Recommendation 6. When informed consent to the research use of human biological materials is required, it should be obtained separately from informed consent to clinical procedures.
The Working Group concurs with Recommendation 6. NBAC’s recommendation is in keeping with 45 CFR 46.116 and 21 CFR 50.20, which require that consent be sought only “under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.” NBAC points out, and the Working Group agrees, that individuals being asked to give informed consent to clinical procedures are often dealing with stressful health issues and complex paperwork. This may temporarily compromise the ability of a prospective research subject to thoroughly consider the relevant issues and effectively participate in the process of informed consent.
The Working Group notes, however, that it is not clear how such separation can best be achieved. Consent “obtained separately” could refer to the times at which consent is obtained, to the person who obtains consent, to separate consent documents, or to combinations of these options. Each of these alternatives has different implications for implementation. The Working Group observes that NBAC refrained from prescribing a specific answer to the question of how best to separate consent for clinical procedures from consent for research use of human biological materials. NBAC refers instead to the thoughtful input provided by other groups, including the National Action Plan for Breast Cancer, “on ways in which to improve the overall consent process, including its design and timing18 and concludes that additional studies are needed. The Working Group agrees and notes that DHHS is already supporting significant endeavors in this area.19 One study in particular that deserves special mention is the field testing of the consent approach suggested by the National Action Plan for Breast Cancer.20 The Working Group endorses NBAC’s conclusion that “the scientific community should develop a consensus regarding a standard method for human biological materials collection in both therapeutic and research contexts – one that would minimize the need for complex efforts to recontact the source.21
The Working Group proposes that OHRP, in conjunction with NIH, FDA, CDC and other appropriate DHHS agencies, sponsor a workshop on informed consent. The workshop, to be convened following NBAC’s forthcoming report Ethical and Policy Issues in Research Involving Human Participants, should bring together investigators of DHHS-funded studies on informed consent, IRB members, and representatives of relevant professional societies and lay advocacy groups to review current knowledge, share findings from recent studies, suggest future avenues of research, and discuss various approaches for obtaining informed consent and their relative effectiveness and practicality. Results from this workshop will assist OHRP in determining what additional studies may need to be funded and what guidance might appropriately be developed in consultation with relevant DHHS agencies.
Recommendation 7. The person who obtains informed consent in clinical settings should make clear to potential subjects that their refusal to consent to the research use of biological materials will in no way affect the quality of their clinical care.
The Working Group concurs with the principles underlying Recommendation 7. NBAC’s recommendation emphasizes the importance of the protection required by 45 CFR 46.116 and 21 CFR 50.20. In particular, 46.116(a)(8) and 21 CFR 50.25(a)(8) state that the potential research subject must be informed that participation is voluntary and that “refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled,” and that the same rights apply to an individual who initially participates in and later withdraws from a study. No one should be denied routine clinical care that he or she would otherwise be receiving as a result of declining to participate in a research study. Although OHRP guidance titled “Informed Consent Checklist”22 and FDA’s information sheet titled “A Guide to Informed Consent”23 already require that this issue be addressed as part of the written consent, the Working Group agrees with NBAC’s suggestion that this topic be accorded special attention.
The Working Group cautions, however, that the terms “clinical settings” and “quality of their clinical care” in the recommendation may mean different things to different people. “Clinical settings” could refer to settings that house routine clinical care, clinical research, or both. It is important that those who are responsible for obtaining consent from potential research subjects be mindful of this fact. The use of the words “clinical care” preceded by “quality” makes the phrase “quality of their clinical care” susceptible to misinterpretation by patients. To state that declining to participate in research “will in no way affect the quality of their clinical care” does not recognize the fact that, as a result of participating in research, some research participants may have access to care procedures that are not generally available. Saying “no” to a request to collect and study human biological materials may restrict an individual’s access to care provided as part of a research study but should not unfavorably impact an individual’s routine clinical care.
- The Working Group proposes that OHRP, in consultation with FDA, reinforce to research institutions that individuals who are responsible for obtaining informed consent should be provided with training that emphasizes the approaches, techniques and sensitivities that are essential to implementing this recommendation.
- The Working Group proposes that this recommendation guide the development of consent forms and be addressed in the workshop proposed as part of DHHS response to Recommendation 6.
Recommendation 8. When an investigator is conducting research on coded or identified samples obtained prior to the implementation of NBAC’s recommendations, general releases for research given in conjunction with a clinical or surgical procedure must not be presumed to cover all types of research over an indefinite period of time. Investigators and IRBs should review existing consent documents to determine whether the subjects anticipated and agreed to participate in the type of research proposed. If the existing documents are inadequate and consent cannot be waived, the investigator must obtain informed consent from the subjects for the current research or in appropriate circumstances have the identifiers stripped so that samples are unlinked.
In general, the Working Group agrees with Recommendation 8, although there are some practical issues could complicate implementation. The Working Group applauds NBAC’s recognition that much research on human biological materials is of minimal risk and therefore potentially eligible for a waiver of consent.
