RE: Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators
Jerry Menikoff, M.D., J.D.
Office of
Human Research Protections (OHRP) 1101 Wootton
Parkway, Suite 200
Rockville, MD
20852
RE: Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators – Advance Notice of Proposed Rulemaking (ANPRM) 76 Fed. Reg. 44512, July 26, 20111 – Docket: HHS-OPHS–2011–0005
Dear Dr. Menikoff:
AVAC welcomes this opportunity to comment on the ANPRM. AVAC is a non‐profit organization that uses education, policy analysis, advocacy and a network of global collaborations to accelerate the ethical research and development and global delivery of vaccines, male circumcision, microbicides, preexposure prophylaxis (PrEP) and other emerging HIV prevention options as part of a comprehensive response to the AIDS pandemic. AVAC partners with domestic and international stakeholders on issues related to the ethics, safety, and oversight of human research as described in the ANPRM. AVAC also publishes policy papers and reports that explain ethical issues in clinical research.2
Good Participatory Practice Guidelines
In 2011, AVAC partnered with UNAIDS to issue the second edition of the Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials (GPP) to provide trial funders, sponsors, and implementers with systematic guidance on how to effectively engage with trial participants in the design and conduct of biomedical HIV prevention trials.3 GPP is designed to provide systematic guidance on the roles and responsibilities of research entities to effectively engage stakeholders at all levels – from trial participants and their communities to national and international policymakers – in the design, conduct, and outcome of biomedical HIV prevention trials.
GPP aims to have a significant effect on the ethical implementation of clinical trials in biomedical HIV prevention research globally by:
- Raising awareness about and disseminating the GPP guidelines;
- Advocating adoption of the guidelines and their minimum elements by key stakeholders and implemented at trial sites;
- Providing materials, resources, and technical assistance to stakeholders to improve their understanding and ability to use and implement the GPP guidelines;
- Monitoring and evaluating implementation of the GPP guidelines globally; and
- Fostering relationships with stakeholders who are using or would like to use the GPP guidelines
These guidelines, developed originally for biomedical HIV prevention trials, are applicable to biomedical research generally and to the issues raised by the ANPRM. For example, the Presidential Commission for the Study of Bioethical Issues, which is identified as a source of guidance by the ANPRM, invited AVAC to be part of an expert panel on August 30, 2011, to present the significance of GPP and its application to the conduct of federally funded research.4
Topical Responses To ANPRM
We present our ANPRM responses topically because many of the questions pose overlapping concerns. Our responses note the several ANPRM questions by number to which they relate. We note at the conclusion of this letter that the ANPRM has not called for comment on other aspects of human research protection that also deserve attention.
1. Institutional Review Boards (IRBs) – Central IRB for multisite research. Questions 30-34
AVAC recognizes the potential efficiencies in the use of a single central IRB for some aspects of multisite research, a feature characteristic of many HIV prevention and treatment biomedical/behavioral trials. Despite these efficiencies, multiple IRBs provide benefits that need to be considered. Multiple IRBs can insure representation and involvement from all the sites and populations tested. Additional review above and beyond a central IRB can also act as a safeguard in light of publicized examples of IRB violations or lack of competency.5 The use of a central IRB may also conflict with the independent requirements for collaborative research in a local jurisdiction, as is the case with studies involving native or aboriginal populations. 6
Our principal concern is that a central IRB may not be sufficiently cognizant of, and engaged in, each of the communities and populations in which research is taking place. Community engagement in research may not function adequately under a single IRB. Although current FDA guidance describes mechanisms whereby a central IRB may be educated about and respond to local factors, those mechanisms may be insufficient and lack the depth and transparency required to satisfy consideration of local community values.7 These concerns are amplified by the nature of IRBs that often lack public access to, and public notification about, their dockets, their review, and opportunities for public consultation.
