July 15-16, 2008 Meeting Minutes
Secretary's Advisory Committee on Human Research Protections
July 15 and 16, 2008 - Arlington, Virginia
TUESDAY, JULY 1
Welcome: Opening Remarks
Samuel J. Tilden, M.D., M.D., J.D., LLM, SACHRP Chair
Dr. Tilden welcomed attendees to the committee's 16th meeting. He observed that two members are rotating off the committee — Dan Nelson and himself. The Chair then welcomed two new members: Barbara Bierer, M.D., is the Senior Vice President for Research, Brigham and Women's Hospital and Professor of Medicine and Pediatrics at the Harvard Medical School. David Forster, J.D., M.A., C.I.P., is Vice President for the Office of Compliance for Western IRB and a member of the Subcommittee on the Inclusion of Individuals with Impaired Decision-Making in Research (SIIIDR).
The Chair reviewed the committee's charge and previewed the day's agenda. He notified those present that Wilson DeCamp plans to make a public comment and has submitted a document for review, "Declaration of Clinical Research rights and Responsibilities for People with Parkinson's Disease."
Minutes for the previous meeting (March 27 and 28, 2008) were approved unanimously.
Report of Issues/Remarks
Ivor Pritchard, Ph.D., Acting Director, OHRP
Dr. Pritchard recognized the new Executive Director of SACHRP, Julia Gorey, and expressed appreciation for her willingness to step in from the Policy Branch to assume that role. He also thanked departing members Samuel Tilden (Chair) and Dan Nelson for their many contributions.
On July 2, OHRP requested "Information and Comments on the Implementation of Human Subjects Protection Training and Education Programs" through a Federal Register notice: http://www.gpo.gov/fdsys/pkg/FR-2008-07-01/html/E8-14917.htm. Information and comments are invited about whether training requirements should be mandatory, and if so, what form they should take and who should be required to fulfill them. A 90-day period is provided, and OHRP looks forward to receiving comments.
The Acting Director informed the committee that OHRP and FDA will soon implement an IRB registration rule requiring all IRBs to register at a shared location between OHRP and FDA. OHRP is also working with FDA to develop a proposal to hold external IRBs responsible for whatever responsibilities they accept through an IRB authorization agreement. Public comments will be solicited. The Director expected to issue the request for information and comments before the next SACHRP meeting in October, 2008. Dr. Pritchard hoped that this change would reduce administrative burden and make more institutions willing to go ahead with this type of arrangement.
Remarks of Assistant Secretary of Health and Swearing in of New Members
Don Wright, M.D., M.P.H., Principal Deputy Assistant Secretary for Health
Dr. Wright expressed appreciation for SACHRP's contributions and stressed the high value placed on its work. He said he was "incredibly impressed" by the quality of individuals willing to share their time to serve on the committee. He hoped and expected SACHRP's work to continue smoothly during the transition to a new administration.
Dr. Wright then swore in the two new SACHRP members. He also thanked both Dr. Tilden and Mr. Nelson for their work and presented each a certificate of appreciation. He acknowledged Dr. Tilden's "distinguished leadership" as Chair of SACHRP.
Panel on Tissue Repositories
- P. Pearl O'Rourke, M.D., Director, Human Research Affairs, Partners HealthCare System, Boston, Massachusetts
- William E. Grizzle, M.D., Ph.D., Department of Pathology, University of Alabama at Birmingham
- Mark A. Rothstein, J.D., Herbert F. Boehl Chair of Law and Medicine and Director, Institute for Bioethics, Health Policy and Law, University of Louisville School of Medicine
- Ellen Wright Clayton, M.D., J.D., Center for Biomedical Ethics and Society, Vanderbilt University
- Barbara Koenig, Ph.D., Professor of Medicine, Mayo Clinic, and Faculty Associate at the Center for Bioethics, University of Minnesota; Co-Director of Mayo Clinic's Program in Professionalism and Bioethics
Dr. Tilden reviewed the panel's charge, which is to explore the following question:
- What are the issues of Informed Consent and HIPAA which most affect tissue repositories and use of biological specimens in research? What approaches are needed to protect patients/donors or racial/ethnic or cultural communities?
He also provided background relevant to this charge as follows:
Human specimens and associated data provide critical resources for basic scientific discoveries and for translating those discoveries into improved medical care. They have become invaluable in supporting emerging technologies that focus on causes of human diseases, in the discovery of predictors of development and course of disease, and in the development of new therapies. Sophisticated information technology has the potential to make an unprecedented amount of accompanying clinical data available for research using human specimens, which will accelerate the pace of discovery. Although these developments offer great promise, the power of these molecular and informatics technologies has heightened concerns about privacy and confidentiality and the need to protect the rights and welfare of persons from whom specimens and data are obtained.
Recent publication of the Report of the PRIM&R Human Tissue/Specimen Working Group and federal activities related to data/specimen data banking such as the NIH Genome Wide Association Study have brought attention to ethical and regulatory issues created by tissue/data banking activities. Particularly problematic are issues involving informed consent in banking activities such as: the appropriateness and validity of consent for unspecified uses, when may consent be waived, the appropriateness and role of community consent versus individual consent, sharing of research results/findings with subjects whose data and specimens were provided from banks, appropriate use of pediatric specimens/assent/consent, and relevant third party considerations. This panel will consist of a series of presentations including a representative of PRIM&R summarizing the recommendations of its report on banking activities, a director of a large tissue banking enterprise, and three other individuals with expertise in ethics, regulation, and legal aspects of conducting research in the area of tissue banking/repositories.
Remarks by Pearl O'Rourke: Tissue Banking — Challenging, to Say the Least
Dr. O'Rourke highlighted pertinent findings of the 2007 Report of the Public Responsibility in Medicine and Research (PRIM&R) Human Tissue/Specimen Banking Working Group: http://www.primr.org/uploadedFiles/PRIMR_Site_Home/Public_Policy/Recently_Files_Comments/Tissue%20Banking%20White%20Paper%203-7-07%20final%20combined.pdf. This White Paper explored the complexity of banking issues, identified barriers, and developed recommendations related to each of the barriers.
The speaker began by identifying a number of issues to consider in analyzing ethical and legal obligations that pertain to a given tissue bank. These include:
- What the bank "looks like" (e.g., single site vs. multiple branches);
- The identity of the owner or responsible party (e.g., academic medical center vs. government agency);
- What is being banked;
- How specimens are processed;
- The source of the specimens;
- How specimens were obtained and coded;
- Permissions required; and
- Provisions for access.
Barriers identified by the working group included:
- The diversity of banks and confusion about what types of banking activities constitute research activities or human subjects research under existing regulations;
- The lack of a single comprehensive ethical and regulatory framework that addresses the full spectrum of activities related to specimen banking and use;
- The lack of harmony among federal regulations;
- Misunderstanding and overinterpretation of the risks associated with the banking and use of specimens (especially genetic risk);
- Differing and confusing regulatory requirements for obtaining informed consent for the use of specimens in research, as well as for authorizing the research use of protected health information;
- Practical implementation issues related to informed consent and authorization; and
- The imposition of additional requirements for research through the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule in areas already covered by the Common Rule, adding unnecessary burden to patients, researchers, IRBs and institutions.
For specific recommendations to address these barriers and additional details, please see the White Paper (a link is given above) or the speaker's PowerPoint presentation.
Other "gnarly" issues pinpointed by the speaker included assessing community risk, handling specimens from children, when research results should be returned to subjects, and issues that arise when minor subjects become adults.
Remarks by William Grizzle: Practical Issues and Logistics — Tissue Resources and IRB/HIPAA
Dr. Grizzle, who directs a tissue collection and banking facility, explained that researchers who deal with tissues want to get the maximum use from them. That means collecting them rapidly, according to specific specifications, using standard operating procedures that will yield a uniform collection. Quality control is important, and the operation must also be cost effective.
The speaker stressed the wide range of materials included in tissue collections. For example, the collection could contain "remnant" specimens, which are collected with no contact with patients, or specimens collected directly from patients. The materials may need to be stored differently (e.g., paraffin blocks vs. frozen sections). Dr. Grizzle observed that a wide variety of specimens may be assembled from very few patients.
If tissue is anonymized, should informed consent required? Dr. Grizzle said IRBs do not agree on the answer and often give priority to "covering themselves" rather than thinking through the issues — including the implications of losing the opportunity for research. The speaker stressed that "we can definitely have too little research from too much regulation."
Key questions related to informed consent include for what actions it should be required; when it should be obtained; where it should be obtained; and finally, who should obtain it. Communication with tissue donors is often complicated. The speaker noted that tissue resource personnel have no direct relationship to the patient who was the source of the tissues. Consequently, they must make a "cold contact" when communication with the subject is required by HIPAA or the Common Rule, and the patient's physician sometimes objects to this contact. When the burden of consent falls to the tissue resource group, one or two nurses may be needed to conduct this activity alone, at a cost of hundreds of thousands of dollars annually. Anonymized specimens, which are less likely to require informed consent, are less useful in medical research because important data, such as the clinical outcome, are unavailable,.
Security issues are also important. Procedures must be in place to prevent unauthorized access to Protected Healthcare Information (PHI). The database structure must be secure, and an audit trail must be established. All access must be controlled and monitored, and the number of people who can write to the database or change its structure must be limited and monitored.
