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Minutes from the March 2010 Meeting

Minutes
Secretary’s Advisory Committee on Human Research Protections
March 9-10, 2010 - Washington, D.C.

 

Table of Contents

 

Welcome and Opening Remarks
Issues and Remarks from the OHRP Director
Summary of Public Comment: OHRP Draft Guidance on IRB Continuing Review of Research and IRB Approval of Research with Conditions
Guidance on IRB Continuing Review of Research
Guidance on IRB Approval of Research with Conditions
DISCUSSION
Panel: Focus on Harmonization: International Conference on Harmonisation (ICH) and Clinical Trials Transformation Initiative (CTTI)
Remarks by Robert J. Temple: The International Conference on Harmonisation (ICH)
DISCUSSION
Remarks by Robert Califf: The Failing Clinical Trial Enterprise in the US: Efforts of CTTI to Improve our National and Global Evidence Generating Capability
DISCUSSION
Remarks by Francis Crawley: The Increasingly Important Role of U.S. and European Union Cooperation in GCP in Europe and Globally: Steps toward Harmonization
DISCUSSION
Report of Subpart A Subcommittee (SAS)
Continuing Review Revisited
DISCUSSION
Questions Relating to Informed Consent and Research Use of Biospecimens
DISCUSSION
DISCUSSION
Frequently Asked Questions (FAQs) and Responses
DISCUSSION
Public Comment
Wrap Up Discussion and Adjourn
Opening Remarks
Report of Subpart A Subcommittee (SAS), Continued
Frequently Asked Questions (FAQs) and Responses (Continued)
SPECIMENS VS. DATA
Frequently Asked Questions (FAQs) and Responses (Continued)
Future of SAS
Introduction of Subcommittee on Harmonization
DISCUSSION
Public Comment
Wrap Up Discussion and Adjourn
 

TUESDAY, MARCH 9

Welcome and Opening Remarks

Barbara Bierer, M.D., Chair

The Chair welcomed everyone to the meeting and reminded them of SACHRP's responsibilities under its charter. New members Carl H. Coleman, Steven Joffe, and Lainie Friedman Ross were welcomed and briefly introduced. Dr. Bierer provided background on the committee's operating procedures, stressing the fact that SACHRP members reach decisions in the public SACHRP meeting rather than through private emails or off-the-record conversations.

In a previous meeting, SACHRP recommended that a representative of the Department of Health and Human Services (HHS) Office for Civil Rights (OCR) be invited to serve as an ex officio member of SACHRP, and Christina Heide has now joined the committee in that capacity. She was also welcomed.

The minutes of October 27-29, 2009, were approved.

Issues and Remarks from the OHRP Director

Jerry Menikoff, M.D., J.D., Director, Office for Human Research Protections (OHRP)

Dr. Menikoff welcomed everyone, especially new SACHRP members, who he described as a "very interesting" group. Significant achievements by OHRP since the last meeting include two new draft guidance documents, one on continuing review (CR) and one on approval of research with conditions. The Director noted that the growing list of SACHRP recommendations is lengthy, but OHRP is making progress in considering them: the new guidance addresses a significant number SACHRP recommendations. OHRP staff hopes that SACHRP is encouraged by the fact that these important issues have been addressed and should have an impact on the field. OHRP sees "great potential" from the new guidance.

Summary of Public Comment: OHRP Draft Guidance on IRB Continuing Review of Research and IRB Approval of Research with Conditions

Michael Carome, M.D., Associate Director for Regulatory Affairs, OHRP; CAPT, U.S. Public Health Affairs

Note: PowerPoints for all presentations by speakers are posted on the OHRP Web site.

Please see these resources for more detailed information.

CAPT. Carome explained that two draft guidance documents - Guidance on IRB Continuing Review of Research and Guidance on IRB Approval of Research with Conditions - were released for public comment on November 6, 2009. The comment period for each document closed January 5, 2010. They are available on the OHRP Web site at http://www.hhs.gov/ohrp/newsroom/rfc/index.html. The continuing review guidance, when finalized, will supersede OHRP's January 15, 2007 guidance on continuing review.

All comments, unfiltered and verbatim, can be found on the Federal eRulemaking Portal at http://www.regulations.gov/ using docket number HHS-OPHS-2009-0016 or HHS-OPHS-2009-0017.

Guidance on IRB Continuing Review of Research

OHRP received comments from eight individuals and ten organizations, including five professional associations, a State university, a private medical school, the IRB office of a private university, an independent IRB, and the Walter Reed Army Institute of Research (WRAIR). Of those who made general comments about the proposed guidance, eight held an overall positive opinion, and one was mixed. Public Responsibility in Medicine and Research (PRIM&R) saw the new guidance as "helpful in clarifying some ambiguities."

Sections B, C, and G (the longest sections of the document) received the most comments. Some respondents were concerned that setting the first continuing review date according to the date on which research is approved with all conditions met would require expensive changes in IRB computer systems.

In regard to the factors to be considered when deciding the appropriate interval for continuing review (section F), PRIM&R supported the recommendation, but suggested qualifying the recommendation with the phrase "like the following." Another respondent thought the list unduly specific and detailed, and a third suggested that examples be added to illustrate these considerations.

In regard to a recommendation that IRBs document the reasons for lapses in approval and steps taken to prevent them in the future, several commenters observed that lapses in approval are usually due to the investigator's failure and not the IRB's. They urged that the recommendation be modified to focus on steps the investigators will take to prevent such lapses.

Several members said they disagreed with OHRP's longstanding position that obtaining identifiable private information includes "using, studying, and analyzing identifiable private information (including biological specimens)" (section K).

Guidance on IRB Approval of Research with Conditions

OHRP received comments from five individuals and seven organizations, including four professional societies or associations, a private university's IRB office, an independent IRB, and WRAIR. Seven of these commenters expressed an overall positive opinion of the proposed guidance, while one had an overall negative opinion. The single negative comment came from an individual commenter who felt that "the guidance reinforces the current understanding and practice but …loses an opportunity to reduce regulatory burden."

Section D suggested that, depending on the nature of the required conditions, the IRB could designate the IRB chairperson, another IRB member, the IRB administrator, or qualified IRB staff to determine that the conditions have been satisfied. This provision drew support from three organizations, but a fourth emphasized that this procedure should be limited to review of issues that involve simple confirmation of concurrence with the IRB's requirement.

Some commenters found the examples given in Section D helpful, but eleven comments called for revision or clarification to specific examples, and the independent IRB found them confusing because of a lack of clarity on which particular person is appropriate to review the investigator's response in different instances.

DISCUSSION

Flexible approval dates. Mr. Forster suggested that FDA and OHRP allow either system of setting a date for continuing review (convened meeting, or when conditions were satisfied) according to the IRB's Standard Operating Procedures (SOPs). He noted that forcing a particular way of reviewing the date could impose a burden on IRBs to change their systems. CAPT. Carome said it was in fact OHRP's intention to provide this flexibility, and this will be made clear in the final guidance.

Review periods longer than a year. Dr. Strauss asked about the status of OHRP's deliberations regarding allowing timelines for CR that exceed a year for certain categories of research. CAPT. Carome responded that this would require a change in the regulatory language of the Common Rule, so it was not addressed in the guidance. OHRP continues to consider the recommendation.

Harmonization between FDA and OHRP. CAPT. Budashewitz asked about the status of discussions between OHRP and FDA on harmonization of their guidances on continuing review. He noted that, in regard to lapses, both agencies allow some flexibility, but the approaches are slightly different. CAPT. Carome responded that the agencies share the iterations of their guidance back and forth, and he noted that OHRP adopted much of FDA's language regarding lapses. He was unaware of any substantive differences in policy.

Dr. Less, ex officio representative for FDA, commented that the public comment period for FDA's version of this guidance has not closed. FDA and OHRP will try to clarify and harmonize any differences.

CAPT. Carome noted that FDA's guidance introduces the concept of a "data lock," and OHRP is still considering what this means. Dr. Less said this refers to a situation when data analysis is continuing using patients' records, but there is no more contact with subjects or with subject records. Members pointed out that this would still involve the use of identifiable data.

Identifiable data. An ex officio member noted that excellent commercial software is now available that can identify subjects where this was previously impossible. She said it was essential to think carefully about the impact of technology in this area. To make data truly unidentifiable may require stripping out so much information that the data are no longer useful.

Lapse vs. suspension. Strauss asked for OHRP's position on what constitutes a lapse vs. a reportable suspension. Western IRB raised the question in regard to the draft guidance of how to handle a situation in which there is no lapse in approval, but there are conditions to satisfy before enrollment resumes. CAPT. Carome said WIRB's comment is under discussion, and SACHRP is welcome to make a recommendation.

A member commented that if a passive lapse in approval is not reportable, the situation WIRB describes should not be reportable. Another contrasted it to a situation in which an adverse event has occurred that has caused the IRB to suspend enrollment. Dr. Strauss observed that several members feel strongly that this instance should not be reportable. Members considered making a recommendation to this effect and intended to write such a recommendation for consideration later in the meeting if time allowed. (Such a recommendation was not brought forward.)

Mr. Forster observed that current guidance says that when there is a lapse in IRB approval, the IRB "must" establish a new anniversary date. He suggested the use of the word "should" to soften this direction.

Dr. Bierer thanked OHRP for responding to SACHRP's recommendations and for its efforts to harmonize its guidance with FDA.

Panel: Focus on Harmonization: International Conference on Harmonisation (ICH) and Clinical Trials Transformation Initiative (CTTI)

Robert Temple, M.D., Deputy Center Director for Clinical Science, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA); Rob Califf, M.D., Director, Duke Translational Medicine Institute; Francis Crawley, Ph.L., Executive Director, Good Clinical Practice Alliance - Europe (GCPA)

Dr. Bierer introduced the panel, noting that it will inform the deliberations of a newly created SACHRP subcommittee focused on issues related to the harmonization of regulations on human subject protection. The subcommittee probably will not get into the details of how issues identified for resolution should be addressed, but instead will focus on identifying priorities that cause areas of disharmony that cause significant difficulty in the field and prioritizing them. The Chair noted that SACHRP is not the only body looking at harmonization; for example, NIH has been addressing harmonization issues pertinent to Adverse Events (AEs). The panel's charge is as follows:

The purpose of this panel is to provide insights to inform the deliberations of the newly created Subcommittee on Harmonization. The subcommittee's charge is to examine issues related to the protections of human subjects in research where multiple regulatory agencies and rules have oversight over the same research studies, and develop recommendations regarding how to achieve the appropriate protection of human subjects while minimizing the administrative burdens created by multiple regulatory requirements. The panel will review how the International Commission on Harmonization (ICH) Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance (GCP) serves to coordinate the ways people in different countries meet the requirements for the protection of human subjects in studies carried out in different participating nations. It will evaluate how ICH E6 GCP is implemented, and what its strengths and weaknesses are. It will also review the efforts to date of the Clinical Trials Transformation Initiative (CTTI) and how the CTTI project sees the opportunities to improve the effectiveness and efficiency of human subject protections in clinical trials where more that one set of regulatory requirements for the protection of human subjects may apply.

