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October 27-28, 2008 Meeting Minutes

Secretary’s Advisory Committee on Human Research Protections

 

October 27 and 28, 2008

Arlington, VA

 

Minutes

MONDAY, OCTOBER 27

Welcome and Opening Remarks
Barbara Bierer, M.D., Chair

Dr. Bierer welcomed everyone to the 17th meeting of the Secretary’s Advisory Committee on Human Research Protections (SACHRP). She noted that two members have completed their terms of service: Neal R. Powe, M.D., M.P.H., M.B.A., and James Powell, M.D., CPI. She thanked them for their service. Gary Gibbons, M.D.; Stephen Sodeke, Ph.D., M.A.; and Suzanne Pattee, J.D., were welcomed as new members. Alan Trachtenberg, M.D., M.P.H., was welcomed as the ex officio representative for the Indian Health Service (IHS). Dr. Bierer informed those present that SACHRP has been rechartered through October 1, 2010.

The Chair noted that the 8th letter from SACHRP to the Secretary was sent in September but has not yet been accepted by the Secretary.

Two members will be rotating off the committee in one year. The Federal Register will contain a notice to this effect, probably in late November of 2008. Recommendations for new members are welcome, although Dr. Botkin and Dr. Genel, who will be leaving, are of course “irreplaceable.”

Dr. Bierer thanked Dr. Pritchard for his many contributions, including his tutelage on how to perform her function. She expressed appreciation for his style and leadership, which she said has benefitted the entire research community. During his term as Acting Director of OHRP, the agency has proved a colleague to the research community and helped to answer many complex and difficult questions.

Minutes for the previous meeting (July 15 and 16, 2008) were approved unanimously.

Report of Issues/Remarks
Ivor Pritchard, Ph.D., Senior Advisor to the Director, OHRP

Dr. Pritchard told members there has been progress in reimbursing them and encouraged all to submit invoices.

The new permanent director of OHRP has been named. Jerry Menikoff, M.D., J.D., began his official duties yesterday. Dr. Pritchard also announced that two valued OHRP staff members, Lindy Lahl, Education and Development Division, and Paul Andreason, Compliance Oversight Division, have accepted other positions. OHRP will work on replacing them as soon as possible. He welcomed new staff member Cecilia Chironos, who will be working with Executive Director Julie Gorey to support the work of SACHRP.

Last week, OHRP published the final version of a guidance document on the meaning of “engagement” in research: http://www.hhs.gov/ohrp/policy/engage08.html.  Dr. Pritchard also reported that the comment period for the Request for Information (RFI) on whether or not to create a new regulation or guidance related to education has closed, and comments received are being analyzed. Dr. Pritchard observed that of the commenters who expressed a preference on the issue, 53 were in favor of a regulation and 31 were opposed. However, counting only the opinions of those submitting comments on behalf of an organization, the majority flips: only seven organizations were on record as supporting an education requirement through regulation, and eighteen organizations preferred guidance.

OHRP is currently preparing another RFI on whether or not external institutional review boards (IRBs) should be held responsible for any compliance problems that occur in regard to responsibilities that they have accepted through agreements. It hopes to publish the RFI in the near future.

Remarks of Assistant Secretary of Health and Swearing in of New Members
Don Wright, M.D., M.P.H., Principal Deputy Assistant Secretary for Health

Dr. Wright stressed the importance of SACHRP to the Department of Health and Human Services (HHS) and expressed his appreciation for SACHRP members’ service. After commending their qualifications, he introduced and swore in each of the three new SACHRP members. He pledged to do his best to help provide consistent leadership through the transition to the new administration.

 SACHRP Recommendations and Federal Process
Julie Kaneshiro, OHRP, and Chris Mahler, OGC

 

Remarks by Julie Kaneshiro: Status of SACHRP Recommendations to Date

Delivering a presentation originally prepared by Michael A. Carome, M.D., Julie Kaneshiro explained the process for reviewing recommendations approved by SACHRP. OHRP prepares a letter to the Secretary of HHS for signature by the SACHRP Chair; this letter is transmitted through the Assistant Secretary for Health (ASH). The Secretary acknowledges receipt of the recommendation and refers it to the appropriate agency or office for consideration. That agency or office then has the option of adopting the recommendations, adopting them with modifications, or deferring actions. Typically, recommendations call on OHRP to develop new guidance, modify an existing regulation, or convene a meeting to foster discussion of a key issue.

Ms. Kanishiro presented a report on the status of SACHRP recommendations to date. An overview of actions taken to date is presented in Table 1 below. Those for which no specific actions have been taken to date are either “under consideration” or have been considered and will not be acted upon. Please see the PowerPoint presentation posted on this Web site for the details of this status report: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/carome.html

Table 1. Actions Taken on SACHRP Recommendations

Subject Area (Number)

Specific Actions Taken to Date

Research involving children and subpart D of 45 CFR part 46 (38)

  • Most of recommendations regarding § 46.407 were implemented via OHRP’s May 26, 2005 guidance on the 407 review process and OHRP’s and FDA’s implementation of a joint review process for research regulated by both agencies.
  • FDA issued guidance on its process under 21 CFR 50.54.
  • Algorithm for analysis under subpart D (part of recommendation I) still under consideration by OHRP.

Accreditation of human research protection programs (HRPPs) (5)

 

Adverse event reporting (1)

  • The Federal Adverse Events Taskforce was formed in 2004.
  • OHRP issued draft guidance on unanticipated problems and adverse events for public comment in October 2005 and final guidance in January 2007.
  • FDA convened a Part 15 Hearing in March 2005. FDA issued draft guidance on adverse events for public comment in April 2007. The final guidance is in agency clearance.

Research involving pregnant women and subpart B of 45 CFR part 46 (1)

 

HIPAA Privacy Rule (9)

  • The recommendations have been forwarded to the Office for Civil Rights and remain under consideration by that office.

Research involving prisoners and subpart C of 45 CFR part 46 (9)

  • The recommendation that a prisoner representative should be one of the reviewers when research involving prisoners is reviewed by an IRB under an expedited review procedure has been incorporated into OHRP guidance (see FAQs

Review of the human subjects protection system (1)

 

Subpart A of 45 CFR part 46 (79)

  • FDA has developed draft guidance on IRB continuing review, and it is in agency clearance.
  • OHRP published a Federal Register notice proposing revision of category 7 as recommended by SACHRP, proposing a clarifying revision to category 5, and seeking comment on the entire list. The public comment period is closed and comments are under review.
  • OHRP published a Federal Register notice seeking information and comment regarding whether additional guidance or regulation is needed regarding training and education of individuals who conduct or oversee human subjects research. The public comment period is closed and comments are under review.

Tribal authority over research involving American Indian or Alaska Native populations (1)

 

OHRP/NIH/FDA to convene workshop on central IRB review mechanisms (1)

  • Such a workshop was held in November 2005, and a subsequent follow-up national conference was held in November 2006; both explored alternative IRB review models. Reports of both events have been provided to the Subpart A Subcommittee and posted on OHRP’s website.
  • OHRP is preparing a Federal Register notice requesting information and comment on whether OHRP should hold external IRBs directly accountable.
  • FDA issued guidance on the use of a centralized IRB review process for multicenter clinical trials in March 2006.

Research in disaster settings (2)

 

 

DISCUSSION

Questions and comments from SACHRP members included:

  • What does “under consideration by OHRP” mean exactly? It may mean an initial step was taken to address the recommendation, such as issuing an RFI or forming an internal workgroup, but it may also mean simply that the recommendation is “in the queue.”