Remarks by Mark Rothstein: Tissue Repositories Logistics —The Common Rule and the HIPAA Privacy Rule
Dr. Rothstein observed that neither the Common Rule nor the HIPAA Privacy Rule was drafted while contemplating the development of vast biobanks, large-scale automated analytical tools, electronic health records and networks, and population-wide studies. The world of research has changed dramatically over the last decade; researchers now use powerful analytic tools such as genome-wide association studies, which are seeking to generate rather than prove hypotheses. Repositories commonly include hundreds of thousands of samples that may be linked to vast networks of electronic health records.
In the current research environment, sometimes it is the provisions of the Common Rule that are more burdensome for researchers; sometimes the provisions of the Privacy Rule are more burdensome. They are "just different." He noted that the National Committee on Vital and Health Statistics (NCVHS) has recommended harmonization of the Common Rule and the Privacy Rule (as has SACHRP). A trans-HHS working group was established in late 2006 to consider the issue.
The speaker highlighted key differences between the requirements of the two laws that are especially relevant to tissue repositories. For example, under the Common Rule, blanket consent for future use is disfavored but not prohibited. Tiered consent often is used to designate broad categories of approved research uses of specimens. Under HIPAA, however, study-specific authorization or waiver of authorization is required for disclosure of Patient Health Information (PHI), making the tiered approach unworkable.
There is a separate problem with authorization for prospective disclosure of health records.
At the time of initial authorization, an individual may not have sensitive information (such as the diagnosis of a mental health disorder or a sexually transmitted disease) in his or her record. It is not clear whether authorization given at this point refers only to the subject's present health records or can be construed as indefinite prospective authorization for health records in the future (which could conceivably contain sensitive information). One possible solution is to authorize specified uses through tiered authorization, but limit additions to the health record to a period of years (e.g., five years) and require new authorization after that.
The differences between the two laws in regard to identifiability were described as "arcane." The speaker contended that identifiability should be only one factor in determining whether there are more than de minimis risks to the subject/individual and not an "on-off" switch for whether or not a specimen should be subject to protection. For example, he noted the potential for harms to groups if a study should indicate that a particular racial or ethnic group is more likely to have a certain genetic predisposition. Conceivably, study findings might in some cases cause women to abort their pregnancies, which would be a result a pro-life tissue donor would find objectionable. Therefore, the speaker argued, use of deidentified tissue without permission risks a loss of trust in biomedical research and the health care system generally.
In regard to the 2007 PRIM&R report, the speaker remarked that it "does a nice of job raising many of the key issues," but he added that he does not support all of its recommendations.
He described the challenge of harmonization as developing thoughtful, nuanced, forward-looking, simple, clear, minimally burdensome regulations that will also do the following things:
- Reasonably safeguard the welfare and privacy of subjects/individuals;
- Empower subjects/individuals to make informed decisions;
- Contain a level of transparency and accountability; and
- Obtain and maintain individual and collective trust in the research and health care enterprises.
Remarks by Ellen Clayton: Returning Individual Information — A Complex Calculus
Dr. Clayton pointed to "fundamental tensions" that arise in regard to the complex issue of returning individual results of research studies to tissue donors. Findings could include overlooked clinical results, incidental findings, or research results. She noted that there are legal barriers to reporting some information to be addressed. Also, not all people actually want this information; when given the opportunity to decide whether personal findings will be reported to them, many decline the opportunity. She suggested that it is best to address the subject of what kind of information will be returned before research is undertaken.
At times, there may be preexisting information in the medical record such as a missed or overlooked clinical result. The speaker gave the example of a study in which the researcher is reviewing genetic variants that may have a bearing on the efficacy of ACE inhibitors to treat hypertension. A well-known side effect of ACE inhibitors (inhibitors of Angiotensin-Converting Enzyme) is angioedema or swelling that can compromise breathing. It is well known that if this happens, the ACE inhibitors should no longer be given. If the researcher finds that these side effects have occurred in a subset of individuals and the ACE inhibitors are still being prescribed, the speaker asked, what is the researcher's obligation, and how should it be fulfilled? In addition, there may be incidental findings, such as misattributed paternity. How should this information be handled?
Finally, the research result itself may be of great interest to research participants. Dr. Clayton argued that there should be a process for assessing the significance of the finding and communicating results. Considerations in releasing results regarding risks that individual tissue donors may face include the analytic and clinical validity of the finding, the level of health risk, the likelihood that the event will occur, and the potential efficacy of interventions. When communication with the subject is planned, there is a growing consensus that findings should be reviewed by someone other than the investigator. Careful consideration should also be given to identifying the appropriate person to communicate the results, an issue that is more complex if the investigator had no prior interaction with the research participant. Depending on the research, the primary care provider might not be equipped to interpret the results. Also, the provider may not have ethical standing to act as arbiter about what information goes forward to participants.
The speaker noted that some feel there is an ethical duty to report such findings, regardless, and that there are legal bases for this. She added that if the practice becomes reporting individual findings to research participants, "it will create a duty." Therefore, a level of caution is justified. A further consideration is that labs that do not report patient-specific results for the diagnosis, prevention, and treatment of any disease or impairment are exempt from the Clinical Laboratory Improvement Amendments of 1988 (CLIA). If guidelines for reporting back results are developed, research labs would then become subject to CLIA's requirements.
Remarks by Barbara Koenig: Community Consent and Problematic Regulatory Areas
Noting that genomics research elicits profound hopes, desires, and social anxieties, Dr. Koenig underlined the need to balance scientific gains with social concerns. She argued for engaging the community in decisionmaking, moving beyond traditional models of informed consent to examine governance models that can be applied to issues regarding collections of biospecimens.
Empirical Studies of Community Involvement
The speaker was particularly interested in applying models based on "deliberative democracy." For example, the Centers for Disease Control (CDC) used such a model to help plan for a pandemic involving avian flue. The International HapMap Project, which compares the genetic sequences of different individuals to identify chromosomal regions where genetic variants are shared, represents another variant in community engagement, though it has not defined a new model for community, as opposed to individual-by-individual, consent ( see http://www.hapmap.org). The speaker emphasized that the role of the community in developing governance and long-term oversight must be "developed, nurtured, and sustained."
Dr. Koenig pointed out that the concept of group harm and the principle of "respect for communities" have not been clearly documented. She argued that respect for communities should be considered an ethical principle similar to beneficence, respect for persons, or justice. This principle confers an obligation to respect the values and interests of the community and, wherever possible, protect the community from harms. This is particularly salient in regard to genomic research, which "elicits profound hopes, desires, and social anxieties."
The speaker cited two examples of empirical studies that have made efforts to involve communities in decisionmaking related to tissue repositories. "Making Every Voice Count" has done focus groups, interviews with community leaders, and town hall meetings to get advice about how the U.S. should proceed in the event of a large study that links biobanks to study the risk of environmental disease. The eMerge network is studying deliberative democracy and other forms of stakeholder deliberation.
Referring back to Dr. Clayton's presentation, the speaker observed that incidental findings will be an increasingly common issue, given the amount of material that will be stored. If DNA is collected on each patient, the understood boundary of what constitutes research may shift, and a fundamental transformation in the way we think about many issues may result.
SACHRP members asked panel members to comment on the following issues.
Future action by SACHRP. A SACHRP member asked for suggestions regarding actions the committee could take. Panel members suggested the following:
- Dr. Rothstein proposed a joint working group of the committee and NCVHS to develop a joint recommendation regarding harmonization.
- Dr. O'Rourke would encourage any action that would help with harmonization "or even a concordance of definitions."
- Dr. O'Rourke also suggested the committee address the following issues: whether DNA should be considered "identifiable," whether reconsent is needed as tissue donors who were children become adults, and procedures for getting consent for tissue banking (including the issue of clear explanations).
- Dr. Grizzle asked the committee to realize the potential impact of requirements on scientific research: "If the requirements are too high, we will just stop collecting tissues on children, because we don't have the resources to collect them."
- Dr. O'Rourke suggested that SACHRP consider issues related to dual use repositories, including the role of the IRB when tissues are stored for both research and clinical purposes.
- Dr. Clayton pointed to the strong pressure to return research results and urged SACHRP to address the issue.
Dr. Genel asked for additional information about the interagency committee on harmonization mentioned by Dr. Rothstein. Ms. Bledsoe explained that the HHS trans-agency task force is trying to address some of the legal and ethical issues related to human specimens and research. It is currently reviewing the recommendations in the PRIM&R white paper and considering areas in which regulatory change or guidance might be needed. Each agency is represented on the task force, and each representative reports back to its own agency. Dr. Genel commented that he did not think such a structure was "likely to prompt quick action."
Representing the Food and Drug Administration (FDA), Dr. Less asked the panel for response to a guidance document FDA issued on the use of leftover specimens. Noting that FDA has been asked to revisit this issue, she asked for any comments FDA might consider. After thanking FDA for the guidance, which he said was helpful, Dr. Grizzle cautioned that if FDA were to set very high standards for what tissues are used in device studies, there may soon be no tissues available to support these studies.
