| Comment Record|
Ms. Katherine Vogel ||
2002-06-04 16:45:36 |
| Comments for FDA General |
1. General Comments
Applied Research Ethics National Association (ARENA)
132 Boylston Street, 4th Floor
Boston, MA 02116
617.423.4112 | Fax 617.423.1185
June 4, 2002
Food and Drug Administration,
5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
Electronically submitted to:
On behalf of Applied Research Ethics National Association (ARENA), we are offering an opinion on FDA¡¦s Notice of Proposed Rulemaking known colloquially as ¡§IRB Shopping.¡¨
The Applied Research Ethics National Association (ARENA) is a subsidiary of Public Responsibility in Medicine and Research (PRIM&R), a nonprofit organization dedicated to promoting the ethical conduct of research. ARENA is a professional association with over 1,200 members who are administrators, chairs, and members of Institutional Review Boards (IRBs) and Institutional Animal Care and Use Committees (IACUCs) throughout the United States. ARENA¡¦s mission is to support those professionals whose responsibilities include the protection of human and animal research subjects.
ARENA agrees with the spirit of the proposed rulemaking.
1. ARENA urges adoption of requirements that offer IRBs the benefit of access to information not currently available to them, but that impose the minimal possible regulatory burden on IRBs.
2 ARENA recommends that FDA make sponsors ¡X who have the information, and are in the best position to disseminate it ¡X responsible for informing IRBs. It is not possible for IRBs to be the disseminators of this information.
Because this notice is from the Food and Drug Administration, ARENA¡¦s comments are focused on FDA-regulated trials. This however does not mean to imply that the issues raised are unique to these trials.
The OIG has identified IRB Shopping as a conscious act of abandoning an IRB with a negative opinion in order to find an IRB that will approve a particular study. IRB Shopping without disclosure omits telling the second IRB about the reason for seeking the second IRB¡¦s review of that same protocol. ARENA¡¦s comments are based on this definition.
We believe it is important to note that there may be legitimate business reasons for a sponsor to move a protocol from one research site to another that have nothing to do with a negative IRB review. For example, ARENA believes that there is no a priori ethical problem with choosing sites based on rapidity of IRB review, provided such review is thorough, thoughtful and fulfils regulatory requirements. Therefore, we hope the final rulemaking recognizes and distinguishes these actions from IRB Shopping without disclosure.
There is no data available about the frequency, seriousness, or root causes of IRB shopping without disclosure. To determine if it is a problem and to create the most appropriate solutions was not the thrust of FDA¡¦s request. We believe it is important to consider these issues in more detail. Nonetheless, we agree that FDA should make every effort to increase transparency and accountability in the research process.
Until recently, there was no thought that an IRB had a ¡§need¡¨ to know, any information about another IRB¡¦s actions. IRBs have been expected to act locally and autonomously since the decentralized system was instituted almost thirty years ago. FDA staff, have, in fact, not released to an inquiring IRB, information about any other IRBs that have reviewed the same protocol. Knowledge that the second IRB was a second choice was assumed to add little information and might, in fact, make that IRB either more eager to approve the protocol in order to retain a new client or more eager to find more to critique than the first.
We believe, however, that such information could be useful to subsequent reviewers. Information about prior disapproval sent, not just to the ¡§replacement¡¨ IRB, but to all reviewing IRBs could yield important information or insights to other IRBs. An additional significant benefit of a rule on IRB Shopping would be improved consistency across IRBs by allowing them access to one another¡¦s review process.
With each added federal reporting requirement, there is an exponential growth in documentation required. Even if sponsors are required to report to IRBs, the IRBs will need to receive, record, report and respond to each item received. As the OIG has previously indicated, IRBs are already overburdened. Consideration must be given to what IRB documentation requirements will be added as a result of the proposed rulemaking.
ARENA¡¦S RESPONSE TO THE EIGHT QUESTIONS POSED IN THE ANPR
Although FDA¡¦s questions are posed in terms of IRB shopping, they are preceded by a statement that ¡§FDA is considering whether to revise its IRB regulations to require such disclosures.¡¨ Our responses are stated in terms of IRB shopping without disclosure.
1. How significant is the problem of IRB shopping without disclosure?
The frequency of IRB Shopping and IRB shopping without disclosure is unknown. As FDA¡¦s discussion noted, IRB Shopping becomes a problem when combined with non-disclosure and the intent to engage another IRB instead of resolving the problems noted.
The problem is significant to the extent that it undermines public confidence in the current system of human subjects protection. We believe that the practice of IRB shopping without disclosure will continue to erode the public¡¦s perception of the IRB system as being an ethical safeguard.
2. Who should make these disclosures?
Sponsors and investigators should be asked to report to the other reviewing IRBs. Although IRBs could ask for information; sponsors are frequently alone in knowing the status of IRB approvals.
