July 21, 2001 Michael A. Carome, M.D.Director, Division of Compliance OversightOffice for Human Research Protections6100 Executive Boulevard, Suite 3B01National Institutes of Health (MSC 7507)Rockville, Maryland 20852-7507
RE: Human Subjects Protections under Multiple Project Assurance (MPA) M-1011
Dear Dr. Carome:
We take this opportunity to respond to the OHRP findings outlined in the letter issued to us on 7/19/2001. OHRP's letter required the suspension of federally supported research at the covered Institutions. On Thursday 7/19/01, faculty and staff were apprised that (i) previously enrolled subjects may continue only where it is in the best interests of individual subjects, and (ii) all enrollment of new subjects must cease immediately except in extraordinary cases approved in advance by OHRP. On Friday 7/20/01, you agreed that a "best interests" standard could be applied to enrollment of new subjects provided there was prior approval by OHRP. We will review on a protocol-by-protocol basis any protocols that clinicians believe must proceed with enrollment in order to meet the best interests of patients. In addition, as discussed with you by our General Counsels, when a determination is made that a case has been identified, you will be contacted personally to review the decision to allow new enrollment.
As you requested on Page 11 of your letter, a list will be developed of all federally supported research protocols that were suspended, including the project title, principal investigator name, IRB project number, and the federal department or agency project number. This list will identify those projects for which a determination was made that the research activities involving previously enrolled subjects may continue because it is in the "best interest of individual subjects." The criteria for making such determinations will be provided along with the list.
The 31 OHRP findings described in your letter are each addressed. We will comply with the corrective action plan approved by OHRP.
Regarding Protocol AAC00-07-26-02 (1) (a) The finding notes that data provided to the IRB and investigators conducting the research failed to ensure that the risks to subjects were minimized and reasonable, as required by HHS regulations at 45 CFR 46.111(a)(1), particularly concerning the published literature concerning hexamethonium. As noted in Hopkins' internal investigation report provided to OHRP, a good faith effort was made to review the literature. As noted in Dr. Dang's letter to OHRP dated 7/13/2001, the Institutions have committed to the development of a standard that both an investigator and the IRB can apply to determine that a literature search conducted in support of an application for human subjects research is both adequate and comprehensive. We are working with outside consultants to develop this standard and expect a draft by September 15th, and will provide explicit guidelines for literature searches that will be helpful to our researchers. We are not aware that such a standard or guidelines have been articulated previously, and we are hopeful that this work may prove useful to researchers at other Institutions.
(1) (b) The finding states that hexamethonium is not currently approved for use in humans and has never been approved by the FDA for administration via inhalation. The facts supporting this statement were contained in Hopkins' internal investigation report submitted to OHRP. As a result of Hopkins' internal investigation, we have determined that the application form for submission of a project to an IRB must change. The form must contain explicit questions regarding use of substances that are currently not approved by the FDA (non-FDA-approved substances). The Institutions have suspended all research involving non-FDA-approved substances and will not proceed unless the criteria for FDA exemption are met or an IND is obtained. Investigators will be required to submit an IND application to the FDA for review or obtain a written opinion from the FDA that an IND is not needed on non-FDA approved substances, prior to any action taken by the IRBs on non-FDA approved substances.
(1) (c) The finding that the IRB failed to obtain sufficient information regarding hexamethonium has been discussed extensively at the Institutions. Several action items are planned. As part of the protocol re-review process, all protocols that utilize drugs or other substances that are to be given to humans will be scrutinized to ensure that they are of human grade, i.e., that information regarding the source, purity, quality and method of preparation of a substance is sufficient to make that determination. A standard operating procedure will be written to assure this process is followed, without exception, in on-going reviews. This procedure will include, among other things, that when a commercial sponsor of a study is involved, the sponsor must provide evidence that an IND number or an appropriate exemption has been obtained. The procedure also will require that for investigator initiated studies, confirmation must be supplied that a substance meets GMP standards for preparation, and the Investigational Drug Pharmacy will be consulted regarding preparation procedures that are to be followed by investigators. We will strengthen the procedures for preparation by requiring involvement of a pharmacist in any study involving a substance that is not already FDA approved for marketing or conducted under an IND number issued to an investigator by the FDA. Prior to taking a final vote on a protocol involving the use of drugs there must be written approval by the P&T Committee.
(2) OHRP found that the JHBMC IRB failed to ensure that all criteria required for IRB approval under HHS regulations at 45 CFR 46.111 were satisfied. The requirement for review, discussion, and documentation at a convened meeting for all research that does not qualify for an expedited review will be followed. We confirm that all protocols that require action at a convened meeting will be presented and discussed at a convened meeting that meets the quorum and membership requirements in the regulations. Documentation associated with the protocol will reflect that criteria for approval (45 CFR 46.111) have been met and will report the number of IRB members voting for, against and abstaining on a protocol.
(3) OHRP found that changes to the research protocol were implemented by the investigators without IRB approval. We wish to state that it always has been the policy of the Institutions that any changes to a research protocol are required to be submitted for IRB review and approval. The statement of policy has consistently been noted in the approval notices mailed to investigators. We recognize that in this case there was a failure on the part of the investigator. To address this failure, we are launching an educational effort to reinforce the absolute requirement to submit protocol changes for IRB review and approval prior to initiation of such changes, except when necessary to eliminate apparent immediate hazards to the subjects, in which case the IRB must be notified within 24 hours. As noted in Dr. Dang's response of 7/13/2001, a broadcast message was sent to all individuals at the medical Institutions regarding the need to comply with this standard.