  • Would it be helpful for SACHRP to suggest priorities? Yes, inviting SACHRP’s input is one of the purposes of this presentation. Related discussion points included:

    • In regard to accreditation, other organizations are addressing the issue, and it does not seem the highest priority for OHRP.

    • Recommendations regarding the Health Insurance Portability and Accountability Act (HIPAA) may be out of date and in need of reframing. Also, it is difficult to predict how the change of administration may affect priorities.

    • SACHRP members are welcome to respond to the RFI regarding central and other alternative IRB review mechanisms, either as individuals or as a committee.

Dr. Pritchard also commented that OHRP is engaged in discussions with the National Cancer Institute (NCI) and the Food and Drug Administration (FDA) regarding the implications of amendments to large, ongoing clinical trials, including those that communicate new information about risks. This is a situation in which centralized review operations may be relevant.

Dr. Pritchard added that some recommendations, from OHRP’s perspective, simply reaffirm the interpretation the agency believes it is following. In such cases, OHRP would welcome SACHRP’s suggestions for communicating its interpretation of the regulations more clearly to the public. Further, he noted that some recommendations require much more time and effort than others; given its limited resources, this is among the factors OHRP considers in prioritization.

  • In regard to the HIPAA recommendation, which went to the Office of Civil Rights (OCR) for review and possible action, is there a feedback mechanism for the committee to get perspective from OCR? OHRP does communicate with OCR, and SACHRP has had an opportunity to ask Dr. Wright and others about progress. This particular set of recommendations may call for regulatory changes that would take longer than a change in interpretation expressed through guidance. OCR has been grappling with these issues.

  • The Subpart A Subcommittee (SAS) saw some of its recommendations, particularly those related to continuing review, as providing relief to the research oversight community. What is OHRP’s thinking about these recommendations? OHRP has reviewed the recommendations but has not yet convened a formal review group to begin active consideration. OHRP does know these recommendations are important and plans to address them.

Remarks by Chris Mahler: An Overview of Federal Agency Rulemaking

Mr. Mahler provided a review of the Federal rulemaking process. He explained that the Administrative Procedure Act (APA) established the basic framework for rulemaking. (See http://usgovinfo.about.com/library/bills/blapa.htm.) APA allows both formal rulemaking and informal rulemaking, and the Common Rule is in the latter category (also known as “notice-and-comment” rulemaking). The basic procedure for rulemaking allows the public to participate by submitting written comments on a proposed rule. Steps in the process include:

  1. The agency publishes a Notice of Proposed Rulemaking (“NPRM”) in the Federal Register.
  2. The public has an opportunity to submit written comments.
  3. The final rule is published not less than 30 days before its effective date.

The agency is required to “consider substantially” the comments made during the public process; courts have invalidated rules in instances when they concluded this was not the case.

Many specific policy and legal questions must be answered before the NPRM is ready for public comment. The NPRM and the proposed final rule are reviewed through a clearance process within HHS and submitted to the Office of Management and Budget (OMB), which allows other agencies that will be affected by the new rule to comment. Unlike guidance, final rules have the force and effect of law. Typically, he said, it takes at least a year to produce a final rule after publishing an NPRM.

Please see the PowerPoint presentation posted on this Web site for more specific information covered in the presentation: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/mahler.html

DISCUSSION

Questions and comments from SACHRP members included:

  • It is frustrating that the Common Rule is not really a living document. Are there any processes for making changes that do not require every Common Rule agency to sign off on them? Mr. Mahler responded that every amendment does have to go through the various agencies. One option to remedy the problem would be to create legislation that directly addresses this issue, but it is difficult to conceive of a more expedient way to promulgate a change rapidly that must be considered by so many agencies. Dr. Pritchard added that it also takes time to allow for give and take within the different agencies within HHS, each of which has its own perspective.

  • Is it correct that Part 46 Subpart A was promulgated as a Common Rule but Subparts B, C, and D were not? That is correct.

  • How does the Department of HHS establish a regulatory agenda or priorities? Does this occur yearly or at the change of administration? How does priority setting occur with a new administration? Intended regulations are published annually in the Federal Register. Often, guidance documents are published there as well. I cannot comment on policy setting.

  • What is meant by “agency”? The term can refer to entities within HHS as well as external ones. OHRP routinely asks other internal entities and external agencies for input about how proposed changes would affect them.

  • If there is an apparent conflict between Federal regulations, which rule “trumps” which under what circumstances? The determination involves looking at the subject of the regulation and the pre-existing statutory authority for the agencies involved. Terms defined by statute may trump later efforts to create a conflicting definition.

 

SACHRP Recommendations and OHRP Process
Irene Stith-Coleman, OHRP; Ivor Pritchard, Senior Advisor to the Director, OHRP

 

Remarks by Irene Stith-Coleman: Guidance and Policymaking within OHRP 

Irene Stith-Coleman presented a review of guidance and the policy-making process within OHRP. This included a discussion of the role of the Interdivisional Policy Coordinating Committee (IPCC), which contains representatives from each Division and component within OHRP, as well as a representative of the Office of General Counsel. The committee selects, reviews, revises, and approves guidance, supplementing its members’ expertise as needed with people particularly familiar with topics under consideration. Topics are selected taking into account SACHRP’s recommendations, as well as questions submitted on the OHRP Web site.

Proposed guidance is then reviewed by each of the three Divisions, and finally by the Director, who will direct “vetting” through other agencies as appropriate. Public comments are often sought on the proposed guidance by means of a notice in the Federal Register. When this is done, OHRP also announces the draft document’s availability to subscribers on its List Serv and posts it on its Web page.

Final guidance is posted by topic at the following location: http://www.hhs.gov/ohrp/policy/index.html OHRP also addresses Frequently Asked Questions (FAQ): http://www.hhs.gov/ohrp/policy/faq/index.html

Please see the PowerPoint presentation posted on this Web site for more specific information covered in the presentation: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/stithcoleman.html

DISCUSSION

Questions and comments from SACHRP members included:

  • What is the process for identifying and developing Frequently Asked Questions (FAQs)? FAQs are explanations that do not require a change in current interpretation, but address some apparent confusion in the field. FAQs do circulate to other Common Rule agencies before they are issued.

  • How would you characterize SACHRP’s influence on the end product? Isn’t it possible that final guidance could result that is inconsistent with the original recommendation? It is helpful to have OHRP at the table as SACHRP’s recommendations evolve, because apparent solutions are not always as simple as they seem.

    Dr. Pritchard emphasized that SACHRP is an advisory committee. Early in its history, some members had the misimpression that recommendations had to be implemented exactly as suggested, but this is not the case. If OHRP can persuade the Secretary of a different point of view, the outcome can go in a different direction. He added that OHRP is wary, based on experience, of issuing guidance that may create more trouble than it solves.

  • How do you get feedback from the human research protection community on issues of importance? The public gives advice through correspondence, conferences, and educational meetings, as well as through SACHRP. Also, when OHRP members attend meetings, they pay attention to what issues seem to draw large crowds.

Remarks by Ivor Pritchard: OHRP Staffing, Budget, and Activities

Dr. Pritchard presented a discussion of OHRP staffing, budget, and activities. This included an overview of the roles and resources of different Divisions within the Office. He noted that many staff members have duties in more than one Division, so he has counted them as staff for the one in which they spend the most time.

The Education and Development Division sponsors Regional conferences, Quality Assurance Meetings for representatives of institutions in a given location, and other presentations. It also manages the OHRP mailbox and responds to many requests for information. This group currently consists of a Director and six staff members.