Toward this end, we believe that basic changes should be made to 21 CFR 312 and 812 rather than to 21 CFR 56. Changing parts 312 and 812 places the obligation on the sponsor to disclose the information. Changing part 56 inappropriately places the obligation on the IRB to get the information from sponsors with little motivation to reveal it.
3. Who should receive the disclosures?
All IRBs reviewing the same protocol should receive the information.
4. What information should be disclosed?
At a minimum, disclosure requirements should include (1) a report of all previous IRB disapprovals of the protocol and (2) a report of any sponsor-initiated withdrawal of the protocol prior to securing approval from an IRB. The report should include the title and sponsor of the protocol, and the name of the IRB, a contact person, and a phone number. Inclusion of IRB identifying information would allow direct contact between IRBs without the sponsor and investigator as intermediaries.
Voluntary best practices and guidances could be provided in addition to the minimal requirements. These could recommend a variety of further measures, such as circulation of disapproval letters or letters with requirements leading to sponsor-removal, distribution of lists of all reviewing IRBs, proactive sponsor posting of all comments received together with their response and, of course, addition of appropriate questions on IRB applications.
5. If a proposal would not require disclosure of all prior IRB decisions, what information should be disclosed?
As FDA notes, although an actual disapproval is clear, the diversity in IRB practices with regard to returning applications for further work makes the reality more difficult. We propose disclosure of (a) any final written IRB disapproval of a protocol and, (b) any sponsor or investigator withdrawal of a protocol from an IRB¡¦s jurisdiction. This information is sufficient to provide the needed signal of possible problems.
6. To permit a subsequent IRB to assess the value of a prior IRB decision, should information about the basis for the prior decision be disclosed?
The minimum standard should include sufficient contact information to allow a subsequent IRB to contact the IRB with the negative opinion. Additionally, in the event of disapproval, a copy of the IRB letter stating the reasons for such action could be provided.
7. How should FDA enforce the requirement?
FDA should include a new item in the inspection manual for the sponsor and investigator audits. If a sponsor fails to make the required disclosure to the IRB and an IRB approves the recruitment of subjects in the absence of this information, the IRB approval should be considered void and no data from those subjects should be accepted by the FDA.
8. Are There Other Ways to Deal with IRB Shopping Other Than Disclosure of Prior IRB Reviews?
One suggestion is to examine the root causes of shopping without disclosure. In addition to learning if it is, indeed, an issue, this examination might yield clues as to why sponsors might being keeping such information confidential. For instance, if a sponsor believes that a requested modification would require submission of a modification request to FDA ¡V requiring substantial time¡V that sponsor might be loath to accept the recommendation. If this contributes to causation, a solution might include rapid turnaround of IRB suggested modifications at FDA. If a root cause is the IRB¡¦s failure to understand the role of the protocol in the overall investigational plan, better communication between sponsors and IRBs might play a crucial role.
CONCLUSION AND ARENA PROPOSAL
„« As a matter of public trust in the system of protection of subjects, it is reasonable to include a regulatory amendment that requires sponsors to disclose prior negative IRB reviews resulting in disapproval and sponsor-initiated withdrawal from review.
„« Each such disclosure should be sent to all reviewing IRBs,
„« Disclosure should be required from the sponsors with the information rather than by IRBs.
„« Each such disclosure should include, at a minimum, the site, contact person, and phone number for each IRB in such a report. The prior disapproval letter may also be included. .
„« A new section (c) should be added to 21 CFR 312.55 requiring sponsors to provide investigators with the above disclosures to be provided to reviewing IRBs. A complementary sentence should be added to 21 CFR 312.66 requiring the investigator to forward such information to the IRB.
„« 21 CFR 20.81(a)(3) should be amended to make clear that IRBs have the right to discuss study related information with other IRBs reviewing the same protocol, without breach of confidentiality and trade secret policies of the sponsor.
„« Concurrently, FDA should provide a mechanism for rapid response to sponsors for IRB requested/suggested modifications.
Thank you for asking our opinions about proposed changes due to IRB Shopping without Disclosure as published in the March 28, 2002 Federal Register. Members of our Public Policy Committee are available to provide more specific, detailed information and clarifications to assist you in reviewing and refining FDA standards, policies, and procedures. ARENA appreciates the efforts of FDA to work with IRBs, principal investigators and sponsors to promote ethical biomedical research and scientific advancements in compliance with all federal rules and regulations.
Erica Heath,Co-Chair, IRB Shopping Sub-committe
Bruce Gordon, Co-Chair,IRB Shopping Sub-committee
Molly Greene, Co-Chair, ARENA Public Policy Committee Karen Hansen,Co-Chair,ARENA Public Policy Committee
cc: ARENA Council
ARENA Public Policy Committee