Dr. Koenig asked whether SACHRP has addressed the issue of whether certain kinds of expenses related to community involvement and communication with subjects could go in direct cost budgets rather than indirect cost budgets. Dr. Marshall added that community engagement and feedback are expensive. Dr. Tilden responded that such a discussion would probably need to involve the funding agency rather than SACHRP or OHRP.
Legal approaches to issues. Noting the wide range of public and private companies, institutions, and agencies that are involved in the issues discussed, Mr. Forster wondered how an overarching legal approach to the issues highlighted by the panel could be devised.
- Dr. Clayton suggested the Federal government would have to establish a rule for the entire country (if possible. without creating further inconsistencies among existing laws). A good deal of work would be needed before such an action could be taken, however.
- Dr. Koenig stressed that institutions have the responsibility to develop policies and procedures regarding tissue return.
- Dr. Rothstein noted that the President signed the Genetic Information Nondiscrimination Act (GINA) this year, but he doubted the law would be effective. Because it applies only to health insurance and employment discrimination on the basis of genetic information, he thought it would probably not achieve its stated goal of assuring people they can engage in genetic research without fear of the consequences.
Returning research results. Panel members continued to explore issues related to returning research results or recontacting subjects for other reasons. Dr. Grizzle cautioned about returning research results to patients before they are validated by additional studies. He added that researchers do not receive funding for recontacting patients. However, Dr. Rothstein saw the central issue as not whether individuals should be recontacted, but whether the researcher should offer to recontact them. He believed there are circumstances in which it is appropriate to return results. However, he acknowledged many subjects do not want to be recontacted. He suggested offering "tiered" recontact options spelling out the conditions under which they would want to be recontacted. Additional points included:
- Differing with Dr. Rothstein, Dr. O'Rourke felt the difficulty of devising a clear consent form to convey tiered options for recontact would preclude this option.
- Dr. Koenig noted that subjects are not offered the option of having a group of people like them make decisions about recontact policies. She agreed that "we are just not smart enough" to develop clear tiered forms that will work well for all contingencies. She pointed out that 10 States now require written informed consent before genetic testing can be done, laws that will be increasingly problematic as testing in clinical settings becomes common.
- Dr. Clayton agreed that it is frequently impossible to predict all the possible uses of tissue well enough to make preliminary agreements about returning information workable. She felt it was problematic to contact a subject once results were known and ask whether the subject also wants to know the results. However, she saw returning incidental findings as a different issue.
- Dr. Pritchard asked panelists to comment on reports that subjects facing tiered consent options tended to choose all or none of them. Dr. Grizzle reported this was usually true in his experience. Dr. Rothstein emphasized that whether or not this were the case, subjects appreciate being empowered to make the choice.
- Dr. Marshall's research indicates that people do care about what they check off; however, she is troubled by the complexity of tiered consent systems. She questioned whether we know, without research, what the choices people make mean to them. Dr. Strauss agreed, stressing the need to determine how well subjects comprehend the distinctions in the choices presented.
Dr. Strauss observed that while there were often risks to returning individual information, in some cases results are meaningful and should be shared. He stressed the importance of debriefing subjects adequately so that they understand the limitations of the information provided.
Dr. Powe asked panelists to respond to a hypothetical situation in which a subject donates specimens and a series of researchers use them. The third researcher demonstrates an intervention that would halt the progression of the subject's disease. Should this result be returned, even if previous results were not? Dr. Grizzle stressed that there must be many researchers looking at the same thing with the same findings before results have a high enough probability of being right to make them worth returning.
Dr. Goldkind described a scenario in which an informed consent document clearly states that research results would not be returned to subjects, but the investigators find information they believe a reasonable person would want to know. Dr. Grizzle felt returning such a finding would be inappropriate for the same reasons. However, he has considered putting all tissue resources studies on a computer in the patients' library for their use. This would present research conclusions in a larger and more appropriate scientific context.
According to Dr. O'Rourke, subjects sometimes request return not only of research results, but of the tissue itself. Dr. Koenig added that families sometimes request tissue return for further analysis after the subject's death.
Consent. Dr. Botkin commented that his institution is encountering the dilemma that tissue bank sponsors want "blanket approval for doing whatever they choose to do" with the samples in the future. He believes that few institutions are deterred by the HIPAA standard. Dr. Grizzle agreed, noting that it is impossible for a tissue resource to specify the type of research in which tissues will be used, which is a HIPAA requirement. However, his tissue bank does require anyone who requests the use of tissues to explain how they will be used.
Dr. Strauss commented that explaining consent issues to subjects can be time consuming, especially for older subjects who grew up in an era when DNA, genetics, and biobanking were not part of their world view. He suggested that consenting subjects one by one was "unrealistic and impractical"; .instead, he proposed moving toward a model in which the researcher assumes a stewardship role of specimens with the understanding that something should be given back to the subjects who donated them.
Oversight. Dr. Bierer asked panelists to elaborate on the role of the IRB in determining when, how, and to whom research results should be conveyed. She suggested that the investigators might return to the IRB when incidental findings become an issue, and the IRB could call upon an expert panel for biomedical advice if needed. She also observed that patients' physicians are often unable to interpret and present the implications of research and wondered how health care providers could be better prepared for this role. Panel members responded as follows:
- Dr. Clayton felt institutions would handle incidental findings in different ways but found Dr. Bierer's suggestion reasonable. She said if results are returned, the IRB and investigator have the responsibility for conveying their meaning clearly.
- Dr. Koenig felt that the national IRB system is overburdened and unable to play a constructive role in the issue. She recommended using a group closer to the management of the repositories, which could conceivably have a consultative relationship with the IRB.
- Dr. O'Rourke suggested that recontact is in effect an amendment of the approved protocol, so the IRB does have some authority and responsibility.
Dr. Marshall asked panelists to comment on the amount of governance and oversight needed, the stakeholders who should be involved, and the implications of the oversight process for permission and consent. Observing that Vanderbilt has established oversight for its comprehensive tissue bank, Ms. Bankert asked whether this is common. Dr. Grizzle responded that each use of his tissue bank is reviewed by an IRB. There were no other comments.
Benefit sharing. Dr. Rothstein has recommended that biobanks that intend to commercialize their holdings set aside a proportion of revenues or profits to benefit the donors. For example, if research is done on asthma, some of the proceeds might benefit indigent patients with asthma. He cited the Canavan Disease case, in which the researcher received specimens and financial support from patient groups, then patented the resulting genetic test. He believed that subjects are more willing to participate in research that benefits humanity and less willing to participate in studies that benefit shareholders in commercial enterprises. He further held that the use of any profits should be clarified as part of the consent process.
Dr. Powe asked whether there was any evidence that subjects cared about this issue and might be deterred from donating specimens that could be used and sold for commercial profit. Dr. Koenig responded that while there is no definitive answer, researchers in the eMERGE consortium do find that subjects care about how the tissues they donate will be used and that community engagement seems to make a difference to them as well.
OHRP guidance on unidentified tissue samples. Dr. Botkin pointed out that OHRP issued guidance on tissue banking in 2004 to the effect that if an investigator receives tissues with no associated identifiers and agrees not to try to identify the tissue source, this does not constitute human subjects research. He asked panel members to comment on the standard. Dr. O'Rourke found this approach problematic because the guidance does not address the key issue of how the tissue was obtained. (Did the subject give informed consent for a more limited use?) Regardless of whether or not the use of the tissue constitutes human subjects research, she said, ethical review is needed.
Dr. Clayton said that Vanderbilt is using deidentified samples from over a million patients for research purposes. The IRB, ethics community, a community advisory board, and external advisers provide oversight for requests to use the information collected. She added that this approach means there is no question of returning research results, since it would clearly be impossible. In response to further questions, she explained that patients can opt out of being in the DNA databank by checking a box on the form with which they consent to treatment. Dr. Koenig questioned, however, whether patients always understand the distinction between research and treatment.
Data bases. Dr. Botkin observed that the increasing development of data repositories is raising a lot of the same issues as tissue repositories; many universities are linking tissue resources to public data bases. He suggested that both situations point to a need to protect subjects' interests without necessarily involving them directly in the research activity.
Report of Subcommittee on the Inclusion of Individuals with Impaired Decision-Making in Research (SIIIDR)
David Strauss, M.D., and Laurie Flynn, SIIIDR Co-Chairs
Dr. Strauss reviewed the subcommittee's charge and progress to date. He also cited pertinent regulations and regulatory guidance (see PowerPoints). The Co-Chair reviewed previously approved recommendations (see minutes of March 27-28, 2008). He highlighted three key concerns that frame SIIIDR activities:
- How do we define (and how do IRBs and investigators identify) the populations requiring additional protection?
- How do we define "reasonable risk" when ability to consider consent is limited or absent?
- How do we decide who may provide consent for those who are unable to consent for themselves?
Co-Chairs then presented two recommendations for discussion. Dr. Strauss stressed the interdependence of all the recommendations SIIIDR is presenting, the balance between permissiveness and restrictiveness that the subcommittee is striving to achieve, and the importance of timing. For example, by the time the new regulation subpart envisioned in Recommendation 7 below is in place, he would hope that guidance is already available to IRBs on how to approve research with subjects who have impaired consent capacity. Dr. Strauss felt that a new subpart would be an "effective and relatively efficient" way to address a dire need for guidance in the area.