The Policy and Assurance Division keeps track of institutional assurances and IRB registration. Currently, there are over 10,000 assurances and over 6,000 registered IRBs, and the Division monitors the data base. In addition, the group has the primary responsibility for activities related to policy and guidance, including §407 research applications. This group currently consists of a Director and nine staff members, with one vacancy.

The Compliance Oversight Division is responsible for site visits, opening new cases, and restricting or suspending assurances when needed. Dr. Pritchard noted that assurances are suspended only when problems are widespread and endemic; the majority of instances of noncompliance are handled by asking the institution to develop a corrective action plan to address the problem area. Members also give presentations at meetings. Currently, the Division has one Director and five staff members.

SACHRP is supported by Executive Director Julie Gorey, with Administrative Support from Cecilia Chirinos (introduced earlier at the meeting).

The Office of the Director is responsible for budget and management oversight, an international program, Co-Chairing the Interagency Human Subjects Research Subcommittee, and numerous meeting presentations. It consists of the Director and six staff members.

In addition, one staff member of the Office of the General Counsel and two from the Office of Public Health and Science Administrative Resource Center work closely with OHRP.

Dr. Pritchard presented the following table, showing how the OHRP Budget has fared over the last several fiscal years.

The OHRP Budget FY 2001 — FY 2009

Fiscal Year

S & B

Overhead

Program

Total

FY 2001

4,100,000

800,000

900,000

5,800,000

FY 2003

4,672,103

1,382,800

1,450,097

7,505,000

FY 2004

4,085,252

1,372,000

1,817,495

7,274,748

FY 2005

4,424,546

1,450,000

1,466,990

7,341,536

FY 2006

4,164,874

1,360,000

1,388,688

6,913,560

FY 2007

4,431,000

1,372,500

1,035,500

6,839,000

FY 2008

4,245,700

1,289,200

1,128,100

6,663,000

FY 2009

4,686,000

1,390,000

625,000

6,701,000

Dr. Prichard observed that the amount available for OHRP programs is lower than in previous years. While there is little flexibility in other aspects of the budget, the program budget does give OHRP the ability to conduct activities it determines are needed. Examples of program expenditures include the budget for SACHRP, funds paid to the National Institutes of Health (NIH) for information technology support for IRB registration and assurances, travel, education, compliance site visits, and expenses such as travel and equipment.

Please see the PowerPoint presentation posted on this Web site for more specific information covered in the presentation: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/ivorpritchard.html

DISCUSSION

Dr. Bierer found the presentation “sobering.” Questions and comments from SACHRP members included:

  • Why is the program budget essentially cut in half? Much of it is due to the increase in funding needed for staff and benefits.

  • What has led to the decline in the budget for this agency? Over the last 3-4 years, many offices similar to OHRP generally share the fate of the overall HHS budget.

  • It seems as if certain things fall into the program budget that should be overhead (for example, the funding for IT support from NIH). Dr. Pritchard explained that the distinction between program expenses and overhead is “admittedly arbitrary.”

  • To what extent does technology help in cutting program expenses? Online training can reduce costs. The education group is working on CDs and videos that may be able to replace in-person presentations. Electronic registration and the electronic database for assurances have also been helpful. OHRP does still accept Federal Wide Assurance (FWA) applications in paper format, but about 70 percent of applicants now submit electronically.

  • Subcommittee discussions repeatedly emphasize the fact that IRBs need education from OHRP. Is it possible to increase the number of staff in the Education Division, perhaps reducing those in the Policy and Assurances Division? Dr. Stith-Coleman explained that about 600 submissions per month are handled by the three people who process documents. Electronic submission has helped in reducing the number of them needed, but those three are busy people.

  • Why the sharp drop in oversight activities? It is not safe to attribute the drop to any single factor. It could be partly due to the regulated community doing a better job. Another factor is that more institutions are “unchecking the box,” which means OHRP is not authorized to investigate some potential compliance problems.

  • How many institutions are unchecking the box? Roughly one-third apply regulations only to HHS-supported or conducted research, one-third apply only Subpart A across the board, and the remaining third apply all Subparts regardless of funding source. Dr. Pritchard added that there are no good data on trends over time because of the way the database is structured. Further, it is difficult to interpret the data because they include, for example, a major institution like Columbia University and a two-person small business.

  • What would prompt a not-for-cause site visit? Ms. Borror responded that these visits are “somewhat discretionary,” but often involve an institution with a previous compliance history. Sometimes there are lingering concerns after a case is closed, and the closing letter to the institution may say that it should expect a site visit within the next two years.

  • To what extent is guidance legally binding? Are there different levels of guidance? All guidance is equal from a legal perspective. However, guidance may use prescriptive language or show alternative ways to comply with a requirement. OHRP tries to make a clear distinction between “must” and “should,” though this is, unfortunately, not always apparent to the regulated community. Mr. Mahler observed that the Department looks to the Good Guidance Practices Bulletin, published by the Office of Management and Budget (OMB), for standards that apply throughout the Federal government when guidance is issued. To view the OMB document, see http://www.whitehouse.gov/omb/memoranda/fy2007/m07-07.pdf

SACHRP considered how best to respond to the invitation to assist OHRP by suggesting priorities among the committee’s recommendations. Dr. Bierer suggested empowering an ad hoc committee to review recommendations and suggest priorities at SACHRP’s March meeting. The committee would be informed by input from current subcommittee chairs.

Discussion points raised by members included:

  • Dr. Botkin was concerned that SACHRP not inadvertently undermine the work of colleagues no longer with SACHRP (for example, members of the Subpart D subcommittee). Consultation with them will be important in the prioritization process.
  • Dr. Botkin also wanted to understand OHRP’s view of priorities. He suggested that it might work best if OHRP prioritized the recommendations and SACHRP commented on the agency’s view.
  • OHRP staff can collaborate with and provide information to an ad hoc committee for this purpose, but could not serve as official members.
  • Dr. Strauss suggested stressing the need for action on existing recommendations to the Secretary. He also proposed discussing the issue with the new OHRP Director.

Dr. Bierer invited ex officio members to comment on issues related to harmonization. Comments included the following:

  • Representing FDA, Dr. Less emphasized that guidance from OHRP and FDA necessarily differ somewhat because their regulations are different. One difference is that FDA’s guidance must focus on the clinical investigator and sponsor. The agency does work closely with OHRP and try to make the guidance issued conceptually similar.
  • Representing NIH, Dr. Budashewitz observed that SACHRP is asking for more than the routine harmonization that occurs whenever either FDA or OHRP issues guidance. He suggested that SACHRP consider the process by which a greater harmonization could occur. This might involve several operating divisions coming together to develop a road map to accomplish this.

Report of Subpart A Subcommittee (SAS)
Elizabeth A. Bankert, M.A., and Daniel Nelson, M.S., CIP, SAS Co-Chairs

Mr. Nelson reviewed the subcommittee’s charge and membership. He said its goals were to:

  • Enhance protection of human subjects,
  • Reduce regulatory burdens that do not contribute to the protection of human subjects, and
  • Promote scientifically and ethically valid research.

To date, the subcommittee has had nine teleconferences and ten in-person meetings, supplemented by working group calls and e-mails.

Mr. Nelson reviewed the recommendations submitted by SAS to the full committee that have been finalized and sent to the Secretary. (For this information, see the PowerPoint in the “meeting presentations” section.)