Remarks by Robert J. Temple: The International Conference on Harmonisation (ICH)

Dr. Temple explained that ICH originated in the early 90s in recognition of the need for harmonization in regard to regulations governing the development of drugs worldwide. Purposes include developing common standards, avoiding waste, and developing databases that could serve regulators and patients. The conference reflects the views of the three primary drug developing regions (the U.S., the European Union [E.U.], and Japan) and their corresponding pharmaceutical organizations.

The speaker noted that although some were concerned that the effort would lead to the adoption of the lowest common denominator, ultimately lowering standards, that fear was not realized.

Guidance documents developed by regulators, with input from manufacturers, include the following key components (see http://www.ich.org/cache/compo/276-254-1.html):

  • E-1: Safety database (for a long time, only thing written on this)
  • E-2: (General) safety reporting, pre and post marketing
  • E-3: Reporting on a clinical trial
  • E-4: Dose-response
  • E-5: Ethnic differences, using foreign data
  • E-6: GCP (describes expectations for the conduct of clinical studies, allowing the use of data obtained globally that comply with these standards)
  • E-7: Studying the elderly (now considered to begin at age 75)
  • E-8: General considerations
  • E-9: Statistics
  • E-10: Choice of control groups (addresses a wide variety of controls, including historical)

Dr. Temple observed that the tasks and purposes of IRBs and Institutional Ethic Communities (IECs) are similar, but they have a different composition; initially, this meant that foreign investigators could not sign FDA Form 157, which they had to do if the study was to be under an IND because they could not state that an IRB that accepted US standards would be used. A waiver process has now been arranged that is easy and allows for use of an IEC, so that more foreign studies are likely to be done under an IND. The overwhelming and wasteful practice of sending 15-day safety reports on Adverse Events not likely to be drug-caused is also being addressed.

An area of particular interest to the Clinical Trials Transformation Initiative (CTTI) as well as to FDA is the extent and nature of study monitoring. The speaker asserted that few matters are more critical to the conduct of the large outcome trials than the need to control the amount of data collected and the extent of monitoring. Monitoring practices, CTTI finds, differ widely. E-6 takes a flexible approach in which the sponsor is responsible for determining the appropriate extent and nature of monitoring. This is based on the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. While on-site monitoring is generally needed before, during, and after the trial, in exceptional circumstances the sponsor may determine that central monitoring is sufficient for GCP.

The speaker felt that ICH E-6 represents a valuable consensus on the expectations and duties of all parties to a clinical investigation, making it possible to have a world-based clinical trial enterprise. It is based on widely accepted principles. Studies done abroad can readily be used if data are "applicable to the US population and US medical practice." Increasingly, data are seen from around the world, and even though ICH E-6 was developed by countries with established sites for trials, it applies broadly to anywhere that trials are carried out.

DISCUSSION

Mutual recognition. An ex officio member asked Dr. Temple if ICH allowed for the acceptance of data not collected through an FDA IND process. Dr. Temple said that the regulations plainly allow such reliance, e.g., for marketing approval, or for a study of a drug not done under an IND. The FDA must be given access to the data; however, he said, we must conduct our own review of the data.

Variability in processes and procedures. The speaker confirmed that the approach allowed for variability as long as principles are met. However, a member commented about the role of cultural differences, and Dr. Temple noted that a person from Singapore at a PRIMR meeting said that it was acceptable for a husband to give consent on behalf of his wife. Dr. Temple said he did not agree that that was acceptable, although in general we recognize cultural differences. He noted also that these kinds of differences have not come up for major discussion, but he noted that even in the U.S., IRBs do come to different conclusions for similar protocols.

Financial conflict of interest (COI) for investigators. Dr. Temple said a statement of financial COI is required; broad stock ownership and significant payments of other sorts raise red flags. Disclosure requirements for trials abroad are the same as those for local trials.

Alternate treatment. Mr. Forster said it was not practical or feasible to document the risks and benefits for all possible alternate treatments in the consent document. Dr. Temple said it was not his understanding that all alternatives need to be listed. For FDA, a major question is what to say about unapproved alternatives. "Available therapy" is generally interpreted to mean something well established or something FDA regulates and has approved.

Monitoring. Dr. Temple noted that more thought is needed on what is meant by adequate monitoring. One Clinical Trials Transformation Initiative (CTTI) project is examining four completely different approaches to monitoring.

Maintenance. Dr. Joffe asked how the documents described are maintained. Dr. Temple said there is no standard body that maintains each document; rather, a new group of people must be convened when revisions are needed. Sometimes the new group develops questions and answers, an easier format than complete revisions.

Remarks by Robert Califf: The Failing Clinical TrialEnterprise in the US: Efforts of CTTI to Improve our National and Global Evidence Generating Capability

Dr. Califf believes that U.S. clinical trials are in crisis. He noted that trial startup times are lengthening, enrollment in trials is slowing, costs are increasing (to the point that most trials lose money), and many investigators are pulling out of clinical research. He attributed much of the difficulty to costs related to bureaucratic requirements associated with research. He cited one estimate that without those costs, a $150 million trial might cost as little as $45 million.

The speaker said that all members of the clinical research enterprise have played a part in this problem, and fixing it will require a collaborative effort involving FDA and other global regulators, industry, academia, the National Institutes of Health, investigators in clinical practice, and consumers. To accomplish this, FDA's Office of Critical Path Programs established a public-private partnership known as the Clinical Trials Transformation Initiative (CTTI). It mission is to identify practices that through broad adoption will increase the quality and efficiency of clinical trials. Through a memorandum of understanding with FDA, Duke University serves as the host of CTTI.

Led by an Executive Committee and Steering Committee that are broadly representative of a variety of stakeholders, CTTI is aggressively trying to generate evidence on how to improve the design and execution of clinical trials by conducting "research on research." It hopes to foster widespread change based on this evidence. For example, one of its current workstreams seeks to improve the reporting of Serious Adverse Events to IND investigators; another addresses the need for effective and efficient monitoring practices.

Although CTTI was created to address a crisis for U.S. clinical research, it recognizes that trials and related issues are a global challenge. It therefore seeks to identify practice improvements that can be applied internationally and is engaging international collaborators in the initiative. It also pursues collaborative activities with other organizations sharing similar goals, such as the Center for Medication Technology Policy (CMTP) and the Sensible Guidelines Conference. FDA and other regulators are completely engaged in the effort, which seeks to keep dialogue open across sectors.

Dr. Cailiff felt that there is "no way to tinker with the current system." Instead, he argued for "disruptive innovation" that would lead to change. He compared the current status of research trials to the solid state radio before the transistor: "it is not fit for the purpose." Research and clinical practice, he argued, should not be separate systems. Emerging technologies and practices such as electronic health records, electronic permission systems for research, electronic surveillance, functional data warehouses in integrated health systems, and learning healthcare systems (a concept articulated by the Institute of Medicine) hold promise. (In regard to learning health care systems, see, for example, the Institute of Medicine's 2007 publication, The Learning Healthcare System: Workshop Summary, available from: http://www.iom.edu/Reports/2007/The-Learning-Healthcare-System-Workshop-Summary.aspx .)

DISCUSSION

Tweaking the system. Dr. Bierer asked Dr. Califf to identify opportunities to improve efficacy and effectiveness and reduce costs for the system as it is. She also asked if he would agree that assent and consent are needed when people enter trials. The speaker agreed that it is not possible to abandon the system as it evolves, and he agreed that there should be individual consent for every randomized trial. He felt, however, that research could be more efficient if individuals realize they are participating in a learning health system when they receive care. He further suggested that each research protocol should define the most appropriate measures of quality for that research protocol. Much money is wasted collecting data that is not relevant to quality. Finally, he asserted that form 1572, which investigators must sign, requires investigators to agree to things that, in reality, no investigator can reasonably be expected to control or even remember. An example is agreeing to review more adverse event reports than any investigator can possibly assess or that can conceivably be relevant to the specific protocol.

Site-based research. CAPT. Budashewitz asked for clarification of whether alternative risk-based approaches applicable to interventional trials may be expected to have an impact on how human subject protection and monitoring functions are addressed. Dr. Califf envisioned that advanced integrated health systems will provide ready access to data in our lifetimes. The site, not the investigator, would be monitored for quality by means of a periodic assessment, and a team would be dispatched to the site if a problem is detected.

Barriers to change. Mr. Forster asked whether other countries were already "doing it right"; the speaker responded that, unfortunately, many of them are "emulating our insanity." He stressed the need for "facile communication" among countries regarding emerging best practices - that is, the strategies that will answer the most questions while protecting human subjects. He hoped that our country's rigidity would not keep it from adapting successfully to better ideas.

Dr. Joffe asked if there was evidence that reduced regulatory burden would result in a higher grade of evidence for best clinical practice. Dr. Califf said that while he believed we could get more answers if the same amount of research money were spent more efficiently, he could not prove the hypothesis. He added that the training of practitioners and public awareness were two critical "legs of the stool."

Dr. Temple observed that many of the possible efficiencies Dr. Califf describes are already doable but are not in common practice because of fear of the consequences of minor errors. He pointed out that we readily accept conclusions from studies that have a lower degree of monitoring, such as those done through the University of Oxford, and the Physicians Heath Study did no monitoring at all.