The Subcommittee on the Inclusion of Individuals with Impaired Decision-making in Research (SIIIDR) recommends that HHS develop a Subpart to 45 CFR 46 to include new regulations related to the inclusion of adults who lack consent capacity.
While this subpart will describe additional safeguards for IRB review and approval of research with adults who lack consent capacity, its primary intent is to define a hierarchy of individuals who may provide consent on behalf of individuals who lack consent capacity when a legally authorized representative (LAR) for research is not defined in state or local law.
SIIIDR makes the following recommendation for inclusion in this subpart:
- When an IRB approves the conduct of research under Subpart A and determines that it is appropriate for consent to research to be obtained from the legally authorized representatives of adult subjects who lack decisional capacity to consent on their own behalves:
- Such determination must be made at a convened meeting of the IRB and not by means of expedited review, unless the research qualifies for waiver of consent. Footnote: An initial determination must be made by the convened IRB. Subsequent review and approval of this research with regard to the inclusion of individuals lacking consent capacity would follow guidance on continuing review.
- Where applicable law exists to determine who is authorized to serve as an LAR to consent to a subject's participation in research, consent may only be obtained from an LAR in accordance with this law.
- In the absence of applicable law determining who is authorized to serve as an LAR to consent to a subject's participation in research, one of the persons listed below, in the following descending order of priority, shall be considered the subject's LAR and may consent to participation on behalf of the subject:
- a person designated by the subject, while retaining the decisional capacity to do so, to make decisions for him/her regarding participation in research;
- a person designated by the subject, while retaining the decisional capacity to do so, to make decisions for him/her regarding non-research health care decisions;
- the subject's legal guardian with authority to make health care decisions for the subject;
- the spouse, or if recognized by applicable law, the civil union partner or domestic partner of the subject;
- an adult son or daughter of the subject;
- a parent of the subject;
- an adult brother or sister of the subject;
- an adult who has exhibited special care and concern for the subject.
- The LAR shall make a decision regarding consent on behalf of the subject in accord with applicable law. In the absence of applicable law, the decision shall be based on his/her judgment as to the decision that the subject, if he/she retained decisional capacity, would have made. If the LAR is unable to determine the decision that the subject would have made, he/she shall make the decision that appears to be in the subject's best medical, psychological, and other interests. Footnote: It is not the intent here to exclude without further consideration studies which are not anticipated to offer direct benefit (and therefore are not in the "subject's interests") but which do not qualify for waiver of consent. Reference here to "medical, psychological, and other" is meant to capture interests beyond those specifically related to healthcare.
Recommendation for new subpart (introductory language). Co-Chairs explained that guidance alone could not address the need because the legal basis for guidance does not exist in the regulation. Dr. Strauss added that there is some question of how the authority of guidance would compare to the authority of a State law on issues of consent. The subcommittee felt a regulation would have greater weight. Ms. Flynn stressed that the recommendation would address a gap in regulations that is potentially compromising protections for a very vulnerable population. The subcommittee also understood that a new subpart would be easier to accomplish than a change to the Common Rule.
Determination by Convened IRB (a above). Dr. Botkin was concerned that the provision might encourage researchers to exclude certain individuals and that the new regulation might "backfire." Dr. Powe agreed, suggesting that applications will almost inevitably be submitted that exclude this population. Another member was concerned that the new rule might result in making the study sample less representative of the population. Dr. Strauss said the subcommittee shared the concern and will continue to strive for balance as it seeks to address the issue of the LAR.
Dr. Bierer asked for a clarification of why a convened meeting was necessary for the incidentally enrolled members of this vulnerable population selected for a minimal risk study. Dr. Strauss observed that "one person's minimal risk is another person's pretty risky research protocol." He felt the presence of nonscientist community members and others familiar with the population would be helpful. Dr. Strauss further clarified that studies involving this audience that would qualify for a waiver of consent would not require review at the convened meeting. Ms. Flynn added that the subcommittee's thinking was influenced by the "very limited expertise" IRBs often have regarding this population.
Ms. Bankert suggested that if the driving concern is the need for expertise, the subcommittee might do well to concentrate on that and explore different solutions, including access to expertise at the level of expedited review. Dr. Strauss appreciated the suggestion, but added that experts can be a form of "tokenism," and not all experts are truly qualified to address the matter at hand. Dr. Botkin was concerned that a given expert acting as a gateway to a body of research might have connections that constitute a conflict of interest. Dr. Genel suggested that regional IRBs with specialized expertise might contribute to a solution.
Dr. Botkin suggested that "such determination" may not be sufficiently clear language; it could refer to more than one determination noted in the previous paragraph.
Ms. Bankert was concerned that the recommendation would contradict some of the previous recommendations related to Subpart A. Dr. Strauss did not see a contradiction; he pointed out the situation that would trigger the review is the decision to allow consent by a surrogate, not simply the involvement of a vulnerable population.
When applicable law exists (b above). Dr. Strauss explained that recommendation 7 is intended to replace existing OHRP guidance with more specific guidance. He added that because of the "patchwork nature" of State laws, some applicable laws may not provide an adequate floor of protection. The subcommittee will continue to explore ways to address this problem.
When applicable law does not exist (c above). Dr. Strauss observed that there could be "considerable discussion" about what constitutes applicable law. He explained that the hierarchy is intended to honor the idea of autonomy to the extent possible.
Ms. Bankert asked what mechanism the subcommittee would recommend for designating someone to make decisions. Ms. Flynn said there are advanced directives for research. Dr. Strauss doubted that identifying a mechanism was within the purview of HHS.
Dr. Bierer asked how much precedent exists for this detailed hierarchy. He noted that those lower down on the hierarchy are "pretty much down in the weeds of family dynamics." Dr. Marshall shared the concern and wanted to be sure there was room for flexibility, given the complexity of family relationships. She wondered how binding the language was intended to be and whether IRBs were likely to follow it too rigidly. Dr. Strauss said there are many similar hierarchies. Dr. Tilden pointed specifically to the hierarchy contained in the Uniform Healthcare Decisions Act, adding that he knows of at least eleven states that have identified such hierarchies specifically for use in research. Dr. Strauss said the intent was to avoid disputes, but he agreed that a "notion of flexibility" was needed.
Dr. Powe asked how a person would cede authority to someone lower on the list. When others responded that this could be done, he suggested adding guidance to the effect that the researcher should document the fact that someone ceded authority.
Dr. Tilden suggested shortening the list in order to get closer to surrogates able to make good decisions.
Basis for surrogate's decision (d above). Dr. Botkin asked about the role of altruism. Specifically, "do you want the surrogate to promote the subject's best interest or just ensure the study is not contrary to the subject's best interest?" He noted, "we don't want surrogates to be altruistic by enrolling someone else." Dr. Botkin suggested saying explicitly that participation must not be contrary to the subject's interest. Mr. Forster, however, felt that when substitute judgment is not possible because the subject's wishes are unknown, the term "best interests" is appropriate.
Dr. Bierer suggested that the word "and" in the last sentence should be an "or" so that medical, psychological, and other are considered independently. Mr. Shore commented, however, that if the decision is to be based on the surrogate's judgment regarding the decision the subject would have made if he or she retained decisional capacity, this is a broader range of references. With this in mind, he did not feel the last sentence added anything new. Dr. Genel agreed. Dr. Strauss argued, however, that persons at the lower end of the hierarchy might appreciate the guidance.
Dr. Botkin observed that the literature shows that surrogates are often not skilled at anticipating at what others would want. He stressed the importance of not implying infallible knowledge on the part of the LAR.
A legally authorized representative is defined at 45 CFR 46.102 (c) as "an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in research."
HHS should support the development of guidance to clarify the current HHS interpretation of "applicable law." This guidance should include the basis for the Department's interpretation of what constitutes applicable law. Specifically:
- As the laws defining who may provide consent to research for a subject who lacks consent capacity take many forms and vary widely among the states, guidance should describe the sources upon which an institution or IRB may rely to determine who may serve as a legally authorized representative.
- Guidance should describe examples of sources of "applicable law" in states with laws or regulations that address consent to treatment but do not specifically consider consent to research. This guidance will serve to clarify the current HHS interpretation that permits institutions and IRBs to allow research consent by individuals authorized under laws that allow consent to the "procedures involved in the research."
- Guidance should clarify that individuals defined by community or other standards (e.g. institutional policies, standards of care) in the absence of specific judicial, statutory or regulatory authority do not constitute legally authorized representatives.
Dr. Strauss explained that the subcommittee was hoping, through this recommendation, to consolidate guidance in this area. He said there was also apparent confusion regarding what constitutes an LAR. States are sometimes "making up their own rules," which may be overly lenient or overly restrictive. Smaller IRBs and institutions may have a particularly hard time understanding what laws "count." Ms. Flynn said the intent was also to distinguish between the ability to provide surrogate consent for treatment and the ability to consent for research.
Dr. Botkin asked for clarification of how OHRP interprets the phrase "procedures involved in the research." He wondered whether, if his spouse were a designated surrogate for clinical decisions, she could also consent to research on his behalf. Ms. Gorey said if this were consistent with State law, she would have that authority. Laws that give authority to consent on behalf of another person to specific medical procedures would also be construed as applying to those same procedures in a medical context. However, OHRP has not parsed the phrase in question more specifically.