Designation of IRBs in Assurances

The Co-Chair presented background supporting a recommendation developed by SAS’s working group on institutional responsibilities that focuses on the designation of IRBs within assurances. He quoted the regulations as follows:

Assurances… shall at a minimum include:
(1) A statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects…
(2) Designation of one or more IRBs established in accordance with the requirements of this policy, and for which provisions are made for meeting space and sufficient staff to support the IRB's review and recordkeeping duties.
(3) A list of IRB members identified by name; earned degrees; representative capacity; indications of experience such as board certifications, licenses, etc., sufficient to describe each member's chief anticipated contributions...
(4) Written procedures which the IRB will follow (i) for conducting its initial and continuing review of research and for reporting its findings and actions…
(5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the department or agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance…(45 CFR 46.103).

Mr. Nelson noted that items 3-5 above are not part of the body of the physical assurance document itself, although the regulations say they must be “included” in the assurance. He observed that the research environment has evolved considerably since the regulations were promulgated, and now uses a multitude of cooperative review arrangements. As a result, institutions that have worked together, even on a single project, remain listed on the assurance. Many collaborative institutions have hundreds of IRBs listed on their assurance. Unfortunately, though they are easily added, the process of removing them is slow.

He suggested that these lists could more easily be maintained separate from the body of the assurance, just as the list of IRB members and required written procedures are maintained separately although they are also required to be “included.” SAS’s proposed recommendation is as follows. 

Recommendation on designating individual IRBs within the assurance document.OHRP should determine if individual IRBs must be listed within the assurance document per se, or if the designation of IRBs could be accomplished more generically or indirectly (e.g., commitment by the institution to rely only on registered IRBs).

If the regulations as currently written do not allow this approach, OHRP in conjunction with other Common Rule departments and agencies should issue a Notice of Proposed Rulemaking to amend section 46 for [OHRP, other agencies].103 of the Common Rule by eliminating the requirement for institutions to designate individual IRBs under their assurances of compliance.

 

DISCUSSION

Rationale for current approach. Dr. Pritchard commented that OHRP has not yet found a way to list IRBs separately from the assurance. Ms. Kaneshiro added that OHRP believes that the regulatory language quoted in the presentation does tie the list to the assurance itself.

Mr. Nelson asked why OHRP has found that items 3-5 in 45 CFR 46.103 can be in compliance without being included in the body of the assurance. Ms. Kaneshiro said this point has been recognized within OHRP and it may need to be addressed.

Mr. Forster asked how useful it is to OHRP to have the list of IRBs tied physically to the assurance. Dr. Pritchard responded that if OHRP receives a report of a regulatory problem, it would want to know what institution was responsible for reviewing and approving the protocol. However, not having the list on hand would not necessarily be a significant problem, because in the course of an investigation it would send a letter to the institution requesting the name of the reviewing IRB, among other information. He could not come up with an instance in which OHRP would need to know the listed IRBs and would not have an alternative means of getting this information. However, he was concerned that a change in interpretation would cause confusion by implying that some parts of the regulation should be taken literally, but others could be interpreted more loosely.

Advantages and disadvantages. Dr. Strauss wondered whether the current situation created such a regulatory burden that a recommendation was needed to address it and asked whether there were not other ways of proceeding. Mr. Nelson rejoined that maintaining the current system requires considerable staff effort within the regulated community (a Full Time Equivalent [FTE] for some institutions). Clearly, significant manpower is used to maintain this interpretation of the requirement that could be reallocated to other tasks. Mr. Forster agreed that maintaining the current system requires extra resources.

Dr. Botkin asked whether there might not be an advantage to maintaining the list on the assurance, in that it requires greater attention to agreements between institutions than might otherwise be the case and encourages helpful dialogue. Mr. Nelson said that in practice, the designation does not attract higher-level institutional attention. Dr. Bierer suggested that it might, in fact, have the reverse effect. Mr. Nelson agreed; noting that nothing in the process of maintaining the list specifically mandates dialogue about the agreement between institutions on any review.

Notification of FWA changes. Dr. Bierer observed that while SAS has expressed concern about the notifications OHRP sends to all listed institutions every time an FWA is changed, it is important that an institution be notified when one of its IRBs has been listed by another institution. Ms. Kaneshiro added that there are also some changes in status at the institutional level that would be of concern to IRBs (for example, the decision to apply the Common Rule across the board to all research). Dr. Leiden proposed that an institution that wants to list another institution’s IRB should have to request its permission.

Next steps. Dr. Genel commented that there is apparently no regular accounting regarding which of the IRBs listed on an institution’s FWA are still relevant. Therefore, he observed that the recommendations before the committee do not speak to the issue.

A SACHRP member wondered whether the proposed Request for Information (RFI) might incorporate some of the elements that have been discussed. Ms. Kaneshiro responded that the RFI related to agreements between institutions, as currently drafted, would probably not shed any light on this issue. However, OHRP has heard the committee’s concern and will consider it further. To do this, it does not need a formal recommendation from SACHRP. Dr. Strauss strongly encouraged OHRP to take the opportunity to address this issue in the forthcoming RFI.

Dr. Botkin asked whether the subcommittee may be bringing forward other recommendations regarding assurances. Mr. Nelson responded that one member recently questioned whether there was a need to link IRBs to assurances at all, but the subcommittee has not had a chance to consider this “out of the box” suggestion.

ACTION

SACHRP decided to table the recommendation for the present.

Update: Work in Progress on Informed Consent

Ms. Bankert reported on the progress of SAS in addressing issues related to informed consent. Her presentation began by reminding listeners of how the issue fits within the regulatory structure, then presented SAS’s ideas on how the current situation can be improved. She acknowledged the major contribution of SAS member Gary Chadwick in shaping the subcommittee’s perspective.

She noted that while the basic and additional elements of consent have remained unchanged in the human subject protection regulations, the level of detail provided in consent forms has “skyrocketed” in the past few years. This issue has negatively affected the trust between IRBs and investigators, respect for regulatory compliance, and the benefits of the consent process for subjects. Clinical investigators report that consent forms are of such length and complexity that they only serve to overwhelm subjects, who are reduced to asking, “where do I sign?” Many IRBs have the impression that consent forms must be extremely detailed and have contributed to the problem.

Regulatory requirements regarding consent are found in 45 CFR 46.116 and 117. In regard to §46.116, Ms. Bankert pointed out:

  • This regulation lists the “elements” of information that are required (and additional elements as appropriate) in the process;
  • IRBs may waive any or all of these elements of consent information; and
  • There is no reference to a “form” in this section of the regulations.

In regard to §46.117, SAS stressed that while the regulation requires “documentation” via “a written consent form approved by the IRB and signed by the subject,” two choices of written forms are permissible:

  • “A written consent document that embodies the elements of informed consent required by §46.116” (117[b][1]), or
  • “A short form … stating that the elements of informed consent required by §46.116 have been presented orally” (117[b][2]).

Because §46.117 (and FDA 50.27) requires documents to “embody” the elements of information given in 46.116 (50.25), the presumption is that the form must contain every piece of information and in the same detail as required in the consent process. However, SAS believes that this presumption is open to debate. If the word “embodies” in §46.117 (and 50.27, FDA) can be understood to mean “information in general” versus “information in detail,” then consent forms can be designed to summarize the key points that are included in the consent process and can become the aid to the subject’s informed consent decision that Belmont envisioned. The use of addenda and alternate formats can support the provision of information in the consent process and the consent form. SAS called on OHRP and FDA to take the lead and actively endorse and support the use of shortened consent forms.