The Working Group agrees wholeheartedly with the first part of Recommendation 8, which indicates that, simply because a consent form for one kind of research was signed, it cannot be assumed that the consent is applicable to all types of research for an indefinite period of time. Conversely, in the absence of specific limitations or restrictions on sample use, the absence of consent for activities not envisioned at the time a sample was collected cannot be presumed to mean that consent would have been denied for the proposed research. The Working Group believes therefore that each case must be judged on its own merits.
The Working Group concurs in principle with the second part of Recommendation 8, which states that “investigators and IRBs should review existing consent documents to determine whether the subjects anticipated and agreed to participate in the type of research proposed.24 Furthermore, the Working Group suggests adding repositories to the list of parties that should be responsible for reviewing the consent documents, where such documents are available to the repository. The Working Group notes that the repository’s review of consent forms is especially important when the repository will anonymize samples before sending them to the researcher. In such cases, the repository may be the only party in a position to honor limits placed on research use of any given sample. The Working Group expects, however, that the majority of archived human biological materials will not be accompanied by any informed consent documents. For example, consents may have been misplaced over time or may be embedded in medical records held by a separate clinical facility. In situations where consents are available, institutions, IRBs and repositories will need guidance and training to institute best practices for evaluating the adequacy of consent documents.
The Working Group also concurs with the third part of this recommendation, which addresses the situation where consent is unavailable or inadequate to determine the wishes of the sample source with respect to the proposed research. NBAC proposed three conditions, any of which, if satisfied, would permit such research:
- waiver of consent from an IRB; or
- obtaining informed consent from subjects; or
- unlinking/anonymizing samples.
IRBs, researchers and repositories will need new guidance in order to implement this recommendation. Guidance is needed both to assess whether previous consent is adequate to permit research that had not been envisioned at the time of sample collection as well as to evaluate the level of risk in the newly proposed research.
The Working Group proposes that OHRP, in consultation with relevant DHHS agencies and appropriate stakeholders, take the lead in developing guidance for researchers, IRBs and repositories on evaluating the adequacy of extant consent documents for proposed use of existing human biological samples in research. In those cases in which consent is either not adequate or unavailable, the guidance should emphasize that the investigator may proceed only if he/she has met one of the three conditions set forth in this recommendation.
Recommendation 9. To facilitate collection, storage, and appropriate use of human biological materials in the future, consent forms should be developed to provide potential subjects with a sufficient number of options to help them understand clearly the nature of the decision they are about to make. Such options might include, for example:
- refusing use of their biological materials in research,
- permitting only unidentified or unlinked use of their biological materials in research,
- permitting coded or identified use of their biological materials for one particular study only, with no further contact permitted to ask for permission to do further studies,
- permitting coded or identified use of their biological materials for one particular study only, with further contact permitted to ask for permission to do further studies,
- permitting coded or identified use of their biological materials for any study relating to the condition for which the sample was originally collected, with further contact allowed to seek permission for other types of studies, or
- permitting coded use of their biological materials for any kind of future study
The Working Group concurs with Recommendation 9 and commends NBAC for having formulated this recommendation to include a variety of examples (emphasis added) of conditions under which a subject’s human biological materials may be used. This flexibility allows for the development of consent forms that vary in the number and types of options that are included, depending upon the nature and objectives of the study.
The Working Group agrees that additional efforts need to be made to develop appropriate consent forms. NBAC refers to work done by “NIH and advocacy groups such as the National Action Plan for Breast Cancer” on “designing multilayered consent forms that are both informative and practical.25 Practical issues to consider in implementation include requirements for personnel and time, the need to ensure that pertinent information from the consent forms accompanies the samples, and the ability of researchers and repositories to understand and comply with the wishes of the sample sources in the years to come. Further study is needed to assess the impact that the number and type of options in a consent form will have on the ability of a potential subject to understand the options and on the researchers’ ability to carry out important research. NBAC concludes, and the Working Group agrees, that efforts to design and use improved consent forms “should be encouraged and continued.26
DHHS, through various agencies and offices, is actively working to improve the consent process in ways that directly address NBAC’s recommendation. As previously noted, NIH, in collaboration with CDC, is currently funding 18 research projects addressing informed consent. This program includes a feature to encourage interaction among researchers and a strategy to translate research results to practice. A component of the National Institute of Allergy and Infectious Diseases has disseminated to investigators an informed consent template that addresses future use of human biological materials. For intramural NIH researchers, the NIH Office of Human Subject Research posted on its website revised guidance on informed consent for the use of human biological materials.27 HRSA is funding the development of model policies for informed consent for storage and research use of samples collected from newborn screening programs. The CDC guide to writing informed consent documents, which includes examples of good practices, is currently being revised to include information directly relevant to NBAC’s Recommendation 9.28 IHS is developing and will post on its website a new model consent form that will specifically address issues raised by Recommendation 9.29 Finally, OHRP plans to revise Chapter 5 (Human Genetics Research) of the IRB Guidebook, which contains guidance pertinent to this recommendation.
- The Working Group proposes that DHHS agencies continue funding studies in this area and that findings from such studies be made available to researchers and IRBs.
- The Working Group proposes that the workshop on informed consent, proposed as part of the DHHS response to Recommendation 6, also address issues related to the development and use of layered consent forms with multiple options.