The ANPRM acknowledges this issue by asking for criteria for determining which IRB shall be designated the single IRB in multi-site research settings. (Question 34). (“How should the IRB of record be selected“). AVAC believes that if multi-site research is to be managed by a central IRB, that IRB should be the IRB most closely engaged with and representative of the community(ies) to be studied. If local IRBs lack capacity to serve as a central IRB, steps should be taken to strengthen that capacity. A central IRB system cannot be recommended outside of a significant supporting structure for community involvement, and meaningful interaction in different phases of ongoing trials by all stakeholders. To the extent comments to the ANPRM would form the basis for formal regulations, AVAC believes a wider discussion of oversight, authority and public involvement under a central IRB system will be needed.
2. Informed Consent documents and procedures. Questions 35-40
The requirement of informed consent is a principle that can be found outside the parameters of the Common Rule. It is the cornerstone of ethically conducted research and is explicitly discussed in many guidance documents that address the overall ethical conduct of research, such as the World Medical Association’s Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) guidelines, the Belmont Report, Good Clinical Practice, the World Health Organization Handbook for good clinical research practice, the Nuremberg Code, the Nuffield Council guidance on health research in developing countries, Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials and UNAIDS/WHO Ethical considerations in biomedical HIV prevention trials, and in relevant national guidelines.
The ANPRM suggests changes to the simplify consent forms. AVAC supports the goal of the ANPRM in creating consent forms that are the right length, comprehensible, and contain all of the key information to aid trial participants in their decision about whether to participate in a study. Trial participants may not fully appreciate the content of consent forms as they are currently prepared especially considering cultural contexts and beliefs about health and illness that may differ from those of researchers.8
To the extent consent forms articulate the proposed terms behind a protocol’s good clinical practice choices on such issues as research related injury, benefits or ancillary care, or access to research results, participants can be placed at a disadvantage in deciding consent. A clinical trial establishes an “unequal balance of power” according to the National Bioethics Advisory Commission.9 Population-level risks to public health from not participating in a trial should not be offered to the person as the choice compared with the individual risk incurred from joining the study. Study participants are partners in population-level research and deserve proper care when injured and protection from stigma whatever the source.10
The ANPRM notes in particular the use of institutional “boilerplate” language that does “little to genuinely inform subjects.”11 In that category, we place these issues of boilerplate language that simply refuse to attend to research related injury or withhold ancillary care which could otherwise build trust and confidence in research or that are lacking in ways to describe longer term benefits.
Consent forms may be used to exculpate when they should educate instead. AVAC is also concerned with trends that primarily serve to protect sponsors and researchers from liability or to specify rights of investigators. The goal of consent must be to respect autonomy, mitigate imbalances of power in research or provide measures to reduce the risks of voluntary participation in research. An informed consent document, which is not signed by the sponsor or explicit in other ways, has been found not to create obligations of a contract that could be enforced.12 Rights to specimens and data can and should be allocated (hopefully with some benefit sharing proposal as noted later in these comments). But it is inappropriate to load up consent forms with language devoted principally to relinquishing rights and exacerbating imbalances of power in clinical trial relationships.
One way to correct these imbalances is to focus on the meaningful subject content of consent tied to protective trial designs. One starting point, among others, to review meaningful content are the “essential information” topics recommended by the ethical guidelines of the CIOMS,13 or the topics of discussion included in the GPP consent development process, along with commitments to design trials that go to lengths to protect participants in ways that correct imbalances of power.
The ANPRM proposes to solve this problem by prescribing the content and format of consent forms in greater specificity to control length and content. Changes to make consent forms more understandable are welcome and long overdue. At the same time, the informed consent process is a dynamic process. It is one of the principal vehicles by which stakeholders can help research develop locally acceptable and effective informed consent procedures and materials through approaches like GPP. Communities can provide researchers and IRBs with invaluable advice to improve the informed consent process and materials.
Consent forms need to be flexible enough to include community concerns and issues relevant to the trial as they arise. Research teams need to have the flexibility to include develop informed consent materials and procedures with community stakeholders.14 Specifically, the consent development process must be designed to understand and incorporate into consent forms local cultural practices may affect individual decision-making ability, and how working within these structures can be facilitated while ensuring protection of individual autonomy to provide informed consent.
Consent Related to Reuse or Additional Analysis of Existing Data and Specimens. Questions 45-53.
