at sites throughout the world. The logistics of planning, coordinating, and implementing such studies requires large investments, such as those of financing and personnel. This necessitates a hard look at how everyone involved communicates, understands, and interacts with each other. It is of paramount importance that all parties involved continue to follow the key concepts of autonomy, beneficence, and justice that make up the core principles of Declaration of Helsinki,1 as well as the ethical principles set forth by the ICH and CIOMS, government agencies, private industry partners, and participants in the research.


  1. World Medical Association Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects, 64th WMA General Assembly, Fortaleza, Brazil, October 2013.

  2. International Ethical Guidelines for Health-related Research Involving Humans, The Council for International Organizations of Medical Sciences (CIOMS) in Collaboration with the World Health Organization (WHO), Geneva, 2016.

  3. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Efficacy Guideline E6(R2) Good Clinical Practice (Finalized Integrated Addendum, November 2016; published on the FDA Federal Register in March 2018)

  4. 21 CFR Part 50: United States Federal register, Title 21 Code of Federal Regulations Part 50, Protection of Human Subjects (May 1980)

  5. 45 CFR Part 46: U. S. Department of Human and Health Services, Code of Federal Regulations, Title 45 Public Welfare, Department of Health and Human Services, Part 46, Protection of Human Research Subjects , Pre-2018 Common Rule -Revised January 15, 2009, Effective July 14, 2009; and the 2018 Revised Common Rule 45 CFR 46.116, Effective January 21, 2019

  6. The Federal Register, Vol. 82, No. 112, Thursday, January 19, 2017, Rules and Regulations - Changes to the Common Rule 45CFR46.116-A.

  7. Fernando Hellman, Marta Verdi, Bruno Rodolfo Schlemper, and Sandra Caponi (2014). 50th anniversary of the Declaration of Helsinki: the double standard was introduced. Archives for Medical Research, 2014, Vol. 45(7), pp. 600-1.

  8. Johannes J.M. van Delden and Rieke van der Graaf (2017). Revised CIOMS International Ethical Guidelines for Health-Related Research Involving Humans. JAMA, 2017, Vol. 317(2), pp. 135-6.

  9. 21 CFR 314.126: U. S. Department of Human and Health Services, Title 21, Code of Federal Regulations, Vol. 5., Date 2016-04-01, Section 314.126 - Adequate and well-controlled studies.

  10. Ivana Zagorac (2016). How Should We Treat the Vulnerable? Qualitative Study of Authoritative Ethics Documents. Journal of Health Care for the Poor and Underserved, 2016, Vol. 27(4), pp. 1656-1673.

About the Author

Catherine Svabek is a Human Subjects Protections Specialist with extensive experience in the pharmaceutical industry as well as critical care nursing. She holds an M.S. in Biotechnology; a B.S. in Biochemistry, Microbiology, and Molecular Biology; and a B.S. in Nursing.






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