Remarks by Francis Crawley: The Increasingly Important Role ofU.S. and European Union Cooperation in GCP in Europe and Globally: Steps toward Harmonization

Mr. Crawley defined Good Clinical Practice (GCP) as a set of responsibilities that, in the words of the DHHS [Federal Register of June 10, 2004 (69 FR 32467), proposed rule to revise 21 CFR part 312], make "all parties to a study responsible for patient safety and study quality." Compliance with good practice provides assurance that the rights, safety, and well-being of trial subjects are protected, and that the results of the clinical trials are credible. GCP forms a national and international agreed structure which provides our strongest assurance that clinical trials contribute to public health as well as health science and economic development. Global efforts to harmonize GCP, particularly that launched by the United States (US) and European Union (EU) on 9 August 2009, contribute to achieving common understandings and practices, shared standards and methodologies, shared knowledge and resources, and improved human subjects protections. A harmonized understanding of the responsibilities toward science and ethics in clinical trials is needed, and challenged, given certain conditions that impact on the national and international contexts of clinical research. The primary concerns affecting the international harmonization of GCP are the following:

  • The extensive reach of clinical trials, which involve not only medical practice, but also issues such as privacy and protection of data, import-export laws, and the widely differing international frameworks for insurance;
  • The complexity of law and regulation;
  • The lack of an internationally accepted code of ethics for human research protections;
  • The progress of medical science; and
  • The lack of appropriately representative platforms on which to have this discussion.

General frameworks for GCP include a guideline developed by the World Health Organization in 1995 (followed by a handbook for GCP in 2005) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), adopted into Step 4 of the ICH process 1996 (and since then not revised). The latter is the best and most focused standard for GCP to date. Regional frameworks for clinical trials exist for the EU and the US, and there are an increasing number of national guidelines that are consistent with ICH but seek to adapt it to serve specific populations. Important new clinical trial destinations that have developed country-specific guidelines include China, India, South Africa, and Singapore.

GCP has been developed through a number of initiatives in the EU since the late 1980's. In 2001 the European Union brought into law the Directive on the Implementation of Good Clinical Practice for Medicinal Products (Directive 2001/20/EC). Statutory law pertaining to clinical trials differs in scope and approach. Examples include the United Kingdom's Law on Clinical Trials Involving Medicines (2004), Belgium's Law Concerning Experiments on Human Persons (2004), and France's Law Concerning Public Health Policy (2004). Now Europe is undertaking a review of this Directive through the European Commission's DG Health. New legislation is expected for October 2011.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use is structured as follows. (The speaker noted that Chapters 3, 4, and 5 are the most important.)

Chapter 1: Glossary
Chapter 2: The principles of ICH GCP
Chapter 3: IRB/IEC
Chapter 4: Investigator
Chapter 5: Sponsor
Chapter 6: Clinical Trial Protocol and Protocol Amendments
Addendum A: Investigator's Brochure
Addendum B: Essential Documents for the Conduct of a Clinical Trial

As Good Clinical Practice guidance is revised and adapted globally (but also regionally as well as within countries), it will need a broader scope that addresses all health research, not just research on pharmaceuticals; modernized guidance that takes into account new developments and issues such as the growth of registries and the locus of responsibility for publishing findings; as well as appropriate national, regional, and international platforms.

DISCUSSION

Registries. Speakers were asked to identify aspects of registries that should be clarified. Dr. Crowley saw the major issue as who bears responsibility for registering the trial and publishing results. He said there is a registry for clinical trials in Europe, but it is not open to the public. Dr. Temple said the sponsor has the responsibility to register trials monitored by FDA and added that noninterventional studies require different guidance.

Reciprocity. Dr. Califf noted that Europe has moved ahead of the U.S. in its approach to multicenter trials. It is "ridiculous," he said, to think of 300 sites reviewing the same protocol. Duke University has established reciprocity with other institutions participating in multicenter trials, and it finds that with the emergence of the "electronic IRB," transparency among IRBs has increased. Dr. Crowley added that Europe has succeeded in getting ethics committees to act together by means of a directive.

Computer-based options. Dr. Temple said the availability of data electronically could dramatically reduce costs and make larger trials practical. He hoped that Health Management Organizations (HMOs) would one day become enthusiastic about the possibilities of conducting comparative effectiveness research. Dr. Temple said that ICH is even exploring the possibility of trials that are conducted entirely via the Internet with no office visits.

Dr. Califf observed that even when electronic health records exist, there is a tendency to print them out for auditors; he felt that auditors should be willing to review them on a computer screen in the interest of efficiency.

The Chair thanked everyone for a wonderful discussion.

Report of Subpart A Subcommittee (SAS)

Dan Nelson, M.S., CIP; Elizabeth A. Bankert, M.A, SAS, Co-Chairs

Mr. Nelson provided background on SAS for the benefit of new members, including its charge, current membership, recommendations developed and forwarded to the HHS Secretary, and meetings held to date.

Continuing Review Revisited

Mr. Nelson reviewed the historical context and working assumptions SAS took into consideration when it developed its recommendations regarding Continuing Review, which were included in a Secretarial letter forwarded on March 14, 2007. He noted that only one section of the regulations addresses the continuing review process with any detail:

An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research (45 CFR 46.109[e] and 21 CFR 56.109[f]).

OHRP's current guidance on Continuing Review (last updated in January, 2007) reads as follows:

Several scenarios for determining the date of continuing review apply for protocols reviewed by the IRB at a convened meeting. To determine the date by which continuing review must occur, focus on the date of the convened meeting at which IRB approval occurs.

SAS members believed that starting the clock at that convened meeting ignores the process employed by most IRBs to complete review and ensure that all modifications required to approve research are implemented before communicating approval. SAS concluded that allowing IRBs to set the date to the day when the research receives its final approval is a more appropriate approach and prevents both premature research activities and artificially shortened approval periods. SACHRP approved a recommendation to this effect:

Recommendation 10.1.OHRP should revise guidance to reflect that the final IRB approval of a study "sets the clock" for continuing review. For multi-site reviews, this may differ by site (November, 2005).

The intent of the recommendation was that the final IRB approval of a study - not the date of the preceding convened meeting - would start the continuing review "clock." SAS envisioned that, as for expedited review, the dates of actual reapproval for studies approved by the convened committee would then determine the next reapproval date. OHRP's proposed approach follows SAS's original concept in the first year, but the date at which the final review of the protocol occurs and all conditions have been met then becomes a set annual date for continuing review.

DISCUSSION

Dr. Menikoff said he had raised the issue highlighted by SAS with other groups that felt the significant problem was the time that starts the continuing review clock. He was also concerned that the approach SAS suggested might result in a gap of more than 12 months between reviews, which would be a violation of regulatory requirements. Mr. Nelson distinguished between review and approval, noting that the continuing review conducted by the convened board might not result in approval, leading to a lag between this meeting and the resolution of issues, with resulting reapproval. Most IRBs, he said, would have a time limit on how long such issues would be allowed to remain unresolved. CAPT. Carome pointed out that OHRP gives IRBs latitude to determine the appropriate lag time.

Mr. Nelson said SAS had recommended a 60-day rule instead of a 30-day one to give responsive investigators sufficient latitude and avoid "punishing" those who submit early. This recommendation was not accepted by OHRP. Dr. Menikoff observed, however, that the regulated community was fortunate to have the 30-day latitude; a further extension would require rewriting the regulation.

Mr. Nelson suggested that few IRBs would be able to make the change in the date set for continuing review because of the need to retool data bases to allow for differing calculations for the first and subsequent review years. Dr. Menikoff thought that software experts should be able to address this change and stressed that making the change at all would be optional.

Questions Relating to Informed Consent and Research Use of Biospecimens

The meaning of "investigator." At the SACHRP meeting of October 27-28, 2009, SAS brought forward a recommendation on the meaning of "investigator" as applied to research involving biospecimens. After discussion by the full committee, SAS was asked to revise its definition for further consideration by SACHRP. SAS did so. Before presenting the revised recommendation, Mr. Nelson reminded SACHRP of key background needed to understand the recommendation. First, he noted that OHRP does not consider research involving only coded private information or specimens to involve human subjects - making it subject to IRB review - if the following conditions are both met:

the private information or specimens were not collected specifically for the currently proposed research project through an interaction or intervention with living individuals; and the investigator(s) cannot readily ascertain the identity of the individual(s) to whom the coded private information or specimens pertain because, for example, there are agreements, IRB-approved policies and procedures, or legal requirements in place that prohibit the release of the key to the code to the investigators under any circumstances until the individuals are deceased.

Guidance on Research Involving Coded Private Information or Biological Specimens, issued August 10, 2004; updated October16, 2008 http://www.hhs.gov/ohrp/policy/cdebiol.html

The meaning of the term "investigator" is critical in determining whether a proposed activity is human subjects research, and therefore subject to IRB review. Current OHRP guidance defines "investigator" as "anyone involved in conducting the research" and opines as follows:

OHRP does not consider the act of solely providing coded private information or specimens (for example, by a tissue repository) to constitute involvement in the conduct of the research. Note that if the individuals who provide coded information or specimens collaborate on other activities related to the conduct of this research with the investigators who receive such information or specimens, then OHRP would consider such additional activities to constitute involvement in the conduct of the research. Examples of such additional activities include, but are not limited to: (1) the study, interpretation, or analysis of the data resulting from the coded information or specimens; and (2) authorship of presentations or manuscripts related to the research.

Guidance on Research Involving Coded Private Information or Biological Specimens, issued August 10, 2004; updated October16, 2008 http://www.hhs.gov/ohrp/policy/cdebiol.html

SAS found this understanding of "investigator" problematic because there are many circumstances where a secondary use of coded information or specimens would not constitute human subjects research, were it not for the peripheral involvement of the individual who gathered the original data or specimens. This involvement may be such that the secondary users, and sometimes even the original collector, are unable to ascertain the identity of subjects. Examples include:

  • The original collector is involved as a coauthor on resulting manuscripts or listed on grants in recognition of his/her work in obtaining the data or specimens, but with an agreement that prevents release of the coding key to secondary users;
  • The original collector joins with others to form a centralized repository, with no continued personal access to identifiers;
  • A professor provides a coded dataset for graduate students to use in secondary analyses, with no intention or reason to share identifiers. (This is common among social science professors.)