This change would place the primary responsibility for fulfilling the requirements of §116 on investigators. IRBs would be able to shift their attention to the process of informed consent and whether or not it is improving the subject’s ability to make an informed and voluntary decision. Institutions would have to develop processes to ensure the adequacy of the consent process. The major benefit of the change would be to subjects, who will still have access to the same information, but presented in a more subject-appropriate and less burdensome way.

For more detailed information on this presentation, see the PowerPoint in the “meeting presentations” section.

The Co-Chair brought forward the following “emerging” recommendation for discussion: 

Recommendation on level of detail required in written informed consent forms.OHRP should clarify that the written consent form used for documentation of signature does not need to contain the same level of detail as information provided through the consent process, as a whole.

OHRP should involve FDA, as appropriate, when developing this clarification.

DISCUSSION

Research. Dr. Marshall stressed that an increasingly large body of research affirms the value of shorter forms and an educational process to increase subjects’ understanding. What is needed is a “dynamic” conversation around consent.

Challenges. While some investigators are proposing shortened forms now and some IRBs are approving them, Dr. Marshall pointed to two specific challenges. One is that IRBs feel constrained to protect their institution and everyone involved in the research. Another is that many investigators feel they have to follow the “rules” about creating these complex, tedious forms. In fact, the rules “give us leeway we don’t necessarily use.” She stressed the need for education on the importance of using the flexibility that is available and keeping the focus on the goal of increasing the subject’s understanding.

Dr. Botkin observed that while flexibility may exist in the regulations, investigators and institutions feel they are better protected from liability by lengthy documentation. He stressed the need for simplification, not just shortening the form, and added that a simplified process is only likely to happen when OHRP says, “you need to have language that people can actually understand.” Dr. Bierer agreed that corporate sponsors might have difficulty with the proposed changes because of their need to mitigate risk to themselves by means of the longer form.

Mr. Forster liked SAS’s ideas, but added that FDA inspectors need to get “on board” as well. He also stressed the importance of working closely with the Association for the Accreditation of Human Research Protection Programs (AAHRPP); currently, accreditation reviews tend to increase, not reduce, the length of consent forms.

Costs and benefits. Dr. Genel said a cost-benefit analysis is needed in regard to proposed changes. Dr. Marshall agreed, but said that money should not become a way of “getting us off the hook.” She believes improvements can be made that do not cost a great deal.

Potential for abuse. Dr. Botkin was concerned about the potential for abuse of a new system that emphasizes process over documentation. Without oversight, he feared people could “cut corners.” Dr. Marshall agreed, noting that there would have to be a way to document the process.

The central obligation. Dr. Strauss emphasized the central obligation to have effective informed consent, regardless of what type of forms are used. It is challenging to achieve what is actually needed: “an empirically driven informed consent process that is tailored to the needs of the subject.” His institution uses cover pages that guide the subject through the informed consent process, but it is difficult to craft a summary that captures the key elements the subject should consider.

Potential improvements. Co-Chairs presented the subcommittee’s initial thinking on both consent forms and the consent process, noting that to improve the quality of consent, the document and the process must both be addressed. Subjects covered in regard to consent documentation included the possible “repackaging” of the consent form, ways to shorten the consent form, the benefits of using executive summaries or cover pages to highlight relevant information, and use of addenda to address items such as HIPAA requirements.

In regard to process improvements, SAS is exploring the use of tools to increase subject understanding of the research and its risks, as well as increased investigator education related to the consent process. Tools are needed to

  • orient the potential subject to research elements prior to the consent process,
  • ascertain comprehension after process but prior to enrollment,
  • determine if subject remains aware of key elements of research throughout the research project,
  • evaluate the quality of the subject’s study experience, and
  • inform the subject of follow-up issues during an exit interview.

Ms. Bankert added that some institutions offer a one-page “pre-consent” checklist to help potential subjects frame their thoughts.


Examples of Executive Summaries Presented by SAS

Example 1

This research study is a comparison of

a) standard therapy, vs.
b) standard therapy plus experimental drug A.

Some subjects will get standard therapy and some will get standard therapy plus the experimental drug A. You receive one of these therapies every three weeks.

You will also have CT scans and other tests, similar to what you would have if you weren’t in this research study.

Your doctor will discuss the risks associated with the standard chemotherapy. The additional risks of the experimental drug A (if you get that drug) include a higher chance of infection, and impotence.

Instead of being in this research you may chose to receive standard therapy.

Example 2

This is a study in which your tissue (blood, leftover surgical specimen, etc.) is stored for future research. If you agree, a teaspoon of extra blood will be drawn, and leftover tissue will be stored frozen.

The sample will have a code number, which can be linked to your name and other medical information. Though we don’t have a plan for using your tissue or blood right now, sometime in the future a researcher may want to use your tissue or blood. The IRB will review this research project, and may ask the researcher to contact you again to ask if this use is OK.

A risk of being in this research is that someone could find out your name or medical information. If you don’t want us to save your blood or tissue you don’t have to. You can also ask us to discard your blood or tissue at anytime in the future.


SAS also proposed the use of educational tools that suggest questions subjects should be prepared to ask, such as:

  • What is the purpose of the research?
  • What are the risks of the research?
  • What are the possible benefits of the research?
  • How is this research different than the care or treatment I would get if I wasn't in the research study?
  • Does everyone on this research get the same treatment?
  • Will being in the research cost me anything extra?
  • Can I stop being in the research once I've started?
  • Who will look at my records?
  • Who do I call if I have questions about being a research subject?

The Co-Chair suggested that the exit interview with the subject provides an opportunity to review the main components of the research, discuss appropriate follow-up care or other issues particular to the subject, and indicate how study results will be shared with the subject. The exit interview also provides an opportunity for using a post-study evaluative tool.

The Co-Chair added that institutions and IRBs will want some assurance that the reduction of a current lengthy consent to shorter version will satisfy OHRP, FDA and accreditation standards. Examples of actual protocols with initial and revised consent forms would be helpful to IRB community.

Next steps for SAS might include pursuing the improvement of the consent document and the process, which could involve a significant amount of time and resources. (Ms. Bankert noted that many others are working on this issue as well.) Another possible direction would be shaping a potential demonstration project on the subject. The subcommittee’s intention, she said, was to obtain feedback from SACHRP on next steps, especially given the many other initiatives that are trying to address the problem.

Update from AAMC. Dr. Tartakovsky provided an update on a related project by the American Association of Medical Colleges (AAMC), which has gathered together stakeholders with similar concerns. Its goal is to develop shorter, simplified consent documents that will increase the subject’s comprehension but still comply with regulatory requirements.

The working group has decided to concentrate its efforts on relatively complicated types of consent documents. It understands that OHRP is interested in reviewing the proposed simplified forms and the protocols for which they are designed. The work group has just received some protocols to work with, but would like to identify some additional protocols for which long consent forms have been prepared. Samples used will be de-identified. The next stage will be a pilot project to assess the difference in the level of comprehension when long and simplified consent forms are used.

Ms. Bankert observed that two members of SAS are on the AAMC workgroup, which will help ensure they are not duplicating each other’s efforts if SAS moves forward in this area. Dr. Tartakovsky noted that a consent form committee was formed as part of the Clinical and Translational Science Awards program (CTSA), but it does not seem to be making rapid progress at present.

DISCUSSION

Dr. Bierer stated that one of the most important that SACHRP could do is to address this issue. It is a critical issue and the fact that multiple groups are also working on this problem may help get traction on how to handle a difficult situation. It is not an area in which one group will find the Only Answer.