AVAC supports measures that allow for the reuse of data collected as part of clinical research. AVAC also believes that consent of such reuse should be obtained as part of the initial consent process. Specifically, consent could be obtained by use of a “standardized, general consent form to permit future research on biospecimans and data.” Permitting reuse where identifiers have been removed is not equivalent to consent and, as the ANPRM notes, biospecimens may be identified even once traditional identifiers have been removed. We would, however, support grandfathering reuse of pre‐existing samples as suggested in the ANRPM.
Treatment of biospecimens and data - Question 23, 45-53.
AVAC strongly supports maximizing collaborative use and responsible repository management of biospecimans (and data derived therefrom) for immediate and long-term research purposes, especially with the growth of “omic” technologies required to advance HIV vaccine and cure research. In our view, treating trial participants with respect, beneficence and justice regarding their rights, recognition of and appropriate reward for the value of their contribution, and cultural sensitivity are significant means to increase voluntary donations supporting effective research.
Review of research protections affecting biospecimens is concurrently underway within this ANPRM, recent draft HHS/OHRP and FDA guidance on “exculpatory language,”15 and within meetings of the Presidential Commission for the Study of Bioethical Issues. Increased regulatory coordination to avoid duplication of effort, missed opportunity for expert evaluations and inconsistency of administrative outcomes is necessary. We request that the draft FDA guidance be suspended and take into account the other administrative efforts on biospecimens. With regard to the ANPRM, we request that the biospecimen questions also be reserved or revisited, pending the outcomes of the Commission’s findings.
In anticipation of improved coordination, we offer these responses to the ANPRM, subject to reconsideration when other studies are concluded:
- The ANPRM makes increased protection of human participants a central aim. Yet with one limited exception,16 its proposals do not offer significant protections to specimen donor participants or with regard to data use. The proposals focus on ways to reduce investigative burdens.
- To secure participant appreciation for and support for research purposes, concessions for ease of use must be aligned with compatible handling and consent structures that actualize respect, beneficence and justice. Increasingly, pharmaceutical companies, academic researchers and clinicians collect biological specimens and other data to characterize genetic determinants of disease or to develop products. The potential public health value of this data deserves enthusiastic support. At the same time, misuse of genetic information could affect family or groups related to the research participant or patient.17 A duty of care exists in these circumstances. That duty includes actions to prevent the sharing of data for any nonmedical purpose or a purpose that could result in discrimination, stigma, and denial of insurance or care. For example, the ANPRM fails to propose codification into regulations of guidance under the Genetic Information Nondiscrimination Act applied to clinical research.18
- Investigators and private companies should take special precautions when data are shared or transferred to others during acquisitions, mergers or combinations that successors who come to own the data maintain the protections that individuals expect. Currently downstream users of data are not regulated to the same degree as originators with respect to privacy and disclosure.
- Another aspect of good clinical practice in the use of genetic data is to consider ways to return value to individuals in exchange for the use and ownership of their biological samples. It is often not practical or possible to recognize a distinct personal ownership interest in products or research tools that emerge years later from long term use of biological samples or data without deterring the very product development that should be encouraged. However, other means are available to recognize the contribution of individual donors through benefit sharing or by providing ancillary care during clinical trials.19
- The ANPRM does not consider cultural or community values applied to specimens or derived data, rights of return, interests in use – issues that were prominent in recent conflicts with handling of specimens donated by the Havasupai Tribe.
- The ANPRM recognizes that modern genetic tools allow any specimen to be linked to a specific individual. There are no longer effective measures to completely de-identifydata and excuse certain trials from coverage on that basis. Although privacy protection assurances are helpful, breaches of privacy have received considerable attention.20 ANPRM proposals should address mechanisms to correct and mitigate widespread and personal harms from breaches of privacy and/or sanctions for failure to do so.