Under these circumstances, Mr. Nelson noted, current OHRP guidance defines the original collector as an "investigator" in the secondary use, even though the investigator's role may still effectively be limited to "solely providing" coded information or specimens. He noted that this interpretation is overly restrictive, poorly understood, and therefore variably applied by IRBs and investigators. Overall, he said, the 2004 guidance by OHRP has provided a valuable mechanism for investigators and IRBs to focus on activities where risk to subjects is a legitimate concern. However, this particular element works counter to that goal and does not contribute meaningfully to human subject protections. SAS recommended as follows:

Recommendation. OHRP should revise its interpretation of who is considered an "investigator" in secondary use of coded information or specimens. In circumstances where neither party will have a need to decode or re-identify data, the original collectors who are providing such information or specimens without identifiers should not be considered to be "investigators" in the secondary use, even if they are involved in analysis of aggregate data or publication of results, provided the secondary users are unable to readily ascertain the identity of subjects.

Mechanisms to support this interpretation could include (a) the presence of an agreement that prohibits release of the key from the original provider to secondary users; or (b) the existence of a repository or banking system that prohibits the secondary users from access to identifiers. These same interpretations and mechanisms should be applied whether the original provider and secondary user(s) are within the same institution or at different institutions.

The intent is to support a conclusion that secondary uses under such circumstances do not constitute research involving human subjects (as defined under 45 CFR 46.102(f)) and therefore do not require IRB review and approval, in keeping with OHRP's "Guidance on Research Involving Coded Private Information or Biological Specimens."

DISCUSSION

Meaning of authorship. Some SACHRP members found it unusual that a person who is not an investigator would be considered an author, although another said the publishing standards for authorship might not be relevant. Mr. Coleman suggested that if the persons providing the sample had a sufficient stake in the research to be considered authors, they should probably also be considered investigators . Mr. Nelson said that the situations described exist in a "grey zone," and the guidance may be interpreted differently.

Identification. A member wondered if the first bullet above - "The original collector is involved as a coauthor on resulting manuscripts or listed on grants in recognition of his/her work in obtaining the data or specimens, but with an agreement that prevents release of the coding key to secondary users" - reflected the definition of not being research involving human subjects. She noted that it is not possible to strip a specimen completely of identification. Another noted, however, that the key is the qualifying term, "readily" identifiable. Specimens that could be identified only through considerable effort still would meet this criterion.

Return of results. Dr. Joffe noted that the original investigator might be obligated to recode and return results. Mr. Nelson held that even if this were done, it would not preclude the upstream flow of information. Dr. Bledsoe commented that many repositories establish operating policies and procedures to address this issue.. These policies often involve IRB review to consider if, when, and how individual research results from identifiable specimens should be returned to subjects. Dr. Menikoff reminded members that OHRP has opined that persons doing research with deidentified tissue do not have to go through an IRB for approval.

Further definition of investigator. Mr. Forster moved that OHRP consider the issue presented and further define the meaning of "investigator." The motion was seconded. He said he made the motion on the assumption that there was sufficient controversy around the recommendation that it would not be approved; he trusted that OHRP would clarify the issue in the right direction. Dr. Strauss thought the first bullet should address the question of investigators' standing " when their only involvement is to provide the coded specimens to another researcher." He said he was concerned that developing a recommendation would lead to "squabbling over terminology" rather than making substantive points.

Members expressed the following concerns regarding the recommendation as drafted:

  • The concern is not whether someone has a need to decode or re-identify data, but rather that someone may do so inappropriately.
  • There is no protection against someone using the information they have to reidentify inadequately coded samples.
  • The main problem is that this allows for something that could end up as human subjects research.
  • This does not allow flexibility that might be needed if results must be returned.

Members agreed that the second sentence should be rewritten to ensure that the necessary protections are in place.

ACTION

The recommendation was tabled. Members intended to confer on a new version that would address concerns raised in the discussion.

Compatibility of Secondary Use with Consent. SAS highlighted the need for a word or phrase to describe the circumstance where the proposed secondary use of specimens is supported by (or not prohibited by) the original terms of consent. While not perfect, SAS determined to use "is compatible with" to carry this meaning. SAS provided points to consider in determining "compatibility."

Recommendation. The determination of whether a proposed secondary research use is compatible with the original consent is subjective and will be context-specific based on a range of considerations. Questions to consider include:

  • Does the consent form prohibit or preclude the new research activity?
  • What is the nature of the proposed secondary research?
  • Could it reasonably be understood to fall within the type of disease or research that was described to the research subject at the time of consent? Or is the focus on a completely different disease or type of research?
  • Does the new research use impose new or significantly greater risks that are not described in the initial consent form?
  • Are there known concerns of the study population(s) about the proposed new use?

DISCUSSION

Dr. Menikoff said that based on the principle of fairness, if the consent form prohibited the activity, it is not appropriate to say it is compatible. If the answer to the question posed in the first bullet of the recommendation were "yes," the answer should be clear, even if the samples collected are 20 years old. Ms. Bankert said that SAS agreed that if the consent form prohibits/precludes new research, it would not move forward in "vast majority" of cases. Dr. Bierer pointed out, however, that when there is no affirmative assertion allowing a specific use, there are grey areas where thoughtful review is needed.

The OHRP Director stressed the need to ensure, in any guidance that addresses the questions above, that the guidance is specific enough to enable different IRBs to reach similar conclusions. Dr. Joffe asked if there was agreement that so long as the consent form does not prohibit or preclude the new research activity, there is an assumption the research should go forward. Several members agreed.

Dr. Trachtenberg expressed appreciation for the insight shown in the final bullet above.

ACTION

The recommendation was tabled and SACHRP was asked to return with a revised version later in the meeting.

Revised Recommendation. The following revised recommendation was presented: for discussion later in the meeting:

Recommendation.The determination of whether a proposed secondary research use is compatible with the original consent is subjective and will be context-specific based on a range of considerations. If the original consent form could be interpreted as prohibiting or precluding the proposed research activity, it is presumed the research is not allowable. If the consent does not prohibit or preclude the proposed use, IRBs should consider several questions to determine compatibility:

  • What is the nature of the proposed secondary research?
  • Could it reasonably be understood to fall within the type of disease or research that was described in the original consent form? Or is the new focus a completely different disease or type of research?
  • Does the new research use impose new or significantly greater risks that are not described in the initial consent form?
  • Are there known concerns of the study population(s) about the proposed new use?

DISCUSSION

Prohibiting or precluding. Mr. Coleman saw no difference between "prohibiting" and "precluding" and suggested that one be dropped. SACHRP agreed.

Dr. Joffe felt the word "subjective" might be unclear or misunderstood; he suggested striking it. Others agreed.

Several persons highlighted the issue of whether or not it was "practicable" to contact the subjects. Others pointed out, however, that this still needs to be considered and may be necessary in some instances.

A SACHRP member raised the specific issue of a consent form that says the specimen will be used for diabetes research but does not use the word "only" ("only for diabetes research"). A member said it would be "slippery" to argue that permission for other uses was implicit, since the plain language interpretation would be that the sample would not be used for other purposes. Dr. Ross pointed out, however, that research on conditions that are precursers or consequences of diabetes might also be construedas acceptable research subjects. Mr. Forster said there were too many places that relevant language might occur in the consent form to try to develop a firm rule about what language should be considered; IRBs need the latitude to consider the entire form and its implications.

Mr. Coleman was concerned about the implication that a use prohibited under the consent form might still be allowable pursuant to a waiver of informed consent. He thought that granting a waiver under those circumstances would not be permissible because it would "adversely affect the rights" of the subject. Another SACHRP member gave the instance of a case in which the samples in question are twenty years old and a significant percentage of subjects are deceased. Dr. Bledsoe observed that large, uniquely valuable collections exist for which it would be impossible to reconsent the subjects because they could not be located. These collections are sometimes used for other types of research if the IRB has determined that the criteria for a waiver of consent have been met.

Scope of research.Dr. Joffe suggested broadening the third bullet by dropping the second sentence and removing the language related to "type of disease." Members agreed that the intent of the recommendation is to address all forms of research, including social and behavioral research, rather than biomedical research alone. The considerations might apply equally well to audiotapes or videotapes.

Risks. A SACHRP member suggested highlighting privacy risks as an example in the third bullet. The proposal was accepted.

Considerations.Dr. Bledsoe suggested that as an alternate approach to questions, a points to consider document could be considered. Mr. Nelson felt that listing issues would be more likely to create the impression of a checklist than the inclusion of questions. Dr. Bierer observed that the considerations listed would give clear direction as to what kind of issues should be considered, adding that she was not confident that most institutions, IRBs, or individuals were considering these at present.

Prospective actions.Dr. Menikoff said there was no reason that consent forms could not use language that was consistent with the scope of research anticipated (e.g., "diabetes or diseases related to diabetes"). The question at issue should be how a reasonable person would interpret the language of the form. Dr. Bierer noted, however, that participants are often less inclined to participate when the consent form is broad. Dr. Ross felt this was reasonable; subjects might be sensitive to how they are grouped for the purpose of research.

Ms. Bankert said that SAS does intend to address the issue of appropriate language for consent forms that will make such dilemmas less frequent.

SACHRP panel.Dr. Bledsoe suggested that SACHRP might want to consider having a panel that focuses on the issue of how subjects/patients feel about giving samples for one purpose that are then used for a different, though perhaps related, purpose. Some research suggests that some patients may have greater concerns about the intrusion of being recontacted than they have about the kind of research the samples would now be used to carry out. She also thought it would be helpful to consider speakers who could address practicability issues in setting up repositories.

ACTION

The following revised recommendation was unanimously approved:

Recommendation.The determination of whether a proposed secondary research use is compatible with the original consent will be context-specific based on a range of considerations. If the original consent form specifically prohibitedthe proposed research activity, it is presumed the research is not allowable. If the consent does not prohibit the proposed use, IRBs should consider several questions to determine compatibility:

  • What is the nature of the proposed secondary research?
  • Could it reasonably be understood to fall within the scope of research that was described in the original consent form?
  • Does the new research use impose new or significantly greater risks (including privacy risks) not described in the initial consent form?
  • Are there known concerns of the study population(s) about the proposed new use?

Frequently Asked Questions (FAQs) and Responses

The Co-Chairs briefly reviewed FAQs 1-10, which were previously approved by SACHRP at meetings held on July 22, 2009 and on October 27 and 28, 2009. They presented additional FAQs, beginning with FAQ 11, which was presented on October 27, 2009 and revised by SAS based on discussion comments.

FAQ #11

An academic medical center has established a centralized tissue bank of specimens that it receives from a variety of sources.