Dr. Botkin clarified that his question pertained to a procedure that is not part of normal clinical practice. Dr. Carome responded that if the procedure is used clinically in the State and State law allows the spouse to consent to clinical procedures, OHRP would accept this interpretation of the LAR's role as reasonable. Dr. Pritchard added that innovative care may also be considered appropriate medical treatment in some circumstances. Dr. Genel observed that the same procedure might be construed as "innovative treatment" for one patient but research if done with several patients.
Dr. Strauss said the situation is indeed complex, but the subcommittee was mindful of the damage that might be done to existing and ongoing research by offering a strict interpretation of this rule at present. Members felt it was more appropriate to encourage the development of appropriate State rules.
Dr. Bierer was concerned that exposing the weakness of the current foundational definition of LAR might push OHRP further into having to address questions that arise in the absence of regulations.
Dr. Bierer also wondered why "judicial or other bodies" are mentioned in Recommendation 4 but not Recommendation 7, which is concerned only with individuals.
Public Comment Period
No comments were made during the first public comment period.
The Chair returned to the issues raised in the discussion on tissue banking and invited members to explore next steps. Various members highlighted the importance of taking any further actions that could "push the process" and encourage harmonization of HIPAA and the Common Rule. These could include:
- Encouraging the interagency committee working on harmonization;
- Recommending harmony between HIPAA and the Common Rule specifically in regard to "blanket authorization"; or
- Developing and signing a joint statement with NCVHS to highlight the importance of the issue.
Dr. Genel said he was now convinced that SACHRP's recommendations to this effect in 2004 were outdated.
Other possible next steps included:
- Recommending guidance on when an IRB should consider sharing results of data from a depository and when it should not;
- Receiving presentations on the results of focus groups and other key research alluded to by speakers;
- Recommending guidance to the effect that research participants should be told whether or not they are going to get results back;
- Asking the Institute of Medicine (IOM) to examine issues and develop best practice standards for the development and conduct of this type of research;
- Stimulating empirical research on community consensus regarding issues like these;
- Reviewing specific recommendations from the PRIM&R white paper with a view to possible endorsement; and
- Exploring best practices, including the Vanderbilt model highlighted by one speaker and related policies and guidelines.
Dr. Pritchard commented that ex officios had hoped that SACHRP would address issues around consent under various scenarios pertaining to research and specimens. However, as Dr. Bierer observed, "the panel didn't lead us there."
Ms. Bledsoe reported on several efforts to develop pertinent best practices. These include the development of best practices addressing technical, legal, and ethical standards by the International Society for Biological and Environmental Repositories (see ISBER Best Practices for Repositories. The National Cancer Institute has also developed best practices for specimen resources (see http://biospecimens.cancer.gov), and NIH is in the early stages of exploring the development of a trans-NIH policy related to repositories.
WEDNESDAY, JULY 16
Samuel J. Tilden, M.D., SACHRP Chair
Dr. Tilden thanked the SACHRP committee for helping him "get through this year" as Chair; he also thanked the ex officios and OHRP personnel, present and past. He especially thanked Dr. Pritchard for an outstanding job of guiding everyone through the transition period.
Report of Subpart A Subcommittee (SAS)
Elizabeth A. Bankert, M.A., and Daniel Nelson, M.S., CIP, SAS Co-Chairs
Mr. Nelson reviewed the outline for the presentation, which included a "fairly diverse" set of recommendations on informed consent, institutional responsibilities, and tribal approval of research. He noted that while he has retired from the SACHRP parent committee, he will continue to serve as Co-Chair of the Subpart A subcommittee.
He informed SACHRP that the committee's eighth letter to the Secretary is being prepared; it will include 30 recommendations from SAS and some from SIIIDR.
Waiving Documentation of Informed Consent
Ms. Bankert reviewed background on waiving documentation of informed consent as described in the Common Rule at §46.117(c). This section is as follows:
c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either:
- That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or
- That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.
In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research.
Ms. Bankert explained that in its Frequently Answered Questions (FAQ) 31, OHRP provides guidance that basically "repeats the regulation." The FAQ gives two examples: drawing a blood sample and asking shopping mall customers about ambient lighting. OHRP has also e-mailed responses to queries on the topic. The subcommittee has observed that IRBs may not use the waiver provision appropriately or may underutilize it because of uncertainty about how to apply it. This leads to undesirable variability across IRBs, which is especially evident when research is conducted at multiple sites.
The Co-Chair explained that Recommendation 1 (see below) was proposed because IRBs appear to be unwilling to show flexibility in social science or behavioral research. For example, the IRB may require a signed consent form for anthropologists working in the field when it is not appropriate. Recommendation 2 is intended to clarify the meaning of the "documentation" that may be waived. Recommendations 3 and 4 request clarification of the wording of the regulation.
Recommendation 1.OHRP should provide guidance on the interpretation and application of 46.117(c), using examples as appropriate, with particular emphasis on social or behavioral research.
Recommendation 2. With regard to §46.117(c)(1), OHRP guidance should clarify that
- there would be no links between the subject and the research (e.g., investigator notes) other than the consent form itself;
- this provision is not limited to minimal risk research, and is appropriate for those studies that involve greater than minimal risk (e.g., domestic violence, illegal behavior); and
- the "documentation" referred to in this section means a signed consent form that would create a link between the subject and the research that would otherwise not exist.
Recommendation 3.OHRP should clarify that the final sentence in §46.117, regarding the provision of a written statement to subjects, applies to both (c)(1) and (c)(2).
- OHRP should clarify that, when the IRB requires a written statement as described under §46.117(c), the statement does not need to include the elements of consent required under §46.116.
- OHRP should also clarify that a waiver of consent under §46.116(d) is not required, unless some elements of consent are not presented either orally or in writing.
Investigator awareness. Dr. Botkin suggestedthat the underuse of the waiver may be attributable, at least in part, to investigators' lack of awareness of the provision. He suggested a recommendation that would aim at increasing awareness so that more investigators propose it when relevant. Others agreed that this was a contributing factor. Dr. Botkin suggested prompting investigators to consider a waiver as part of the application process, noting that this would be especially easy to do with electronic submissions.
Dr. Genel saw it as the responsibility of the IRB to recommend that the waiver be applied. Dr. Strauss added that the IRB also should be prepared to engage in dialogue with the investigator about whether she or he really does not want to collect links that would make follow-up or the use of a longitudinal study approach possible. Ms. Bankert thought examples could address these concerns.
Procedures. Dr. Strauss observed that the term "procedures," as used in §46.117(c)(2), is unclear. He noted that it is not common practice to get written consent before giving a patient a chest X-ray; he asked whether documentation of consent should be waived for this procedure. Ms. Bankert felt it should not. Dr. Bierer was less concerned, noting that the language says the IRB "may waive" written consent, not that it must, leaving discretion. Dr. Pritchard reminded SACHRP that the rules under discussion are intended to apply primarily to field settings, such as ethnographic studies, or telephone conversations. Mr. Nelson suggested that examples could clarify the intent.
Linking documentation requested by the subject. Mr. Forster called attention to the second sentence in §46.117(c)(1): Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern. He observed that investigators in the field see this request as introducing distrust in some situations. Several other members agreed that the provision is generally quietly ignored. IRBs also do not typically ask about this at the continuing review stage, and in any case it is not possible to verify that the provision is being followed. Dr. Strauss said he did not see the provision as adding protection.
Dr. Bierer wondered whether guidance could suggest that this provision is not appropriate in some circumstances (despite the word "will," which is synonymous with "must"). Mr. Forster suggested, alternatively, that OHRP indicate it will not enforce the requirement, which FDA has done in regard to the in vitro device exemption. However, Dr. Pritchard explained that unlike FDA, OHRP has a regulatory responsibility to secure a Secretarial waiver in such a case. OHRP does, however, have discretion to decide on a case-by-case basis whether or not it makes sense to pursue a particular violation. A new recommendation was developed to encourage OHRP to explore its options (see Recommendation 5 below).
Dr. Botkin questioned whether the documentation referred to is necessarily the consent form. Mr. Nelson said that SAS had been unable to identify any other logical possibility. Dr. Bierer suggested, however, that it could refer to a fact sheet. A member thought a subject might want a signed form that provides some liability protection but simply contains contact information and enough data to identify the study. Dr. Strauss suggested that some subjects might want a document to show an employer to explain their absence from work. Dr. Tilden said that while it might be unusual for a subject to want such a link, in the spirit of yesterday's panel on tissue donation, subjects may want to be offered a choice. If the word "document" does refer to the consent form, a member was concerned that the interpretation suggests an informed consent form must always be developed just in case someone wants to sign it, which would represent a significant regulatory burden. In response to the uncertainty about the meaning of "documentation," the last bullet of the recommendation was altered to ask OHRP to clarify the meaning without assuming a particular interpretation.
Elements of informed consent. Mr. Forster suggested a revision that would tie together the two bullets of Recommendation 4 together and avoid the implication that the written statement must have all the elements of consent. A common example cited by another member would be getting consent in a telephone conversation. The introduction to the telephone survey is sometimes construed as a consent process. Sometimes researchers complain that IRBs require them to send a consent form by mail before they can talk to the subject.
Dr. Strauss clarified that the regulatory language is intended to mean the IRB could elect to waive the presentation of any written document. He questioned whether subjects are not still meant to have the right to a written document if they want one.