Potential for shortcuts. Ms. Pattee said she liked the ideas presented, but was concerned about the possibility for abuse of the consent process. She envisioned that shortcuts might be taken and real protections lost “that the current form, as lengthy awkward as it is, does provide.” She added that many tools to assist in the consent process are already available and do not need to be reinvented. Dr. Gibbons was also intrigued by the ideas presented but concerned about the potential for “shortcuts” that could adversely affect the consent process for vulnerable populations.

Monitoring. Dr. Gibbons asked how the type of process envisioned could be monitored. Ms. Bankert responded that SAS is not currently advocating for a particular approach. What is appropriate would vary depending on the nature of the study and its subjects. She was aware of at least one institution that currently requires consent monitoring for high risk studies.

Resource implications. Primarily, Ms. Bankert said, what SAS would like to help accomplish is to shift attention from documentation to the best way to protect human subjects. Mr. Forster added, however, that the field has gravitated toward forms and away from process in part because it is less expensive to rely on a form. What is needed is a “real conversation.” He was concerned, though, that the ideas being explored would require increased resources and might be perceived as an “unfunded regulatory mandate.”

The meaning of “embody.” Dr. Strauss suggested exploring whether or not the word “embody” (§ 117) could be understood to mean information in general rather than in detail, which would open up the exploration of alternate formats. Mr. Forster observed that the word “embody” is not used in reference to the short form, and FDA has stated that the same “quantum of information” must be contained in the short form as in the long form. Ms. Pattee invited Dr. Less to comment on behalf of FDA. Dr. Less said the short form would not be useful if it had all the same information, but she would have to doublecheck the regulatory language and FDA guidance.

Next steps. Dr. Botkin suggested that SACHRP needs to think not in aspirational terms but in terms of the “floor.” What does “language understandable to the subject” actually require?

Dr. Strauss thought it was valuable for SAS to look at the issues involved, though it was not yet clear to him how SACHRP and OHRP could best facilitate thinking on the topic. He reminded SACHRP that the committee has already approved a recommendation presented by SIIIDR that reads this language as requiring some level of assessment of the subject’s understanding (see minutes of March 27-28).

Dr. Genel wondered whether further input from experts would be helpful to SACHRP, including a status report on CTSA. Dr. Sodeke stressed the importance of involving end users. He said his institution asks investigators to involve participants in the production of the consent process. Dr. Marshall reminded members that a strong body of literature exists to inform next steps.

Summarizing possible next steps for SAS, Dr. Bierer suggested that SAS do the following:

  • Consider (perhaps) how a potential demonstration project might be framed;
  • Determine what “buckets” we should be thinking about as components of the form;
  • Determine how legal, regulatory, and personal issues will be addressed, as well as comprehension, in the newly conceived form;
  • Explain what a short form really means and in what situations it is appropriate; and
  • Frame issues for SACHRP so it can consider what is acceptable or unacceptable from regulatory and other standpoints.

Mr. Nelson then reviewed the issues SAS plans to address. (See his PowerPoint.) There were no comments from SACHRP.

Public Comment

Dr. Mather of Unicorn Consulting found the “enormous drop” in OHRP’s program budget “appalling” in view of the many pressing needs for education. He urged SACHRP to recommend strongly that at least $500,000 be found to reconstitute the program budget.

Wrap-up Discussion
Barbara Bierer, M.D., Chair

Dr. Bierer reminded members that the subject of a recommendation regarding OHRP’s reduced budget capacity is still under consideration and may be resumed on Tuesday, preferably with the aid of a draft version.

 

TUESDAY, OCTOBER 28

Remarks
Barbara Bierer, M.D., Chair

Dr. Bierer invited discussion of how to move forward on prioritizing SACHRP’s numerous recommendations to assist OHRP in establishing its own priorities.

Dr. Genel proposed the following:

SACHRP will establish an ad hoc committee to review and prioritize pending SACHRP recommendations to the Department of HHS, with a report to be presented to SACHRP at its next meeting (March 3-4).

Various members made the following points:

  • Chairs of subcommittees should be involved in the process.
  • It is important that recommendations are not unintentionally lost through the process, which should be one of determining whether earlier or later action is preferable.
  • OHRP staff are requested to act as consultants to the ad hoc committee.

ACTION

SACHRP unanimously approved Dr. Genel’s recommendation without changes.

The Chair asked those interested in serving on the ad hoc committee to talk with her before the end of the day.

Dr. Bierer asked if members had further thoughts on the OHRP budget. Dr. Leiden proposed sending a letter to the Secretary requesting additional program funds and noting that many efforts supported by these funds are required by law. The Chair suggested working on the language and bringing the motion back after lunch.

Report of Subcommittee on the Inclusion of Individuals with Impaired Decision-Making in Research (SIIIDR)
David Strauss, M.D., SIIIDR Co-Chair

Dr. Strauss provided an overview of SIIIDR activities. He placed the subcommittee’s work in its historic and regulatory context, highlighting key policy questions germane to the subcommittee’s charge. He stated that the SIIIDR is striving to strike a balance that recognizes the rights and welfare of vulnerable subject populations, but that also recognizes the long-term needs of those populations, who could be the beneficiaries of good and important science. It must also find a balance that protects subjects without diminishing autonomous decisionmaking, since it would be stigmatizing to provide protection that is not needed.

The Co-Chair then reviewed key concepts in SIIIDR’s deliberations to date. SIIIDR recognizes that decisional impairment occurs in many populations and in many settings, and that it is not limited by any means to patients with specific disorders or conditions. The subcommittee uses the term “consent capacity” to denote “the specific abilities necessary for a prospective research participant to understand and use information relevant to consent.” Consent capacity is not simply present or absent, but occurs along a continuum. It is also task-specific, varying according to the complexity of the task.

Dr. Strauss reviewed the recommendations SIIIDR has presented to date and introduced Recommendation VIII, which consists of two parts:

  • Part One: Guidance on IRB Review Membership, and Subject Selection addresses IRB review procedures when the IRB is considering research with subjects who lack consent capacity, including IRB membership and reviewer qualifications. It also addresses subject selection.

  • Part Two: Guidance on Risk-Benefit Analysis considers the deliberative task of determining what risks are reasonable in relation to anticipated benefits for persons who lack consent capacity, including the issue of whether or not it matters what the relationship of the legally authorized representative is to the individual.

SIIIDR members have concluded that protections for subjects who lack consent capacity can be tailored to the nature of their impairments and framed to be proportional to the extent of impairment, the magnitude of experimental risk, and a meaningful assessment of benefit. They believe that absolute thresholds and second tier reviews, which have been recommended in other settings, may create insurmountable hurdles rather than providing genuine protections.

The Co-Chair argued that protections afforded by IRB review should address the extent to which the subject is able to protect his or her own interest through the consent process. When the subject cannot do this, then the IRB should assume greater responsibility in protecting the subject through the risk-benefit analysis. What is considered a reasonable risk will need to take into account both the subject's susceptibility to risk and the subject's ability to protect himself or herself through the process of initial and ongoing consent. Conceivably, an IRB might approve a study that would enroll subjects with no impairment but create a different threshold of approvability for subjects who were impaired.