Demonstration Projects – Question 26
The ANPRM recognizes that confusion exists as to the scope or merit of exemptions for “demonstration projects.”21 Other studies of the Common Rule have examined inconsistencies across agencies in applying these exemptions.22
Increased confusion may result from new efforts to advance implementation and clinical science translation when new interventions become available but require further study to determine interrelated effects of cost and insurance, acceptability, best delivery practices within public service programs, identification of populations for greatest impact and benefit, adherence to therapies, and related behaviors of disinhibition. The HIV prevention field currently confronts at least one such example of study based on new data for a currently off-label use of HIV infection preexposure prophylaxis with FDA approved antiretroviral drugs permitted to treat HIV (oral PrEP).23 A suite of federal and state agency, private and other sources of PrEP implementation study are available, including NIH sponsored translational and implementation grants, Patient Centered Outcomes Research under the Affordable Care Act, CDC studies, California state grants, required study under regulatory approval arrangements and federal program benefits analysis.
Because implementation science for novel interventions may involve coordinated and overlapping resources, expertise and purpose, a categorical exemption for “demonstration projects” could interfere with the participant protections in those studies. The term “demonstration project” lacks flexibility of definition required to advance translational efforts. AVAC requests that proposed rulemaking account for needed flexibility and retain many such projects within the scope of research requiring Common Rule protections for research participants.
Extension of Common Rule to Federally Funded Researchers - p. 44514
AVAC supports extending federal regulatory protections to apply to all research conducted at U.S. institutions receiving funding from the Common Rule agencies. Extension of the Common Rule to these additional areas lacking strong infrastructure or experienced ethics review systems should be evaluated to guarantee at least baseline protections afforded under the Common Rule.
Excused Social Science and Behavioral Research – p. 44518
AVAC recognizes that much social science research generally, particularly undertaken through surveys, often carries few risks to participants. At the same time, research into questions around HIV status or acquisition are deeply personal and carry high informational risks in most settings or subject persons in some cases to physical assault. In focus group settings of research, genuine risks remain that are not merely “informational” as the ANPRM states. Participants who experience abuse or domestic violence may be recruited for focus groups of social research yet face threats and dangers from partners. AVAC proposes retaining some limitation within this category of information that if disclosed could lead to social or physical harm.24
General Considerations
In addition to the ANPRM responses above to specific questions, we would like to respectfully suggest that OHRP consider a change in fundamental vocabulary: to substitute the term “trial participant” or “human research participants” for “human subjects.” The use of the terms “subjects” has come to represent many of the civil society objections to notorious past practices of inflicting harm, neglecting patient concerns, power imbalances between investigator and participant, serious ethical lapses and other barriers to research dependent on voluntarism, respect, beneficence and justice that should be part of the research process. In 2001 the U.S. National Bioethics Advisory Commission (NBAC) stated:
“Traditionally, and in current regulations, those studied in experimental research are referred to as research subjects. This term accurately captures an important aspect of the relationship between an investigator and the individual being studied. However, the term subject also connotes society’s worst fears about research participation, rather than its aspirations. There are methods, such as obtaining voluntary informed consent, by which investigators can show respect for the human dignity of those involved in research. By securing consent, individuals become volunteers, not mere subjects, who are active participants in the research process. Therefore, this report uses the term human participants to refer to those who are studied in research protocols.”25
AVAC agrees and adds that under GPP principles, all stakeholders play a vital role in advancing research and must be engaged in comprehensive discussion throughout the phases of research even before individuals are enrolled. Failure to use effective participatory practices results in delays, halts and stoppages that are more burdensome and antithetical to the conduct of science than the administrative burdens the ANPRM is designed to correct. A change in terminology will also advance ANPRM aims and should be substituted throughout HHS and FDA regulatory and guidance materials.
Finally, as you are aware, the Secretary's Advisory Committee on Human Research Protections (SACHRP) has been instrumental in developing and reviewing the ANRPM. We commend the SACHRP for its work in this area, but note that the SACHRP would have been greatly aided by a representative of patients or research subjects as members of the committee. A volunteer or patient representative would be invaluable to SACHRP in considering the effect of changes to the Common Rule and in particular the effect of changes upon privacy and informational risk. The Charter for SACHRP states that the committee shall be composed “ from among individuals possessing demonstrated experience and expertise in any of the several disciplines and fields pertinent to human subjects protection and/or clinical research.” This prerequisite would not preclude membership by representatives from patient groups, or trial participants and AVAC urges SACHRP to consider adding such representative to the committee when vacancies arise.