"May require." Dr. Strauss suggested, in regard to the last sentence of §46.117(c), that guidance would be helpful in clarifying circumstances in which an IRB should require a written statement. He also stressed the importance of examples in clarifying intent.
Recommendations were approved by SACHRP as follows. (Changes are shown in bold). All approvals were unanimous except for Recommendation 5, on which there was one abstention (reported following the meeting).
Recommendation 1.OHRP should provide guidance on the interpretation and application of 46.117(c), using examples as appropriate, with particular emphasis on social or behavioral research. Additional resources should be provided to OHRP to educate IRBs on these provisions.
Recommendation 2.With regard to §46.117(c)(1), OHRP guidance should clarify that
- there would be no links between the subject and the research (e.g., investigator notes) other than the consent form itself;
- this provision is not limited to minimal risk research, and is appropriate for those studies that involve greater than minimal risk (e.g., some studiesof domestic violence, illegal behavior); and
- what the term "documentation" used this section means.
Recommendation 3.OHRP should clarify that the final sentence in 46.117, regarding the provision of a written statement to subjects, applies to both (c)(1) and (c)(2).
Recommendation 4.OHRP should clarify that, when the IRB requires a written statement as described under §46.117(c), the statement does not need to include the elements of consent required under §46.116 as long as the elements are addressed orally.
This guidance should include examples of situations where the IRB may choose to require a written a statement.
OHRP should also clarify that, if some of the elements of consent are not presented either orally or in writing, the criteria for waiving consent under §46.166(c) or (d) must be met.
Recommendation 5 (proposed following discussion).OHRP should explore options for modifying or accommodating the requirement under 45 CFR 46.117(c) (1) that each subject will be asked whether they want documentation linking them to the research, including the possibility of a Secretarial waiver of this requirement.
Additional Issue for Subpart A Consideration
Dr. Bierer asked Subpart A to consider addressing instances in which it is appropriate to delay informed consent rather than ask for it "prior to participation." An example would be drawing an extra tube of blood from a patient admitted to the emergency room when neither the patient or an appropriate person is able to consent, with the intent of getting full consent for the use of the blood for research purposes at a later time.
Institutional Responsibilities and the Role of Institutional Officials
Mr. Nelson explained that despite the centrality of the institutional official's role, understanding of the nature and extent of specific responsibilities varies. The intent of the recommendations is to clarify what is expected from the institutional official (IO) for organizations, the officials themselves, and the research community. The Co-Chair reviewed a short document that is intended to serve as informal draft guidance to assist OHRP in responding to the recommendations (see attachment). Mr. Nelson thanked Dr. Cates of the Veterans Administration (VA) for sharing an extremely draft useful document on IOs the VA is developing.
The following recommendations were presented:
Recommendation 1.Given the key role in human research protections played by Institutional Officials (IOs), OHRP should continue and strengthen its efforts to reach this group through training, outreach, and guidance. Among other approaches, this includes outreach through professional organizations more likely to encompass IOs who may not participate in "IRB-related" venues, conferences and organizations (e.g., NCURA, COGR, AAU, AAMC, COSSA, et al).
Recommendation 2. OHRP should develop standard nomenclature and definitions for terms that are currently used interchangeably or variably, such as
- "Organizational Official"
- "Institutional Official"
- "Signatory Official"
- "Head Official"
Recommendation 3.OHRP should continue to define the IO as the individual who is legally authorized to act for the institution and, on behalf of the institution, obligates the institution to the Terms of the Assurance. This should includethe authority and responsibility to provide adequate resources to maintain an effective Human Research Protection Program (HRPP). It is recognized that, within some organizational structures, theseresponsibilities may reasonably be delegated to someone other than the chief executive officer, president or counterpart, in order to ensure an active role for the IO in the HRPP.
Recommendation 4.OHRP should develop expanded guidance on the expectations and responsibilities of IOs, including their ethical and regulatory obligations, and highlighting issues of both authority and autonomy. The guidance should recognize that some operational functions may be appropriately delegated by the IO; to the extent that selected obligations should not be delegated, these should be identified. This guidance might take the form of a simple bulleted list (draft example provided).
Recommendation 5.OHRP should provide periodic (e.g., annual) reminders to IOs that reinforce their central role and responsibilities in human research protections, including the guidance recommended above. These reminders might be accomplished easily using e-mail contacts on file with OHRP through the Assurance process.
Recommendation 1. Dr. Leiden agreed that external communications with IOs could be extremely helpful, but he also stressed the importance of ongoing internal communication with IRB leaders.
Dr. Tilden stressed the importance of HHS providing sufficient resources to allow OHRP to strengthen its efforts to reach this group as recommended. Dr. Powe added that it was also important for institutions themselves to provide adequate resources, especially for training and education. Dr. Botkin suggested that a future SACHRP meeting include a presentation by OHRP on its structure and resources.
Recommendation 2. Dr. Bierer suggested removing the words "interchangeably" and "variably" since SACHRP is not sure how the terms should be used and is requesting clarification.
Recommendation 3. In reference to Recommendation 3, members agreed that there is a difficult tradeoff between designating an IO who is highly placed but less knowledgeable and one who is knowledgeable but lacks authority. The individual who signs the assurance must be placed high enough to bind the institution to the agreement. The aim of delegated authority should be to ensure that someone who is knowledgeable is able to act on the IO's behalf, ensuring that the goals of the human research protection program (HRPP) can be met.
Members debated whether the IO would always have the authority to ensure the HRPP has adequate resources. At some institutions, the IO is in direct control of a budget, while at others, the IO would have to advocate for adequate resources to be allocated by a higher official.
Recommendation 4. Mr. Nelson explained that many elements of the draft guidance came either from the terms of assurance or from the training module on assurances.
In regard to the draft guidance, some members suggested that an additional role of the IO is to bring forward reports on the HRPP to the highest organizational level. Dr. Botkin suggested emphasizing that the responsibility for maintaining compliance with State and Federal regulations cannot be delegated.
Recommendation 5. There was no discussion.
Recommendations 1-3 were approved with the following changes. Recommendations 4-5 were approved without changes.
Recommendation 1.Given the key role in human research protections played by Institutional Officials (IOs), OHRP should continue and strengthen its efforts to reach this group through training, outreach, and guidance.HHS should provide additional resources to OHRP to achieve this goal.Among other approaches, this includes outreach through professional organizations more likely to encompass IOs who may not participate in "IRB-related" venues, conferences and organizations (e.g., NCURA, COGR, AAU, AAMC, COSSA, et al).
Recommendation 2. OHRP should develop standard nomenclature and definitions for terms that are currently used, such as
- "Organizational Official"
- "Institutional Official"
- "Signatory Official"
- "Head Official"
Recommendation 3.OHRP should continue to define the IO as the individual who is legally authorized to act for the institution and, on behalf of the institution, obligates the institution to the Terms of the Assurance.This individual should havethe authority and responsibility to provide adequate resources to maintain an effective Human Research Protection Program (HRPP). It is recognized that, within some organizational structures,theseresponsibilities may reasonably beexecuted by someoneother than the chief executive officer, president or counterpart, in order to ensure an active,knowledgeable role for the IO in the HRPP.
In addition, SACHRP members unanimously approved Dr. Botkin's suggestion that a future SACHRP meeting include a presentation by OHRP about the structure of the office and the resources needed to run it.
Mr. Nelson reminded members that the following recommendation was presented to SACHRP at the March 2008 meeting at the request of Dr. Francine Romero, former SACHRP member. At that time, it was referred to the Subpart A Subcommittee for further consideration.
There is concern that Tribal governments are not aware of the fact that any research done within a Tribal jurisdiction is subject to Tribal authority. Some larger tribes have implemented research codes; however, most smaller tribes have not. SACHRP should consider a recommendation that the following language be added to the Common Rule at 46.109:
"(f) For human subject research to be conducted within the jurisdiction(s) of federally recognized American Indian or Alaska native (AIAN) Tribal government(s), the IRB shall require documentation of explicit Tribal approval for the research. This approval shall come from the Tribal Council or other agency of Tribal government to whom such authority has been delegated by the Council."
SAS subcommittee members endorsed this recommendation in principle and supported the underlying aims. However, there were concerns that modifying the Common Rule was neither the most efficacious, expeditious, nor appropriate vehicle to accomplish those aims. Also, some felt that issues related to other groups besides Tribes should also be addressed if this were done. After substantive discussion, the Subcommittee agreed to propose the following:
Recommendation Regarding Research Involving American Indian or Alaska Native Populations.SACHRP recommends that HHS promote the development of guidance and grants policy, in consultation with OHRP, other staff- and operating-divisions, and other appropriate Departments and Agencies, that address research involving American Indian or Alaska Native (AIAN) populations.
This guidance might address general issues that would be of interest and value to any investigators considering research with these populations. Specific issues to be addressed should include the requirement for Tribal approval for research that is to be conducted within the jurisdiction(s) of federally-recognized AIAN Tribal government(s). Such approval should come from the Tribal Council or other agency of Tribal government to whom such authority has been delegated by the Council. The requirement for Tribal approval should be reinforced through educational outreach, and through the terms and conditions of HHS grants supporting such research, as a matter of grants policy.