DISCUSSION

Following the presentation, members raised questions and commented as follows:

  • To what extent do people draw the research definition of Legally Authorized Representative (LAR) from the medical sphere? Dr. Strauss responded that in certain ways, this is “the” question. IRBs and investigators play the time-consuming game of “find the LAR” in jurisdictions where it is not well defined. OHRP has interpreted this term such that an LAR authorized to consent to the procedures used in a medical context is also authorized to approve the use of the same procedures in a research context. However, ethical questions remain about the differences in engaging in each type of procedure in these different contexts.

  • Are all IRBs qualified to judge this type of research, even with guidance? Should we be thinking of specialized IRBs? Dr. Strauss responded that he saw no case for “exceptionalism” with regard to this population; he believed IRBs could make decisions for this vulnerable population as competently as they do for others.

Dr. Botkin advocated the “Subpart D” approach to the issue of risk, which he said had the advantage of maintaining a category of research for which there is no prospect of benefit. He observed that this category of research is the most difficult one for this population.

Recommendation VIII. Part One: Guidance on IRB Review, Membership, and Subject Selection

The text of the working draft of Part One of Recommendation VIII is filed with “presentations” at the following address: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/siiidrrec8doc1.html

Dr. Strauss read through the subcommittee’s recommended approach to IRB, membership, and subject selection when subjects who lack consent capacity are included in research. The scope of the presentation included

  • IRB review procedures,
  • IRB membership and reviewer qualifications, and
  • Subject selection (the decision to include subjects who lack consent capacity).

SACHRP members raised the following questions and concerns:

  • The preamble should address the axis of risk-benefit in relation to the disorders or conditions that are the cause of the incapacity.
  • There is too much rigidity regarding what would be adequate representation on the IRB.
  • Clarify what constitutes a “potential benefit.”
  • In the preamble, clarify that there should be a positive rationale for including this population to present their exploitation.
  • Whenever you are saying something needs special attention, precede it with, “it is appropriate to do research with this population if…

Dr. McNeilly was concerned that having a recommendation labeled “guidance” would appear to circumvent the normal process for preparing guidance. He suggested calling it “commentary” or “recommendations for guidance.” Dr. Strauss clarified that the subcommittee’s intent was simply to indicate the kind of information needed by the field to adequately protect subjects from research risk in this population.

Specific suggestions for Part One included:

  • 1d. This reads as if the waiver of consent and expedited review are being linked.
  • 2. The “or” after “this information…maybe available” could be interpreted by IRBs as meaning the investigator is the only one who needs to be present for the review.
  • 3. Make clear in the introductory paragraph that you want IRBs to consider all these things.
  • 3d. Look at this in context. We don’t want to inadvertently prohibit the enrollment of people who failed in other treatments.
  • 3d. Mr. Boyer thought this looked like an attempt to link waiver of consent and expedited review.
  • 3e. As written, this would lead people to believe that people with impaired decisionmaking should be excluded from a study that is not very risky, but of potential benefit.
  • 3f. Delete the last clause: “and their participation is important to research.”
  • 3f. Given the history of exploitation, this should clearly say that there should be some justification for including people who lack consent capacity in research. Dr. Botkin suggested that there is no problem with having inability to provide consent as an exclusion criterion, although there are studies in which the investigator would not want that criterion (for example, when the subjects should represent the population of hospitalized patients).

Ms. Bankert asked for clarification of the intent of 3f, noting that her IRB has struggled with cases in which one of many oncology patients might not be able to give consent at a certain time. Some felt that not enrolling that individual would be unfair. Mrs. Forster said the intention was do say that if the research can be done with people with consent capacity, it should be done with them and those who cannot give consent can be excluded. However, it would be acceptable to include them in a broad quality assurance study or if there is a prospect of benefit — for example, other standard treatments have failed to help them and there is a prospective benefit available only through research.

Recommendation VIII. Part Two: Risk-Benefit Analysis

The text of the working draft of Part Two of Recommendation 8 is included with “presentations” at the following address: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg10-08/present/siiidrrec8doc2.html

Dr. Strauss read through the subcommittee’s recommended approach to risk-benefit analysis when subjects who lack consent capacity are included in research.

Mr. Forster asked for SACHRP’s opinion on whether too much emphasis is placed on issues related to consent and the LAR. He felt the risk-benefit section should stand alone. Dr. Genel agreed. However, Dr. Bierer pointed out that SIIIDR is pointing to issues rather than writing guidance; the issues might be clearer if LAR and risk-benefit were separate. Dr. Strauss asked Mr. Forster whether he wants to remove the question of whether the LAR is equivalent to the subject’s consent in regard to risk-benefit considerations or whether he simply feels it belongs elsewhere. Mr. Forster said his preference is to remove it form the section and put it elsewhere. Dr. Botkin, however, did not feel that the issue of decisionmaking authority could be disentangled from the risk calculation.

Dr. Marshall suggested that in item 5 b, second sentence, the following words should be eliminated: “the value of these benefits in relation to the same or similar benefits that exist outside the research.” She felt that the issue of populations without access to care should not be included in that context. Dr. Strauss commented, however, that the issue is a daily concern, and the way it is resolved is case specific.

In regard to footnote 2 for 5b, Dr. Gibbons questioned whether access to a drug or procedure should be considered a direct benefit for an indigent patient. Dr. Strauss commented that many people do not have mental health care coverage, and standard treatment is inaccessible to them. Dr. Gibbons said he would not want to encourage including this vulnerable population in a clinical study because of the inadequacies of our medical care system. Dr. Budashewitz asked that in line 5 of footnote 2, the word “cost” be changed to “coverage.”

Dr. Bierer suggested, in regard to item 8, that developing written policies and procedures is one of many ways to approach this concern. She suggested allowing regulators to find the appropriate methodology. Dr. Botkin commented that the language is a compromise between people who are comfortable with a Subpart A approach and those who are more attracted to a Subpart D categorical approach. The intent is to say that some upper limit is probably appropriate, and individual IRBs should think this through and develop policy accordingly. Dr. Strauss added that SIIDR does not want to “pull the rug out” from under the IRBs that operate within Subpart A and have well-defined approaches to this issue.

Community Perspectives on SIIIDR Recommendations
Bill Thies, Ph.D., Alzheimer’s Association; Ron Honberg, J.D., National Alliance on Mental Illness (NAMI); Sue Swenson, developmental disabilities representative, and parent of disabled child; Eileen Zacharias, J.D., Acute Respiratory Distress Syndrome Foundation (ARDS); Jere Boyer, Ph.D., human subjects research professional and parent of disabled child

The Chair reviewed the charge for this panel, which is as follows:

This purpose of this panel is to obtain feedback from patient, research subject, and family advocates regarding recommendations currently being considered by SACHRP from this Subcommittee. The three central issues to be discussed regarding research with subjects who lack consent capacity are: (1) the decision to include such subjects in research, (2) the role of the “legally authorized representative” (LAR) in research decision-making, and (3) the degree of acceptable risk in research involving subjects for whom consent is provided by others. Panelists representing consumer and community perspectives will discuss these questions in relation to SIIIDR proposals, focusing on clinical and ethical considerations.

Specifically, with regard to the circumstances and restrictions under which individuals who lack consent capacity be involved in research:

  • Are the populations requiring additional protection appropriately defined in the proposals?
  • Would the proposals for IRBs, institutions and investigators, as outlined, provide a reasonable balance between the rights and welfare of research subjects and the need to advance the understanding and treatment of conditions affecting them?
  • Are the roles of the research subject and involvement of the LAR, as described, ones that provide appropriate protections and adequately respect subject autonomy?
  • Are the procedures for IRB review and the specific risk/benefit considerations outlined ones that appropriately safeguard the interests of subjects?
  • Does the proposals, or components of the proposals, introduce protections that are not necessary for subject protection and create obstacles to the conduct of important research?
  • Are additional safeguards necessary or desirable to protect subject rights and welfare?