The bank was reviewed as human subjects research and has IRB-approved policies and procedures in place. These policies and procedures stipulate that the bank will release only coded specimens to researchers, without identifiers.

The institution would now like to begin moving excess clinical specimens to the bank in an ongoing manner, after their original purpose has been served. The specimens would be identifiable going into the bank, in order to facilitate linkage back to clinical data. Is this permissible if there was no research consent obtained from the patients?

Response.Because the excess clinical specimens are identifiable, this is human subjects research and consent would be required, unless the IRB determines that the conditions for a waiver of consent have been met.

The criteria for waiver of consent under 45 CFR 46.116(d) include that the research involves no more than minimal risk; the waiver would not adversely affect the rights and welfare of subjects; the research could not practicably be carried out without the waiver; and whenever appropriate, the subjects will be provided with pertinent information after participation.

Points to consider in applying these criteria include mechanisms for the governance and oversight of the bank; protections in place to maintain privacy and confidentiality (e.g. coding, limited/controlled access, honest broker mechanisms, de-identification processes, limited data use agreements); policies regarding access to specimens; the nature of the research for which the specimens may be used; the ability to locate or contact subjects; risk of introducing bias into the collection; potential anxiety or confusion for subjects; the number of subjects; the length of time since specimens were first collected; and the likelihood that subjects would object to the research use of their specimens.

DISCUSSION

Waivers. Dr. Menikoff noted that OHRP considers the creation of a repository to be research in itself and believes that consent is needed whenever a person's name is attached to a sample. He was concerned that the FAQ response implies that a waiver would be appropriate, while he thought it would be appropriate only in rare cases. Dr. Strauss said most SACHRP members would agree, and a more thorough discussion of the principle involved was needed to show when it would be reasonable to waive consent.

An ex officio commented that a great deal of research is conducted using medical records and is almost uniformly done by means of a waiver of informed consent. Dr. Menikoff said that getting consent should be the default option. Dr. Strauss agreed, but argued for language such as "in ordinary circumstances." He said considerations related to human subject protection should be highlighted.

Speaking as ex officio for OCR, Ms. Heide commented that like OHRP, OCR considers the movement of information into a tissue bank to be a research activity. Its criteria for a waiver of authorization under the HIPAA Privacy Rule are similar to those for informed consent under the Common Rule.

Data vs. tissue. Dr. Bierer asked if Dr. Strauss felt differently about how the case would be handled for data and tissue. He saw data as different because of the use of new technologies. Dr. Ross added that unlike data, tissues or blood samples cannot be completely deidentified, and she can't think of an example in which consent should be waived. She found it difficult to conceive of a medical center that is not using a broad consent process. Mr. Forster, however, pointed out that if tissues are 30 years old, it is easier to make the argument that consent is "impracticable."

Mirror systems. Dr. Menikoff commented that Vanderbilt University is creating a mirror version of its biological specimens without identifiers. NIH does the same thing. He said that OHRP's rules do allow a mirror system without identifiers. The assumption is that use of tissues with identifiers would require consent unless the waiver criteria are met.

Dr. Bierer said she understood that the Vanderbilt system does not allow the patient to be recontacted under any circumstances. Instead, it retains a constant but nonaccessible one-way code. She explained that the Partners HealthCare uses a repository of data that can be queried in a deidentified manner; no cell is small enough to allow identification of the individual. Dr. Cates observed, however, that the example speaks of a repository that will be the only home for the samples in question. She added that it is not always possible to completely deidentify biological tissues.

Summary of concerns. Mr. Nelson asked for very specific guidance if a rewrite is expected. He added that SAS realizes that this is not an IRB meeting and has faith in the system; therefore, there is a line to walk between being too general to be helpful and overprescribing specific solutions. Dr. Strauss suggested beginning with a broader summary statement highlighting the regulatory principles to be elaborated. Dr. Bierer saw the primary issue to be addressed as the need to make clear that there are boundaries around what is and is not an acceptable approach.

ACTION

Following discussion, FAQ 11 was tabled. SAS was again asked to return with a FAQ that reflected members' comments.

Public Comment

There was no public comment.

Wrap Up Discussion and Adjourn

Barbara Bierer, M.D., Chair

Dr. Bierer informed attendees that future directions for the Subpart A Subcommittee (SAS) will be discussed Wednesday. She asked SACHRP members to consider their recommendations and particularly encouraged ex officios to make suggestions. She thanked all participants for their commitment.

 

WEDNESDAY, MARCH 10

Opening Remarks

Barbara Bierer, M.D., Chair

The Chair welcomed everyone back, reopening the 22nd meeting of SACHRP.

Report of Subpart A Subcommittee (SAS), Continued

Dan Nelson, M.S., CIP; Elizabeth A. Bankert, M.A, SAS, Co-Chairs

Frequently Asked Questions (FAQs) and Responses (Continued)

Co-Chairs continued their presentation of FAQs related to biospecimens.

FAQ #12

A research participant agrees to allow extra blood to be stored for future research purposes. Blood samples will be stored with identifiers, but released for subsequent uses in a coded manner. The participant later changes his/her mind.

Is this allowed, once tissue has been stored?

Response.Yes. Subjects have the right to withdraw from research, and this extends to withdrawing their specimens from future research. Subjects should be informed upfront about the procedures for withdrawing specimens from a repository. Requests should be made in writing. For many repositories, it may not be feasible to retrieve specimens that have already been distributed to investigators. Analyses already completed will generally not be destroyed or removed from datasets. These practical limitations to withdrawal should be disclosed to subjects as part of the consent process.

NOTE á PENDING OHRP GUIDANCE ON WITHDRAWAL

HIPAA Issues.With respect to HIPAA authorizations, the HIPAA Privacy Rule provides an individual with the right to revoke an authorization in writing, except to the extent the covered entity has already acted in reliance on the authorization. For example, a covered entity is not required to retrieve information that it disclosed under a valid authorization before receiving the revocation. Thus, if a covered entity obtained an individual's authorization to disclose identifiable health information to a repository, then the covered entity is not required to seek the return of the information. Further, for research conducted by a covered entity, the reliance exception would permit the continued use or disclosure of PHI by the covered entity already obtained pursuant to the authorization to the extent necessary to protect the integrity of the research.

DISCUSSION

HIPAA Requirements. Mr. Coleman commented that if future projects use coded samples, they could not be considered research with human subjects. However, he wondered if HIPAA addressed this differently. Ms. Heide for OCR said the following with respect to a revocation of authorization under HIPAA for identifiable information: the first step is to determine whether the research is being done by the covered entity. If the covered entity discloses protected health information to a researcher, the covered entity is not required to get the information back from the researcher. If the researcher is the covered entity, then the researcher can only continue to use the information to the extent needed to protect the integrity of the research. She added that HIPAA requires that the request to revoke authorization be made in writing (although two SACHRP members found this problematic in view of privacy concerns).

Rationale for Withdrawal. Dr. Strauss proposed a more specific clarification that subjects have the right to withdraw consent. Mr. Nelson thought the second sentence might be serving as a distraction from the key issue and suggested it be dropped.

Dr. Bledsoe suggested clarifying in the question that the specimens are stored in a repository, since this fact is mentioned in the answer.

Dr. Menikoff said OHRP is still evaluating its position and would like to be in harmony with FDA on the point in question.

ACTION

FAQ #12 was approved with the following revisions:

FAQ #12

A research participant agrees to allow extra blood to be stored for future research purposes. Blood samples will be stored in a repository with identifiers. but released for subsequent uses in a coded manner. The participant later changes his/her mind.

Response.Yes. Subjects have the right to withdraw from research, and this extends to withdrawing their specimens from future research. Subjects should be informed upfront about the procedures for withdrawing specimens from a repository. Requests should be made in writing.The obligation to honor subjects' requests to withdraw does not extend to retrieving specimens already distributed to secondary users. Analyses already completed will generally not be destroyed or removed from datasets. These practical limitations to withdrawal should be disclosed to subjects as part of the consent process.

FAQ #13

A research subject agrees to allow extra blood to be stored with identifiers for future research purposes. The individual later changes his/her mind and requests that the specimen be destroyed. The lead investigator who manages the repository proposes to the IRB that, rather than losing valuable specimens, all identifiers and coding be permanently removed, so that it would be impossible for anyone ever to link to this subject's identity; doing so would mean that any subsequent uses are not human subjects research, per OHRP guidance.

Is this an acceptable approach?

Response.While it is true that permanently stripping a specimen of all identifiers or codes would mean that subsequent uses are not considered to be human subjects research, doing this after the fact would generally not be viewed as acceptable, if done solely to avoid withdrawing specimens on request. If the specimen is identifiable at the time of the request, failing to follow through when it is possible to do so would violate the ethical principle of respect for persons, and possibly the terms of original consent. (See also FAQ #3.)

DISCUSSION

A SACHRP member asked to clarify the meaning of "after the fact" and thought that the response should be much stronger than "would generally not be viewed as acceptable." Mr. Nelson explained that "after the fact" is intended to mean "after the request comes in."

Mr. Coleman asked whether the sample could be deidentified before the request came in. SACHRP members thought most IRBs would not see a problem with this. The difficulty lies in taking this action to evade a specific request. A member noted that there is rarely if ever a request to strip all identifiers from samples, so it does not come up as an issue; going back to subjects to seek permission for a higher degree of protection does not make sense. Once the samples are deidentified, Ms. Bankert observed, the subject does not have the right to withdraw.

Dr. Bledsoe stressed the importance of encouraging repositories to think about these issues up front, establish policies to deal with withdrawal issues, and include any limitations on the subject's right to withdraw in the informed consent process and form. She suggested adding more information about what the subject was told regarding withdrawal. Dr. Lux felt, however, that a FAQ is not the optimum way to define standards for nforming subjects of the limitations to their ability to withdraw their specimens and data.

Dr. Leiden suggested telling a subject it would be permissible to withdraw up to a point, but that at some point identifiers might be stripped and that would be impossible. The subject might need more information about what this means and why it would be done.

Mr. Coleman asked whether the answer implies that in order to strip identifiers, either the IRB must waive consent or the action must be consistent with the consent. Mr. Nelson suggested that an additional FAQ might be needed to deal with this; the current one addresses a specific request and action.