In regard to the final sentence, Dr. Trachtenberg suggested that HHS and NIH both have grants policy statements to which appropriate language could be added.
Dr. Tilden observed from his own experience that many well-meaning investigators are unaware of the need to work with the Tribal council.
Some SACHRP members preferred "shall" to "should," since it is a stronger word and implies that the action is mandatory rather than simply preferred.
Dr. Botkin proposed qualifying the language to avoid the implication that OHRP governs all research on reservations. Dr. Budashewitz observed that multiple agencies within HHS do research with native tribes. Dr. Lux suggested also explicitly encouraging HHS to consult with other Federal agencies on the issue.
The recommendation was approved by SACHRP with the following changes highlighted in bold:
Recommendation Regarding Research Involving American Indian or Alaska Native Populations.SACHRP recommends that HHS promote the development of guidance and grants policy in consultation with OHRP, other staff and operating divisions, and other appropriate Departments and agencies that address research involving American Indian or Alaska Native (AIAN) populations.
This guidance might address general issues that would be of interest and value to any investigators considering research with these populations. Specific issues to be addressedshall include the requirement for Tribal approval for research that is to be conducted within the jurisdiction(s) of federally-recognized AIAN Tribal government(s). Such approval shall come from the Tribal Council or other agency of Tribal government to whom such authority has been delegated by the Council. The requirement for Tribal approval shall be reinforced through educational outreach, and through the terms and conditions of HHS grants supporting such research, as a matter of grants policy.
Diversity in Clinical Trials
Co-Chairs reported that SAS has continued to discuss this topic and is preparing recommendations for SACHRP's consideration. Dr. Less added that FDA is preparing a report to Congress on the impediments to certain groups entering clinical trials and will probably call for public comments.
Individual Remarks by SACHRP Members on the Human Subjects Protections System
The Chair reviewed the charge for the session:
This panel session is intended to be a dialogue in which SACHRP members make brief presentations on the problems and issues they see with the present Human Subjects Protection (HSP) System, followed by a period of discussion.The session's focus is broad and should include the desirability for complete major/ minor overhaul of the current HSP infrastructure. Issues to be addressed include the vision for a new model of HSP protections; OHRP's central role in HSP oversight, its vision and resources; and major problems currently facing the HSR system. Discussion should emphasize pragmatic solutions.
Up to 2 hours will be allocated for individual SACHRP member presentations, to be divided equally among members (approximately 10 minutes each), followed by 45 minutes of open discussion among committee members and ex-officios. This will be followed by a period for public comment. The goal is to identify key areas for future exploration, discussion, and recommendations on human subject protection activities.
Remarks by Daniel Nelson, M.S., CIP
Mr. Nelson commented as an outgoing member and as a Co-Chair of SAS. He highlighted the following issues:
- The human research protection system is spending too much time "drowning in the details." It is essential to spend more time looking at the system from a higher perspective so it is clearer how it works as a whole.
- The Common Rule is not truly common. Rather, there is a patchwork quilt of regulations with overlapping jurisdictions and gaps. Some human subjects research in the U.S. is not covered by any regulation or policy. A more comprehensive framework is needed.
- Variability in treatment of the same protocol is not a helpful expression of diversity. It is possible to minimize systemic variability without sacrificing flexibility where it is appropriate.
- We have single-site systems in a multi-center world. Our oversight system must evolve to keep pace with the volume, complexity, and nature of modern research. Every IRB thinks it "knows" it is the only one that can write a perfect consent form.
- A combination of factors has led to "mission creep." Unfortunately, IRBs do not do well reviewing and overseeing activities other than human subjects research.
- We have a system that seems to be based on "worst case scenarios." Are we justified in assuming the worst?
Remarks by Lisa Leiden, Ph.D.
Dr. Leiden shared her recent experience as a member of a University of Texas task force on which 15 institutions were represented. The task force is working toward system-wide reciprocity and wishes to foster a "culture of conscience" within the network of participating agencies. The group is trying to map out inter-institutional agreements, identify areas of legitimate concern, and identify best practices within the system. However, she said, "there are a lot of upset faculty." She stressed the need to look at alternative IRB models and to work cooperatively. However, cooperating has proven a difficult challenge for the task force even on such a seemingly simple project as developing a shared list of consultants that any participating institution could use. Other issues highlighted by this SACHRP member included:
- There are real advantages to regional IRBs.
- "Unchecking the box" on the FWA may allow flexibility and increase the use of expedited review when appropriate.
- Accreditation offers institutions a chance to explore the fabric of their human research protection programs, though the resources available for this process are not always available to smaller institutions. To help meet this need, the University of Texas system is planning to provide peer evaluation to smaller institutions.
- Empirical data exists that could be made available through a data base.
- More people should be involved in making decisions about IRB review, such as whether or not a project should be classified as human subjects research.
Remarks by David G. Forster, J.D., M.A., CIP
Mr. Forster reported spending time hosting visitors from other countries interested in learning about the U.S. system of human subject protection. Through this process, his own perceptions of its strengths and weaknesses have evolved. Issues stressed by this SACHRP member included:
- Our current patchwork is "crazy"; we have a great deal of difficulty "trying to remember why we're doing what we're doing."
- Strong government support is important to ensure compliance.
- Mandatory accreditation might be a good idea.
- Lack of sufficient resources is a critical problem. The human subject protection program should not be a budget item to be cut when there are no perceived problems.
- System resourcing must be structured to avoid conflicts of interest that can compromise IRB independence.
- There are far too many IRBs in the U.S., and many of them have inadequate staff and expertise. There are some advantages to regional model used in Europe.
Remarks by Myron Genel, M.D.
Dr. Genel stressed the need for actions in four critical areas:
- Harmonize the HIPAA Privacy Rule with the Common Rule. SACHRP's original recommendations to this effect should be updated.
- Foster specialized national and regional IRBs (for example, IRBs specializing in children's research or research on persons who are decisionally impaired).
- Limit Adverse Events reported to IRBs to significant events or unanticipated events that occur locally.
- Assess the impact of the accreditation process and analyze its costs and benefits.
Remarks by Jeffrey Botkin, M.D., M.P.H.
Dr. Botkin framed his remarks by recalling a 1966 review of 22 clinical research cases that found serious ethical problems even among studies conducted by well-regarded institutions and published in mainstream literature. Physician-patient relations were problematic; informed consent and peer review were absent; there was a sense of "professional arrogance and public subservience." Today, he argued, there are still tragic cases, but systematic abuses of ethical principles are no longer widespread. He noted that applications that enter into the IRB process are largely ethically sound and approvable with modest revisions. The oversight system is largely a success, with three key elements that work: ethical standards, peer review, and informed consent. Implementation of those three elements has transformed the system
Needs and issues that remain include the following:
- Shockingly little attention is given to preparing investigators.
- Higher standards must be met in managing COI.
- More efficient review mechanisms are needed for multicenter trials.
- More careful attention to human ethics is needed in Phase I research.
- A more robust auditing system is needed to see how investigators are meeting their commitments.
- Benchmarks are needed for staffing and institutional support.
Dr. Botkin argued for the following points:
- All human subjects research should fall under the same regulatory requirements.
- Conflicts of interest resulting from control by people who have vested interest in research must be addressed.
- There is not enough clinical research. What passes for modern medicine has a "shockingly poor foundation" in many circumstances. Informatics must be used intelligently to end the use of "ineffective" and expensive procedures.
- We need a true, informed collaboration and partnership with subjects and with the general public all the way through the trial.
Remarks by Elizabeth A. Bankert, M.A.
Ms. Bankert highlighted the following concerns related to relationships among stakeholders:
- IRBs and researchers do not have a relationship based on mutual respect. IRBs are viewed by researchers as bureaucrats who are overly focused on regulatory documentation and do not provide useful review comments.
- Researchers are viewed by IRB administrators as not well versed in regulations and/or not concerned enough about human subjects.
- OHRP is viewed as compliance driven, and IRBs are fearful of contacting OHRP for advice.
- OHRP and the FDA do not appear to work together on important issues in human research protections.
- There has been no proof that increased regulatory burden has improved human subjects research review system.
She also commented on review processes, noting that:
- Minimal risk research review is burdensome to IRBs and researchers. Minimal risk review diverts valuable time and resources from full committee reviews.
- "Mission creep" is a real problem.
- Multi-site review is redundant, inconsistent, and does not necessarily enhance overall review quality.
- There is insufficient networking across IRBs.
Ms. Bankert urged OHRP leadership and staff to shift from the perceived focus on regulatory documentation and compliance. Instead, they should:
- Educate IRBs on review of minimal risk research;
- Develop best practice forms;
- Encourage trust and networking among IRBs engaged in multi-site research;
- Become a proactive, collective voice for IRBs and researchers in order to improve the system;
- Encourage and organize national dialogue on human subjects research issues; and
- Take actions to help build trust in the research enterprise.
SACHRP, in turn, should focus on "really key issues" such as improvement of the consent process.
Remarks by David H. Strauss, M.D.
Dr. Strauss observed that although the human subject protection field has grown, "well-meaning, well-intentioned, smart people still don't know what to do." The field's needs have created demands on OHRP that are unrealistic; its resources have been cut, and the agency is inadequately staffed. A top-down, compliance-driven model, he said, will continue to fail us. The real action is "at the front line" with the subject and researcher. We need to address the contemporary demands of the field by creating a rational and more fully developed best practice model that is empirically and clinically informed. The focus should be on enriching the field with useful information.