Bill Thies: Alzheimer’s Disease: Course, Prevention, Treatment Strategies

Dr. Thies reviewed the current status of our understanding of Alzheimer’s Disease (AD), noting that in his view a diagnosis of AD does not equate with an inability to consent. Determining the ability to consent, he felt, would require an in-depth interview for each individual. However, the literature on this issue is “tiny.”

Questions from SACHRP members included the following:

  • What do you know of how IRBs are addressing issues that arise with people who have AD? The greatest issue is inconsistency. Some are too restrictive and some rubber stamp proposals without understanding the issues. Education is needed.

  • What is the role of the Alzheimer’s Association? They are making an effort to help get more people into clinical studies. The best place to start is by helping people understand what it means to be in a clinical trial. Dr. Thies frequently gets outraged letters from people who found they received a placebo in a study. Primary care physicians also need education.

  • Do you think there should be an upper limit of risk beyond which we say no? It’s hard to say exactly what triggers the “no.” I know it when I see it.

  • Do you have any experience with research advance directives? No, but it is an interesting idea.

Sue Swenson: Research Participation and People with Intellectual and Developmental Disabilities

Ms. Swenson provided background on U.S. policies related to persons with disabilities and various interpretations of the meaning of “disability.” She made the following recommendations to SACHRP:

  • Recommendation 1. Discussions of “consent capacity” should consider, support, document and periodically review how a person’s decision-making and participation are accommodated. Guidance should address the concepts of supported decision-making, supported participation and the general impact of support in the life of a person with intellectual or developmental disability.

  • Recommendation 2. Guidance should provide information on inclusion of people with intellectual, developmental and other disabilities and their advocates on IRBs.

  • Recommendation 3. Guidance should address the evolving contributions of communications technology. For example, “avatars” offer an online presence that helps many people with disabilities interact.

  • Recommendation 4. People with disabilities should be able to participate in research that is specific to their primary disability as well as specific to other health concerns.

  • Recommendation 5. Guidance should help IRBs consider training of potential participants and their supporters as an adjunct to recruitment to serve in studies and boards.

Following the presentation, Mr. Forster stressed the importance of understanding the principle and techniques for “accommodations.” He invited Ms. Swenson to offer comments on a subsequent draft of SIIIDR recommendations.

Ron Honberg: Achieving the Right Balance? NAMI’s Perspectives on Research Involving Individuals with Impaired Decision-Making Capacity

Mr. Honberg presented specific suggestions on behalf of the National Alliance for the Mentally Ill (NAMI). Specific recommendations included:

  • All IRBs that regularly review research on serious mental illness should include consumers and/or family members.
  • Members of IRBs that review research on mental illness should receive specialized training. There may not be anyone with background on schizophrenia, etc.
  • Training should include information about medical issues, life experiences, and on legal, regulatory, and ethical requirements.
  • IRBs should include as many members from outside of the research institution or facility as possible.
  • Risk assessment should include multiple factors, including:
    • Psychological as well as medical factors,
    • Long-term as well as short-term risks, and
    • The possibility that research subject will incur risks as a consequence of research participation.
  • When questions about potential capacity of subjects exist, determination that research is beneficial should be based solely on potential benefits to subject, not to the field.

He proposed the following framework for including persons with serious mental illness who lack the capacity to consent for themselves in studies:

  • For minimal risk studies, regular IRB approval guidelines should be followed.
  • Mr. Honberg was not certain whether the category of “minor increment beyond minimal risk” would apply to this population.
  • If the study poses greater than minimal risk and the prospect of direct benefit to the research subject, consent by an LAR is permissible when:
    • The LAR has been specifically authorized by subject or a Court to consent to research; or
    • The LAR has been personally informed of potential risks and benefits.
    • Surrogate consent by institutional or government bodies should not be permitted.
  • If the study is greater than minimal risk with no prospect of direct benefit, participation in research by subject who lacks capacity should not be permitted unless a surrogate LAR consents and there is an advance directive with explicit instructions consenting to particular type of research

Other specific recommendations included:

  • Capacity assessment should be conducted by someone other than principal investigator or others involved with research.
  • Verbal or nonverbal expression of dissent should always serve as basis for discontinuing the individual’s participation in research.
  • When an individual discontinues participation, efforts should be made to link the individual with needed services.
  • Individuals who benefit from experimental medications should be provided with continued access until the medication is approved or a third-party source of payment is found.

Questions and comments from SACHRP included the following:

  • Does previous participation in research provide a good indicator of the subject’s wishes? It should not be the sole indicator, especially if the research involves risk with little prospect of direct benefit.

  • I wonder whether diseases with biomarkers offer more tangible potential benefits, possibly influencing the direction of the field and levels of interest. I don’t want to present an anti-research perspective — NAMI has many interested members, and there is standing room only at NAMI meetings with scientist presenters.

  • What does NAMI do to fund research or educate members? We used to train consumers and family members to participate on IRBs, but we haven’t done that in the last few years. It was a worthwhile thing to do. We do post some research-related information on our Web site, but we review protocols and consent forms carefully to be sure they meet our standards.

Eileen Rubin Zacharias: From Active Attorney to ARDS/Sepsis Patient, in Only Days…

Ms. Zacharias described her experience as a survivor of Acute Respiratory Distress Syndrome (ARDS). She stressed the importance of clinical research to the large group of patients with this life-threatening condition, even though patients will be unable to personally consent.

Questions and comments from SACHRP included the following:

  • What is your feeling about who should be able to give consent for an incapacitated patient? My family was advised to “pull the plug.” We had not discussed what to do in a situation like this, but they made the right decision — I felt it was better to try something than nothing. The decision should be made by the next of kin or a relative if possible.

Jere Boyer: Assessment of Recommendation Eight: Approval Criteria

Dr. Boyer spoke of his experience as the parent of a daughter with Down’s syndrome. He described a process of preparing his daughter to give her assent to participate in a study, which involved discussions over several evenings. He pointed to the challenge of working subjects with “variable IQs” and stressed the need for flexibility.

Closing Discussion and Action

SACHRP closed by considering minutes on two items of concern. First, members unanimously approved the following letter of appreciation for Dr. Pritchard’s leadership:

SACHRP appreciates Dr. Pritchard’s outstanding efforts during this time of transition. Those efforts have required balancing two critical interests: the pre-eminence of the human research enterprise and the protection of human subjects participating in research. He has partnered with the research community in providing education, determining public policy directions, addressing difficult oversight issues, and in fulfilling challenging compliance mandates. He has ensured research integrity while also working to ensure public trust in behavioral, social science, and biomedical research. We thank him and value him for his vision, his dedication, and his leadership.

Members then turned their attention to the issue of OHRP’s reduced program budget, with its resulting decrease in a capacity to perform essential duties such as education. The following motion was approved unanimously:

[Following the two opening paragraphs of SACHRP’s charter:]

To enable OHRP to oversee human subject protections in the multibillion dollar clinical research enterprise in the U.S., we respectfully ask you in your capacity as Secretary to increase its program budget line to at least its 2008 level plus 15 percent.

Public Comment

Public comments were invited, but none were offered. The meeting was adjourned.

 

 

 

 

Secretary’s Advisory Committee on Human Research Protections

October 27 and 28, 2008

Arlington, VA

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., ChairDate