Mr. Forster proposed revising the first sentence of the response to read as follows: "While it is true that permanently stripping a specimen of all identifiers or codes would mean that subsequent uses are not considered to be human subjects research, and an IRB may determine that this is acceptable under some circumstances, doing this to avoid withdrawing specimens on request is not acceptable." However, members decided to retain the original language, but with more definite direction on acceptability.

ACTION:

FAQ #13 was approved unanimously with the following revised response.

Response.While it is true that permanently stripping a specimen of all identifiers or codes would mean that subsequent uses are not considered to be human subjects research, doing this after the fact would not be acceptable, if done solely to avoid withdrawing specimens on request.If the specimen is identifiable at the time of the request, failing to follow through when it is possible to do so would violate the ethical principle of respect for persons, and possibly the terms of original consent .

FAQ #14

An investigator collected specimens from a large number of cancer patients and stored them with identifiers. Some of the patient-subjects are now deceased.

Is research using the specimens of those subjects who died still considered to be human subjects research, and under the oversight of an IRB?

Response.No. 45 CFR 46.102 defines a human subject as a "living individual."

However, deceased individuals would still have protections under the HIPAA Privacy Rule.

HIPAA Issues.The Privacy Rule generally protects the Protected Health Information of decedents in the same manner as that of living individuals. However, in the research context, the Privacy Rule allows the use or disclosure of decedent information without the authorization of a personal representative and without waiver of authorization by an IRB or Privacy Board if the covered entity receives representations from the researcher that the decedents' protected health information is necessary for the research and is being sought solely for research on the information of decedents and, upon request of the covered entity, receives documentation of the deaths of the individuals.

DISCUSSION

Members agreed with the substance of the recommendation, but suggested a clarification of the wording of the HIPAA response. Although the language is regulatory, members felt it would not be clear to the ordinary reader.

ACTION

FAQ #14 was approved unanimously with the following revision in the last line of the response regarding HIPAA issues:

However, in the research context, the Privacy Rule allows the use or disclosure of decedent information without the authorization of a personal representative and without waiver of authorization by an IRB or Privacy Board if the covered entity receives representations from the researcher that the decedents' protected health information is necessary for the research and is being sought solely for research on the information of decedents (and not related living individuals) and, upon request of the covered entity, receives documentation of the deaths of the individuals.

FAQ #15

An investigator who collected and stored thousands of identifiable specimens from a number of studies accepts an offer at another institution, and plans to move the specimens to the new institution.

What are the issues that the IRB and/or institution should consider when faced with this situation?

Response.Institutional polices would generally govern. The transfer of specimens to the new institution may be appropriate, provided the consent under which the specimens were collected is compatible with such a transfer. In addition to this determination (which might typically involve the IRB), institutional policies regarding intellectual property will need to be considered. Formal agreements should be established that govern the transfer of specimens from the institution that provides the specimens to the investigator. These agreements may take the form of Material Transfer Agreements (MTAs) or other similar legally binding agreements, appropriately tailored for the transfer and use of human biological specimens and signed by the appropriate parties (e.g., authorized representatives of the provider and recipient). These agreements should specify as appropriate the rights and obligations of both the provider and the recipient, including intellectual property terms and publication rights, as well as the rights of subjects (e.g., right to withdraw identifiable specimens).

HIPAA Issues.If the institution is a HIPAA covered entity, then the institution also needs to consider whether the transfer of information from it to another entity was encompassed in the original HIPAA authorization or waiver of authorization, or if another HIPAA permission applies.

DISCUSSION

Mr. Nelson observed that this FAQ enters the field of institutional obligations and is not strictly focused on human subjects protection. He said the intent was to educate investigators that in such a situation, the IRB is not the only decisionmaker. IRBs themselves may not realize that theirs is not the only voice to consider. Dr. Trachtenberg agreed that the FAQ would be educational for researchers: "You can't just take your freezer with you, you need to discuss it." Dr. Bledsoe added that the FAQ gets to the issue of "custodianship" and underlines the importance of making sure agreements are in place when samples are transferred.

Contractual relationships. Dr. Joffe asked whether continuing review encompassed the contractual relationship among investigator, institution, and research subject. If one of the contracting parties decides to transfer the party's obligations, what is the legal framework for doing so? Dr. Menikoff said that there are limits on the subject's right to approve such a transfer. Mr. Coleman suggested the contractual issue would turn on whether or not the particular repository was material to the agreement. If it were clear the individual was donating only to a particular institution and that was the heart of the bargain, they would presumably not have the authority to transfer the specimen. Dr. Ross observed that the subject often is not told whether the sample is donated to the researcher or to the institution.

Need to address issue. One SACHRP member said the FAQ should be dropped because it essentially points to a societal dispute on which institutions, courts, and others are "all over the map." Dr. Bierer and Mr. Nelson, however, felt the situation in question is a common one on which it is not helpful to be silent.

Narrow the FAQ. Members felt it would be helpful to narrow the example. One SACHRP member suggested a panel that would include a variety of perspectives and expertise on issues like this, including that of an intellectual property lawyer. A member noted that current guidance is "outdated." Suggestions included:

  • Consider paring it down to keep it within the OHRP spectrum as much as possible. What does the consent form say? What was the subject's understanding?
  • Note the importance of an institutional agreement that confers the rights and responsibilities of the original institution to the receiving institution.
  • Consider reframing the question to focus on what the investigator and the IRB should do.

ACTION

FAQ #15 was tabled, and SAS was asked to return with a new version taking SACHRP members' comments into account.

FAQ #16

A clinical trial is funded by an industry sponsor, and the contract provides for specimens to be transferred to the sponsor.

What factors should be considered in such an arrangement?

Response.Material Transfer Agreements (MTAs) or other similar legally binding agreements should be in place that describe the rights and obligations of the providing researcher and institution and the industry sponsor. These should include stipulations that the specimens will be used only for research purposes that are compatible with the informed consent.

DISCUSSION

Members emphasized that the critical element is the emphasis on consent. It might matter to the subject that the samples would go to a pharmaceutical company. Dr. Bierer observed that the element of consent adds a wrinkle not present in FAQ 16. A member suggested clarifying that "the use of the specimens will be compatible with the terms of the consent form and the approved protocol." Another member said the exposition of the situation should state clearly, in the first sentence, that the consent form describes the plan to transfer specimens to the company or sponsor.

Dr. Joffe asked whether there were HIPAA issues. Ms. Heide from OCR responded that a covered entity is permitted to disclose PHI to the sponsor of the clinical trial, provided that the disclosure is encompassed within the authorization. A member asked that the HIPAA implications be spelled out.

Dr. Strauss said the issue would remain the same whether the transfer is to the sponsor or to any other institution. Clarifying language was added to make sure this intent was clear.

ACTION

FAQ #16 was unanimously approved with the following changes:

A clinical trial is funded by an industry sponsor or other entity and the contract provides for specimens to be transferred to the sponsor or other entity.

What factors should be considered in such an arrangement?

Response.The consent form should describe the plan to transfer specimens to the company or sponsor. Material Transfer Agreements (MTAs) or other similar legally binding agreements should be in place that describe the rights and obligations of the providing researcher and institution and the industry sponsor. These should include stipulations that the use of the specimens will be compatible with the terms of the consent form and the approved protocol.

FAQ #17

The protocol for a clinical trial stipulates that all samples should be destroyed after the study is completed. The consent form is silent on the disposition of samples after the study.

What should be done if there are 10,000 identifiable specimens and new science becomes available?

Response.The investigator could amend the protocol, describing the circumstances and seeking IRB approval to retain the specimens for additional research. The IRB should consider if this additional research is compatible with the original terms under which samples were obtained.

DISCUSSION

There was no discussion.

ACTION

FAQ #17 was approved unanimously.

FAQ #18

A tissue biopsy was obtained for clinical diagnostic purposes, which have now been satisfied. The hospital pathology department is willing to provide a portion of the remaining biopsy specimen to an investigator, who will perform research assays with no clinical relevance. If the specimen is coded and identifying information is removed so that the identity of the patient cannot be readily ascertained by the investigator before it is provided to them is the investigator conducting human subjects research under the purview of an IRB?

NOTE á REINFORCES EXISTING OHRP GUIDANCE

Response.No, this is not research involving human subjects, because the recipient investigator will not be able to readily ascertain the identity of patients from whom specimens were obtained.

DISCUSSION

Additional issues. Dr. Strauss wondered if it matters whether multiple samples are involved - for example, if the investigator asks that all leftovers will be coded and given to him in the future. Dr. Cates also wondered if the scenario in question might lead to a policy of always getting more of the sample than is needed. Mr. Nelson asked SACHRP to take the scenario at face value and assume that a single specimen is at issue.

Coded vs. deidentified. A member asked for a clarification of the meaning of "coded," which Mr. Nelson indicated is unchanged from the definition OHRP provided in its 2004 guidance. It means that the investigator has no link to individual identity.

An attendee pointed out that the term "deidentified" is specific to HIPAA. Members agreed to clarify that the sample will be "deidentified for the purpose of HIPAA."

Prospective vs. retrospective. Two attendees raised the question of whether or not it matters if the arrangement is made prospectively or retrospectively. Dr. Menikoff said this would make no difference as long as there is no current human subject with whom an interaction is taking place. Ethically, he said, it would be possible to assert that our society has determined through public processes that deidentified samples can be used for anyone's benefit.

ACTION

FAQ #18 was approved with the following changes to the final sentence.

If the specimen is coded and identifying information is removed so that the identity of the patient cannot be readily ascertained by the investigator before it is provided to them (so that it is deidentified for the purposes of HIPAA),is the investigator conducting human subjects research under the purview of an IRB?

FAQ #19

A tissue biopsy was obtained for clinical diagnostic purposes, which have now been satisfied. The hospital pathology department is willing to provide a portion of the remaining biopsy specimen to an investigator, who will perform research assays. If the specimen will be identifiable to the researcher, is this considered to be human subjects research under the purview of an IRB?

Response.Yes. If subjects will continue to be identifiable to investigators (e.g., they retain a record number that would allow matching to the identity of the subject), the research is non-exempt human subjects research that is potentially eligible for expedited review.

DISCUSSION

Members wanted to make it absolutely clear that this "is human subjects research" and that the investigator has received information that would allow the subjects to be identified. They agreed the example should be written to "close the door on exemption."

ACTION

This FAQ was approved unanimously with the changes below.