He used informed consent as a striking example of what is not working at present. Despite a vast and growing literature that shows how the increasing length of informed consent documents undermines understanding, overly long documents continue to be used. These long consent forms and the consent process as followed commonly fail to address such common misunderstandings among subjects as the expectation that research participation will offer individualized care. Choices are driven by a compliance-focused concern with the regulations, not clinical or empirical understanding. Informed consent has become a "hold harmless" document to protect the institution, investigator, and sponsor from liability instead of a tool to facilitate the subject's decision.
Dr. Strauss envisioned HHS playing a key role by collaborating with funding agencies, academia, industry, and the public to help produce an understanding of best practices that will influence the field. At the same time, he said, there is a need to reinterpret the 30-year-old regulations and rewrite regulations as needed to address contemporary problems. The focus should be placed on activities that really require IRB review. By engaging with other stakeholders to address these challenges, OHRP can help craft a new orientation that is more clinically and empirically informed.
Remarks by Neil Powe, MD,MPH
Dr. Powe also pointed to the need to "shift our culture around human subjects protection from one based on compliance and penalties to one that focuses on rewards, feedback, education, and guidance." Currently, he said, we have all those — but not the right balance among them. We are living with a "CYA mentality"; instead, we need to reward best practices. We need to "look at what we're doing" and create policies that are outcome-driven, ushering in a new solutions-based orientation. Quality improvement initiatives can assist in maintaining a focus on protecting human subjects. We need to "push the frontiers of human subject protection instead of falling into the same traps."
The SACHRP member was also deeply concerned that young people who want to do research, especially physicians, are becoming an "endangered species." He has seen too many trainees dropping out. He attributed this to the funding climate as well as to the amount of information new investigators must master. It takes longer to learn the process, he said, when "the checklist is long."
Remarks by Samuel Tilden, M.D., J.D., L.L.M.
Speaking from the perspective of a university compliance officer, Dr. Tilden began by highlighting challenges related to the research entering the oversight system for review. He argued that:
- Failure to apply exemptions results in large amounts of no/low risk research to IRB review;
- Exemption practice by IRBs largely a failure and suffers from an inherent bias against exemptions;
- Because of this practice, any directed scholarly or investigative inquiry involving human subjects tends to be subject to review.
Other challenges include:
- The need to adapt to an electronic environment in which information is handled very differently;
- The overlay of HIPAA, which was not designed to cover research, with the Common Rule, leading to confused and conflicting requirements for privacy and confidentiality;
- OHRP is not appropriately resourced and has little room to assume more than a reactive role.
The Chair called for a focus on the following recommendations of the National Commission: accreditation of IRBs, appropriate resources for OHRP functions, monitoring IRB compliance, providing IRB education, and focusing on improving performance.
Members noted many common elements among presentations, including the bias against exemptions, the need to make consent safeguards work, the need to disseminate best practices, and the need to appropriately address privacy risks. Dr. Tilden stressed the need to evolve a human subject protection system capable of assessing itself and making modifications. Other members emphasized the need for effective benchmarks to help identify projects that do not need review and standard forms that would enable programs to avoid wasting effort "reinventing the wheel."
Possible future directions include:
- Engaging other groups in addition to OHRP to develop best practices (the best forum remains to be determined);
- Developing demonstration projects that could contribute empirical data about the process of human subject protection; and
- Balancing compliance with proactive education and training.
SACHRP unanimously passed the following motion:
The Department should explore opportunities for demonstration projects related to system-level changes as presented in the discussion.
PUBLIC COMMENT PERIOD
Wilson Decamp, a former FDA employee who has been diagnosed with Parkinson's disease, stressed that the "missing ingredient in new therapies is voice of the patient." He also underlined issues related to the consent process, including the lack of adequate time to review relevant documentation, the overly high reading level of informed consent documents, and the need to explain policies on travel reimbursement clearly to prospective subjects. He related the experience of a friend who was unable to receive a report related to an adverse event she experienced because of the investigator's unwillingness to break the research's "blinding." He stressed that it is "essential that clinical researchers recognize the patient volunteer is a human being."
Zachary Schrag from George Mason University recommended a close review of the following article, which comments on the potentially inhibiting effect of policies and procedures on research with tribes:
Janovicek, Nancy (2006). Oral history and ethical practice: Towards effective policies and procedures. Journal of Academic Ethics, 4 (1-4), 157-174.
He reminded SACHRP to continue to think about the implications of proposed policies for social and behavioral research.
Dr. Pritchard again thanked the Chair for his service, noting that he has been a "model of flexibility" and that he consistently strove for an inclusive approach to planning that involved staff, members of the committee, and ex officios.
Institutional Official Responsibilities
Draft Example of Guidance to be Developed Drawing on Current OHRP Materials, Draft VA Guidance, and Subpart A Subcommittee Suggestions
Who should be the Institutional Official (IO)?
- The Institutional Official (IO) is the individual who is legally authorized to act for the institution and, on behalf of the institution, obligates the institution to the Terms of the Assurance.
- The IO is responsible for ensuring that the Human Research Protection Program (HRPP) functions effectively and that the institution provides the resources and support necessary to comply with all requirements applicable to research involving human subjects. The IO represents the institution named in the Federalwide Assurance (FWA).
- The IO should be an individual of sufficient rank who has the authority to ensure that all obligations of the HRPP are carried out effectively and efficiently. This person is usually the President, Chancellor, Director General, Chief Executive Officer, or Chief Operating Officer for the legal entity that constitutes the institution conducting research. The IO should be at a level of responsibility sufficient to allow authorization of necessary administrative or legal action should that be required. Thus, department chairs, division directors or other officials who only have authority over one portion of the institution would generally not be an appropriate IO. Similarly, OHRP recommends that the IO not be the chair or member of any IRB designated under the FWA.
What are the general administrative obligations of the IO?
- Designating one or more Institutional Review Boards (IRBs) that will review research covered by the institution's FWA;
- Providing sufficient resources, space, and staff to support the IRB's review and record keeping duties;
- Providing training and educational opportunities for the IRB and investigators;
- "Setting the tone" by promoting an institutional culture of respect and conscience, so that the ethical conduct of human subjects research is supported at the highest levels of the organization;
- Ensuring effective institution-wide communication and guidance on human subjects research;
- Ensuring that investigators fulfill their responsibilities;
- Encouraging that all staff engaged in the conduct or oversight of human subject research participate in education activities;
- Serving as a knowledgeable point of contact for OHRP and other federal agencies, or delegating this responsibility to another appropriate individual;
- Depending on the organizational structure at a given institution, other administrative arrangements may be appropriate.
What can the IO or designee not do?
- Approve research that has been disapproved (or not yet approved) by the IRB.
What are some responsibilities that may be delegated by the IO to a designee?
The IO may delegate the performance of certain oversight and operational duties to one or more individuals. Any delegation of duty must be in writing. Upon designation of a new IO, all delegation letters must be reviewed and renewed by the new IO if the new IO chooses to maintain delegation.
- Appointing IRB members. Suspending or terminating the IRB membership of any individual for whom it has been determined that he/she is not fulfilling membership responsibilities and or obligations;
- Appointing the IRB chair or co-chairs. Suspending or terminating the appointment of any chair or co-chair who is fulfilling his/her responsibilities and or obligations;
- Performing periodic evaluation of the performance of the IRB chairs and co-chairs and administrative staff;
- Managing and administering funds. Ensuring that adequate personnel, space and other resources are allocated to the HRPP;
- Reviewing and signing memoranda of understanding and cooperative agreements between the institution and other organizations, including those that establish reliance on IRBs of record for collaborative research (e.g., IRB Authorization Agreements, Individual Investigator Agreements);
- Being the point of contact for correspondence addressing human subjects research with the OHRP, FDA and other agencies as applicable, including reports to federal agencies;
- Ensuring that IRB members and investigators are knowledgeable to conduct research in accordance with ethical standards and all applicable regulations;
- Developing and implementing an educational plan for IRB members, staff and investigators;
- Ensuring that IRB members and investigators are knowledgeable to conduct research in accordance with ethical standards and all applicable regulations;
- Performing periodic evaluation of the performance of the IRB members and administrative staff;
- Recruiting qualified members to include expert, non-scientific and unaffiliated representation on the IRB;
- Reviewing and approving Standard Operating Procedures (SOPs) for the IRB and HRPP;
- Overseeing daily operations of the IRB and HRPP in accordance with the SOPs.
What responsibilities should not be delegated by the IO to a designee?
- Signatory authority for the FWA;
- Completing recommended Assurance training for the IO;
- Ensuring that the IRB functions independently and that its chair or chairs and members have direct access to the IO for appeal if they experience undue influence or if they have concerns about the function of the IRB;
- Ensuring that adequate resources, including funds, space, and personnel are provided to support the operation of the HRPP.
Secretary's Advisory Committee on Human Research Protections
July 15 and 16, 2008
Certification of the Summary of Minutes
I hereby certify that, to the best of my knowledge, the foregoing summary of minutes is accurate and complete.
Sam Tilden, M.D., J.D., L.L.M., Chair Date