Thank you again for this opportunity to comment. If you have questions about this letter, please contact the undersigned at mitchell@avac.org.
Sincerely yours,
Mitchell
Warren
Executive Director
Footnotes:
1) This letter cites to page
numbers of the Federal Register when referring
to the ANPRM.
2) AIDS Vaccine Handbook: Global Perspectives (2nd edition) hereinafter “Vaccine Handbook” http://www.avac.org/ht/d/sp/i/2311/pid/2311
3) Available at http://www.avac.org/ht/d/sp/i/309/pid/309
4) Community Engagement - Needs, Models and U.S. Actions at http://bioethics.gov/cms/node/319. The transcript of the AVAC presentation is noted with the request to incorporate its content and also the GPP 2nd edition into the record. See http://www.avac.org/ht/a/GetDocumentAction/i/35219.
5) Human Subjects Research: Undercover Tests Show the Institutional Review Board System Is Vulnerable to Unethical Manipulation, GAO-09-448T March 26, 2009 at http://www.gao.gov/products/GAO‐09-448T); FDA Imposes Restrictions on Coast IRB due to Violations: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm149565.htm; http://www.circare.org/FOIA/irblast.htm
6) Brugge, D. and Missaghian, M. Protecting the Navajo People through Tribal Regulation of Research. Science and Engineering Ethics (2006) 12, 491-507.
7) Using a Centralized IRB Review Process in Multicenter Clinical Trials, http://www.fda.gov/RegulatoryInformation/Guidances/ucm127004.htm
8) Graham Lindegger. Informed Consent in HIV Vaccine Trials. Vaccine Handbook, section 3-chapter 16 at http://www.avac.org/ht/a/GetDocumentAction/i/2681
9) Report on Ethical and Policy Issues in Research Involving Human Participants, Ch. 2, Definition of Research Involving Human Participants http://www.onlineethics.org/cms/8027.aspx
10) “They that have power to hurt and will do none...They rightly do inherit heaven's graces and husband nature's riches from expense.” William Shakespeare, Sonnet 94.
12) Abney
13) International Ethical Guidelines for Biomedical Research Involving Human Subjects, Guideline 5 at http://www.cioms.ch/publications/layout_guide2002.pdf
15) Guidance on Exculpatory Language in Informed Consent; 76 Fed. Reg. 55390, September 7, 2011 at http://www.hhs.gov/ohrp/newsroom/rfc/exculpatorydraft2011.html
16) “Participation in a research study (such as a clinical trial) could not be conditioned on agreeing to allow future open-‐ended research using a biospeciman.” p. 44520.
17) UNESCO. International Declaration on Human Genetic Data (October, 2003) http://www.unesco.org/new/en/social-and-human-sciences/themes/bioethics/human-genetic-data/; CIOMS “International Ethical Guidelines for Epidemiological Studies.” at http://www.cioms.ch/frame_ethical_guidelines_2009.htm
18) Office of Human Research Protections. Guidance on the Genetic Information Nondiscrimination Act: Implications for Investigators and Institutional Review Boards (2009) http://www.hhs.gov/ohrp/policy/gina.html
19) Human Genome Organization Ethics Committee, Statement On Benefit-Sharing; April 9 2000 at http://www.hugo-international.org/img/benefit_sharing_2000.pdf
20) To date, HHS has investigated and resolved over 14,527 cases by requiring changes in privacy practices and other corrective actions by the covered entities. http://www.hhs.gov/ocr/privacy/hipaa/enforcement/highlights/index.html 21) p. 44521.
22) Ethical and Policy Issues in Research Involving Human Participants, P.10 at http://bioethics.georgetown.edu/nbac/human/overvol1.pdf (hereinafter NBAC) (2001)
23) PrEP: Roadmap to the Real World. Establishing the Real-World Effectiveness of PrEP Through Demonstration Projects. (2011) at http://www.projectinform.org/pdf/prep_roadmap.pdf
24) The current qualifier language provides important protection for “any disclosure of the human subjects’ responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation." This language should be expanded.