FAQ #19

A tissue biopsy was obtained for clinical diagnostic purposes, which have now been satisfied. The hospital pathology department is willing tosenda portion of the remaining biopsy specimen to an investigator, who will perform research assays.If the specimen will be provided to the researcher in an identifable manner, is this considered to be human subjects research under the purview of an IRB?

Response.Yes,this is human subjects research. Because investigators will receive a specimen with identifiable information, the research is non-exempt human subjects research that is nevertheless potentially eligible for expedited review.

FAQ #20

Blood samples were obtained for research purposes with informed consent of the subjects, and the original study has been completed. The samples remain under the control of the original investigator. Another investigator wants to use a portion of the remaining samples to perform research unrelated to the original study. If the samples are coded and identifying information is removed so that the identity of the subject cannot be readily ascertained by the secondary investigator before they are provided to him/her, is the secondary research considered to be human subjects research under the purview of an IRB?

Response.No, the secondary use is not considered to be research involving human subjects, so long as the original investigator is solely providing specimens. There should be an agreement in place that prohibits the linkage code to be shared with the current investigator.

However, if the specimens remain identifiable under the HIPAA Privacy Rule (see FAQ #2), a permission for use (e.g., HIPAA authorization, waiver of authorization by an IRB or Privacy Board, or use of a limited data set with a data use agreement) would still be required.

DISCUSSION

Members discussed whether this FAQ should go after or before FAQ 3, which is closely related. Mr. Nelson commented that there is no specific limitation in FAQ 20; we know only that the research is unrelated to the original research.

Dr. Menikoff noted that it would still be an issue what the consent says. Dr. Bierer clarified her understanding that the intention is that in this case the samples remain under control of the original investigator, and the original consent form was silent on future use. Mr. Nelson noted that FAQ 7 already addresses a case in which the consent form is silent, and he wondered whether the twist of handing the samples on to another investigator was too fine a point to be worth a separate FAQ. Members agreed and decided to delete the FAQ.

ACTION

SACHRP agreed to delete this FAQ because of its similarity to FAQ 7.

FAQ #21

This FAQ has been deleted, but the number is maintained to avoid confusion.

FAQ #22

This FAQ has been deleted, but the number is maintained to avoid confusion.

FAQ #23

Many hospitals have a sentence on the standard admission form to the effect that "This is a teaching and research institution, and any specimens remaining after your care is complete may be used for teaching or research purposes." Is this sufficient to allow identifiable specimens to be used for research purposes, without any additional consent or waiver?

Response.No. If the information provided to prospective subjects is limited to the above statement, with no opportunity to engage in a consent dialogue or to give active consent, this would not be sufficient to meet the requirements of informed consent for research under 45 CFR 46. However, the IRB should review each protocol that proposes to use such specimens and, as part of that review, consider whether the criteria for a waiver of informed consent have been met at 45 CFR 46.116(d).

HIPAA Issues.This approach (single sentence on the hospital admission form) would also not be sufficient for HIPAA authorization purposes.

DISCUSSION

A member pointed out that engaging in a consent process and giving consent should be joined by "and" rather than being presented as either/or.

A member stressed the need to clarify that consent or a waiver of the elements of consent would be required. It should also be clear that the information provided to the subject is limited to the statement cited in the scenario.

ACTION

FAQ #23 was approved unanimously with the following changes to the response.

Response.No, an additional consent or waiver is required.If the information provided to prospective subjects is limited to the above statement, with no opportunity to engage in a consent dialogue and to give active consent,this would not be sufficient to meet the requirements of informed consent for research under 45 CFR 46. However, the IRB should review each protocol that proposes to use such specimens and, as part of that review, consider whether the criteria for a waiver of informed consent have been met at 45 CFR 46.116(d).

FAQ #24

Many hospitals have a sentence on the standard admission form to the effect that "This is a teaching and research institution, and any specimens remaining after your care is complete may be used for teaching or research purposes." Is this sufficient to allow identifiable specimens to be placed into a tissue bank, if they are coded and released to researchers through an honest broker mechanism?

Response.The plan to remove identifiers from the specimens and manage them through a bank might be factors the IRB considers when assessing the risks to subjects, but it doesn't change the fundamental answer above (FAQ #23). The creation of a bank containing identifiable specimens would be considered human subjects research and thus, subject to IRB review and informed consent. As above, the statement on the admission form would not be considered sufficient to meet the requirements of informed consent under 45 CFR 46. However, the IRB could consider whether the criteria for waiving informed consent have been met at 45 CFR 46.116(d). The research use of specimens would not be considered human subjects research if the conditions of the OHRP guidance on coded private information or biological specimens have been met.

DISCUSSION

A member thought the key points were expressed more succinctly in FAQ 23. Mr. Nelson pointed out that this one contains an additional wrinkle: "If we put it in a bank with an honest broker, is that enough?"

Members agreed on clarifying language.

ACTION

FAQ #24 was approved unanimously with the following change to the last two lines of the response.

Response #24

However, the IRB could consider whether the criteria for waivingor alteringinformed consent have been met at 45 CFR 46.116(d). Thesubsequentresearch use of specimens would not be considered human subjects research if the conditions of the OHRP guidance on coded private information or biological specimens have been met.

FAQ #25

This FAQ is on hold pending an upcoming NIH workshop on incidental findings and/or return of results.

Specimens vs. Data

Dr. Menikoff invited SACHRP's comments on whether there should be a distinction between specimens and data in terms of subjects' right to withdraw. Responses included:

Mr. Forster suggested that data and specimens should be treated the same way, since distinction will lead to confusion.

Dr. Bierer observed that while consistency would be ideal, many investigators batch the samples and work in a way that is markedly different from the way data are handled. Not including samples batched for analysis done up to the point at which a subject asks to withdraw may bias results dramatically.

FDA and OHRP have provided differing guidance on this point.

Dr. Joffe felt the spirit of the consent process is violated if the subject cannot withdraw on request. However, he also saw the need to protect the integrity of "downstream" analysis.

Dr. Bledsoe stressed that a critical issue is the need to clarify in the consent form what "withdrawal" means and explain any limitations. Dr. Ross agreed, adding that it is the rare participant who wishes to withdraw. Dr. Bierer differed.

Frequently Asked Questions (FAQs) and Responses (Continued)

FAQ #26

A 13-year-old child is enrolled by his/her parents in a tissue banking protocol that involves storage of specimens for future research. Is the child's assent required at the time of the original enrollment in the repository, in addition to parental permission?

Response. Yes. As with any research involving children, the IRB should determine whether children are capable of providing assent, taking into account the ages, maturity and psychological state of the subjects [45 CFR 46.408(a) and 46.116]. Given that most projects that store tissues for future unspecified research are not likely to hold out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, it is anticipated that active assent on the part of the child would generally be required.

DISCUSSION

When assent can't be given. A SACHRP member asked if the answer should clarify that assent should be "considered" rather than being required. Mr. Nelson said the intended answer was "yes," but assent could be waived because of specific circumstances. He said there is an ongoing debate about whether assent is required under Subpart D in the same way consent is required under Subpart A.

Dr. Joffe observed that the response implies a 13-year-old would be capable of giving assent. Mr. Nelson said the age was chosen because at that age, assent would ordinarily be assumed to be possible.

Age of majority. A member asked what would happen when the child reaches the age of majority. Mr. Nelson said this is addressed in FAQ 27.

Uncertainty. A member asked whether there was uncertainty on this point, since the answer seems obvious. Mr. Nelson said all the examples came up because there was uncertainty and therefore a need for guidance.

ACTION

FAQ #26 was approved unanimously with the following changes to the response.

Response.Yes, if the IRB determines that the children are capable of providing assent,taking into account the ages, maturity and psychological state of the subjects [45 CFR 46.408(a) and 46.116]. Given that most projects that store tissues for future unspecified research are not likely to hold out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, it is anticipated thataffirmative agreementon the part of the child would generally be required.

FAQ #27

A child is enrolled by his/her parents in a tissue banking protocol that involves storage of specimens for future research. Should there be a process in place for the child to give consent for continued storage and use of specimens when he/she turns 18?

Response.In and of itself, storage of specimens is not considered to be research involving human subjects. However, ongoing use of such specimens (e.g., continued analysis of specimens or data for which the subject's identity is readily identifiable to the investigator(s), or ongoing collection of identifiable information, is human subjects research. In these cases, it would be necessary for the investigator(s) to seek and obtain the legally effective informed consent of the now-adult subjects.

The IRB may consider, if appropriate, a waiver under 45 CFR 46.116(d) of the requirements for obtaining informed consent in order for the subjects to continue their participation in the research. Factors that may make it impracticable to conduct the research, and therefore would support a waiver, include the number of subjects, length of time since first enrolled, and ability to locate subjects (see also FAQ #5).

HIPAA Issues.A valid HIPAA authorization signed by a parent, as the personal representative of a minor child at the time the authorization is signed, remains valid until it expires or is revoked, even if such time extends beyond the child's age of majority. However, if the authorization expires on the date the minor reaches the age of majority, a new authorization (or other HIPAA permission) would be required at that time for continued use or disclosure of protected health information.

DISCUSSION

Mr. Nelson clarified that the scenario draws on existing OHRP guidance that simply storing samples is not research involving human subjects. Another member noted that collection, storage, and analysis of samples are all distinct processes.

Dr. Joffe observed that implementation is very difficult; every few days, someone may become 18. He wondered if the consideration could be done once a year for people who will become 18 in the year to come or have become 18 in the year passed. He suggested that the issue be revisited as part of continuing review.

Mr. Nelson agreed that implementation is hard, but there is an understanding that consent must be affirmed at the age of majority if the research is ongoing.

ACTION

FAQ #27 was approved unanimously with the following changes to the response:

In and of itself, the retention of specimens in a biobank is not considered to be research involving human subjects.However, ongoing use of such specimens (e.g., continued analysis of specimens or data for which the subject's identity is readily identifiable to the investigator(s)), or ongoing collection of identifiable information, is human subjects research. In these cases, it would be necessary for the investigator(s) to seek and obtain the legally effective informed consent of the now-adult subjects.

The IRB may consider, if appropriate,a waiver under 45 CFR 46.116(d) of the requirements for obtaining informed consent in order for the subjects to continue their participation in the research.Such a waiver may be considered at the time of initial review or during a subsequent amendment.Factors that may make it impracticable to conduct the research, and therefore would support a waiver, include the number of subjects, length of time since first enrolled, and ability to locate subjects (see also FAQ #5).

FAQ #28

What issues should be addressed in the consent process with regard to sponsorship, ownership, control, access, commercialization and possession of stored specimens?

Response.Consent documents for such projects should disclose sponsorship and address issues including (but not limited to) disposition of samples, who will have access, how samples will be used, and the potential for commercialization, if any. Subjects should be informed to what extent, if any, they can expect to control or receive compensation from future commercial uses.

Some of these matters are subject to state laws, and consent documents should reflect that.

As with any part of the consent form, care should be taken to communicate these complicated issues in simple terms understandable to the subject.

DISCUSSION

Dr. Cates wondered whether the issues encompassed in the FAQ are so complicated that it will not be helpful. A SACHRP member noted that each of the elements listed could be addressed in detail. Mr. Nelson said that while the FAQ did not focus on human subject protection, it did address important issues that should be addressed in the consent process. Another member felt that the minimum direction it provides on these complex issues would still be helpful in pointing to things to consider.

ACTION

FAQ #28 was approved unanimously without changes.

Dr. Bierer stressed the need to be sure, as final versions of FAQs are prepared, that the term "is compatible with" is used consistently as agreed. It is also important to be sure the reasoning behind the effort is clear and that principles used to address common problems are presented. She added that the FAQs are not meant to replace other important work, such as the effort to clarify issues related to standards of disclosure. She thanked subcommittee members and Co-Chairs for a "remarkable contribution" and a "significant piece of work."

Future of SAS

Insufficient time was available to discuss this agenda item. The Chair asked SACHRP members to contact Julia Gorey, Executive Director for SACHRP, if they have input on SAS's future agenda.

Introduction of Subcommittee on Harmonization

David Forster, J.D.; Mark Barnes, J.D.

The Chair said she was delighted to announce that the subcommittee on harmonization, established following a discussion of priorities in which both SACHRP members and ex officios participated, is now empaneled. The recommendation to establish the Subcommittee on Harmonization (SOH) was made and approved at the July 22, 2009 SACHRP meeting.

Mr. Forster reviewed the subcommittee's charter, which is as follows:

The Subcommittee will identify and prioritize areas in which regulations and/or guidelines for human subjects research adopted by various agencies or offices within HHS would benefit from harmonization, consistency, clarity, simplification and/or coordination.

The Subcommittee will then develop recommendations, for consideration and possible adoption by SACHRP, to harmonize and simplify these guidelines and regulations. The goal of this subcommittee effort is to reduce unnecessary burdens on research efforts, thus resulting in better allocation of research resources and promoting the safety and welfare of human subjects.

Co-Chairs said the subcommittee has an opportunity to bring to HHS's attention various areas that cause difficulty for regulated community and make some constructive suggestions. They said the regulated community currently puts a great deal of effort into coming up with administrative approaches to dealing with differing requirements.

The subcommittee's nine members have a broad base of experience working with HHS, FDA, and OCR regulations. The perspectives of investigators, the social behavioral community, the Association for the Accreditation of Human Research Protection Programs (AAHRPP, the accrediting body for IRBs) , and stakeholders in a variety of IRB/institutional settings will be represented. No research subjects or representatives of advocacy groups have been included, however, due to the limitations on subcommittee size.

Co-Chairs said the subcommittee will begin by addressing the "low-hanging fruit" - issues that can be resolved without new rulemaking - within the purview of three HHS agencies: OHRP, FDA, and OCR.

The range of harmonization issues to be addressed include:

  1. Direct conflict between regulations. These are limited in number and difficult to resolve because of the time and effort required to change regulations (especially the Common Rule, to which numerous agencies are signatories who would be affected by any changes). Examples include differing definitions of "human subject" and exemption categories for FDA and HHS.
  2. Direct conflict between guidance documents. These are also limited in number and easier to change than regulations. Agencies have taken many steps to address conflicts, but some do remain. An example is whether or not subjects can waive all future commercialization rights stemming from the use of their biospecimens in research. The differences in the definitions of a clinical investigation (FDA) and research (OHRP), the exemption categories, and waiver of consent are well known. Another (one on which agencies have been working for a number of years) is the need for written vs. oral translations when enrolling subjects who do not speak English. Both of these are areas of conflict between HHS and FDA.
  3. One agency has guidance, but the other agency (or agencies) is silent. This is a more difficult area. Continuing review, an area in which FDA is silent, is an example. On occasion, FDA inspectors have been known to say that OHRP guidance on this subject does not apply to FDA. An issue on which OHRP is the silent party is whether or not it is appropriate to identify a study as IRB-approved. Resulting uncertainty in such areas can cause concern and unnecessary expenditure of resources.
  4. Guidance documents don't conflict, but don't correspond either. Issues related to closing Federally and non-Federally funded studies are an example. Another example is the variety of OHRP, FDA, and OCR positions and guidance on screening medical records prior to consent for recruitment purposes..
  5. HHS positions not aligned with state laws, legal trends, or regulations of agencies outside of HHS. Such issues are currently outside the scope of SOH's activities.

Co-Chairs invited SACHRP members to comment on other issues and problems related to harmonization they would like to see SOH address.

DISCUSSION

Scope of harmonization. Members and ex officios raised a number of issues regarding the scope of the subcommittee's deliberations, Co-Chairs clarified that the subcommittee will address the concerns not only of industries, but also academic medical centers, community hospitals, and other kinds of regulated entities that have IRBs and are subject to regulations regarding human research protection. CAPT. Budashewitz, an ex officio representing NIH, had several suggestions. He urged the subcommittee to do the following:

  • Look broadly and globally, considering what research will look like in the 21st century geographically and in terms of scientific technology. He noted that other countries such as China will increasingly be partners in multi-site studies. NIH is involved in addressing international harmonization issues.
  • Consider both the U.S. Department of Veterans Affairs (VA) and the Department of Defense in addition to HHS. He noted that VA has exhibited leadership in the area of central IRBs and in other harmonization efforts. (Dr. Cates, representing VA, expressed support for the subcommittee and assured members she planned to "attend and speak up.")
  • In addition to inconsistencies in regulations, the subcommittee consider how best to facilitate timely coordination among HHS agencies when regulations are released.
  • Engage in a principles-based discussion that considers the concept of "equivalence" among agencies with different regulations.

Mr. Barnes asked if it was a definite decision not to examine issues related to VA and the Department of Defense and not to consider international issues such as the European Clinical Trials Directive. The Chair said that while there is enthusiasm for a broad scope of activity among SACHRP members and ex officos, there is concern this might make the task unmanageable. She also noted that SACHRP's specific charter is to advise the Secretary of HHS. A SACHRP member observed, however, that there are inconsistencies in how HHS issues address research from abroad that might be addressed.

Mr. Forster doubted there would be time to delve into issues stemming from differences in State laws (for example, definitions of Legally Authorized Representative).

Dr. Trachtenberg, ex officio representative for the Indian Health Service, also suggested issues for subcommittee consideration:

  • Consider legislation such as the Controlled Substance Act that has implications for human subject protection, such as special confidentiality requirements for persons with substance abuse problems.
  • Consider how Federal agencies and IRBs interact with the Indian Nations as well as States. For example, in the Navajo Nation, exempt human subject research is not exempt but must e reviewed by the IRB.

Dr. Lux, ex officio representative for the Environmental Protection Agency, noted that EPA frequently collaborates with HHS agencies and that there are some Centers funded jointly by the two agencies. Therefore, harmonization issues frequently arise.

Dr. Goldkind, ex officio representative for the FDA, said FDA has participated actively in harmonization initiatives and is looking forward to participating in this group. Carolyn Hommel will be the agency's representative to the subcommittee.

Other HHS issues. A number of those present commented on harmonization issues within HHS:

  • Dr. Strauss noted that FDA and HHS take different stands on thresholds for disclosing financial conflicts of interest.
  • Dr. Bledsoe highlighted issues in the development of the national health information infrastructure regarding policies on privacy, security, and consent. There is a need to be sure these policies are consistent with the current understanding of regulations.
  • Dr. Bierer hoped for the kind of analysis that will change the field, as NIH's seminal work on harmonization regarding Adverse Events will do.

Mr. Barnes noted that different agencies within HHS have different motivations; FDA's mission, for example, is not to protect human subjects, but to guard against data manipulation for personal gain. CAPT. Budashewitz noted, however, that all agencies within HHS share a concern for human health and welfare. He hoped that harmonization could help agencies rededicate their systems so that all can carry out their mandates more efficiently in fiscally restrained times.

Ms. Heide, ex officio representative for the Office for Civil Rights (OCR), observed that differences sometimes exist for important reasons because of the differing scopes and purposes of the regulations and thus, may not be able to be harmonized. In such cases, the focus may be on educating the regulated communities on the reasons for such differences and how to comply.

New models and approaches. Bierer hoped that the subcommittee would bring creativity to its consideration of possible changes that would reduce the regulatory burden. She noted, however, that SACHRP does not expect the subcommittee to parse each word to come up with "the fix" for the issues it discussed. CAPT. Budashewiz wondered, "If we had a single human protection entity, what would a single approach look like?"

Next steps. Mr. Barnes said the subcommittee will try to identify and rank the most significant issues, then consider - where possible - suggested approaches to harmonization. The subcommittee's first meeting will focus on the methodology it will use to address its mission.

Requesting input. Dr. Bierer asked about the possibility of requesting input from organizations such as PRIMR and AAMC. Ms. Odwazny said such a request could be placed in the Federal Register on behalf of SACHRP.

Publicizing deliberations. An American Society of Clinical Oncology (ASCO) representative asked whether the deliberations of the subcommittee would be made public. The Chair responded that subcommittee meetings are not public, but SACHRP meetings are public, and no work from subcommittee goes forward without a recorded vote by SACHRP. She invited ASCO to actively participate and comment on the work emerging from the subcommittee at these meetings.

Public Comment

No comments were offered.

Wrap Up Discussion and Adjourn

Barbara Bierer, M.D., Chair

The Chair thanked everyone for their efforts and looked forward to the next meeting of SACHRP, July 22-23, 2010.

 

Secretary's Advisory Committee on Human Research Protections
March 9 and 10, 2010
Washington, D.C.

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.

 

 _____________________________________________________________________________
Barbara Bierer, M.D., Chair           Date


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