Moreover, as noted in remarks made by Dr. Dang at the site visit session on 7/16/2001, the Institutions conducted an audit process in 2000 that reviewed all gene therapy protocols conducted at Hopkins. The Institutions had planned to extend this audit process in the current year. Funds were allocated to employ 3 auditors to conduct reviews of protocols to determine compliance with the stipulations of approval of a human subjects project in collaboration with the federally funded GCRCs. We have been developing standards for the auditor positions in preparation for hiring auditors. As part of the action plan to address finding #3, the implementation of an audit system is given a high priority. Audits of ongoing protocols will allow the Institutions to determine that the requirement for submission of amendments is followed.
(4) The findings at 4(a) and (b) restate conclusions expressed in Hopkins' internal report of the investigation of the adverse event in the hexamethonium protocol. Our corrective action plan includes use of a consent form checklist required for investigators who submit an application to the IRB. The application is being revised to include this requirement. In addition, the IRB re-review commencing July 21, 2001 will incorporate a checklist to specify the required 8 basic elements in an informed consent document, with particular attention to a description of the reasonably foreseeable risks and discomforts associated with the research as required in 45 CFR 46.116(a)(2). This will be used in new reviews as well.
(5) Commencing July 21, 2001 the consent form will be assessed by the IRBs to determine if these additional elements must be present in each consent form. A checklist has been developed to assess these criteria.
(6) OHRP found that the investigators failed to promptly report an unanticipated problem involving risks to subjects. The Hopkins' internal investigation report noted the lack of reporting to the IRB or other appropriate authorities, both internal at Hopkins and external to Hopkins. The deficiency already has been addressed through e-mail notices to all faculty and will be further addressed through intensive education of faculty members regarding adverse event reporting requirements. We are developing written policies to define the steps required to assure that research must be halted by an investigator when exposure of additional subjects to a research procedure would result in increased risk to subjects. The investigators in the research application will be asked to describe a plan for collecting, monitoring and analyzing adverse events.
(7) OHRP acknowledged and concurred with the conclusions in (a) (b) and (c) of the internal investigation report. No further comments are provided on finding 7.
OHRP Findings Regarding Human Subjects Protections Under MPA M-1011 (8) We note that we respectfully disagree with finding 8. During the site visit and in previous correspondence, IRB chairs and staff explained the extensive review process which precedes review at the full convened meetings. The review process undertaken before a convened meeting is designed to assure a triage process which assures that all issues relevant to the review process are identified and documented prior to the convened meetings. However, as noted by Dr. Melody Lin, Deputy Director, OHRP, at the discussions with IRB chairs, use of an executive subcommittee system provided a "Triple Review" of protocols before they are approved at a convened meeting. She appeared to favor this process, i.e., (i) circulation of protocols to all IRB members for comment, (ii) re-review by the executive subcommittee, and (iii) recirculation of the protocols and their correspondence before final approval.
We have documented in our MPA applications, multiple correspondence with OHRP and reiterated in discussion at Hopkins, how our review system works. Protocols and the associated correspondence are provided to all IRB members prior to convened meetings. At these meetings, there is opportunity for further review and discussion prior to approval.
We recognize that OHRP takes exception to not presenting protocols individually at convened meetings. As we have stated before, our interpretation of the Regulations is that individual presentation is not required. We set forth Hopkins' position on this in the December 28, 2000 letter. Nevertheless, we will assure that protocols are presented individually, discussed individually, and that the minutes will document such discussion and votes on each protocol requiring review at a convened meeting. We will educate IRB members on this.
(9) The Institutions responded to OHRP on 12/28/2000, indicating the procedures followed to assure that such review occurred. OHRP did not respond to the Institutions' response, which specifically indicated that the changes outlined would be implemented by mid-January. The application for continuing review of protocols has always included some of the elements described in section (a) through (c) of this finding.
We will change the application for continuing review to include those elements that OHRP believes are lacking. Specifically, the application will require a summary of the protocol, a summary of the adverse events or unanticipated problems involving risks to subjects or others, complaints about the research, and a summary of recent literature. For multi-center trials, we have requested summaries of reports available, but will make this an explicit requirement in the continuing review application.
We recognize that OHRP takes exception to not presenting protocols for continuing review individually at convened meetings. As we have stated before, our interpretation of the Regulations is that individual presentation is not required. Nevertheless, the IRBs will make separate deliberations and actions on continuing review applications, and document votes for each protocol that requires continuing review at a convened meeting.
OHRP found that the IRB review of continuing review applications was not substantive nor meaningful. We disagree with this finding. We believe the issue is one of documentation at IRB meetings, and this issue will be addressed by the changes in procedures to document that deliberations and actions taken at convened meetings will be appropriately documented.
(10) (a) OHRP found that minutes for meetings did not exist for 18 of the last 21 meetings. At the time of the site visit, Hopkins explained the many factors that led to this delay. OHRP was informed in a forthright fashion that minutes were not available, but tapes of meetings were available and would be transcribed. The site team was provided with tapes for their consideration. The tapes themselves, of course, are the best evidence of what transpired at a meeting. We have retained the services of a firm to furnish us with the services of professional typists who will prepare transcriptions of the tapes. We have been informed that this task will likely take up to 13 days to complete. The regulations do not contain a timetable specifying when written minutes must be on file. Nevertheless, we commit to the completion of the missing written minutes and will send them to OHRP in our response of August 10, 2001.
We wish to further advise you that in order to avoid this problem in the future, whenever our own secretarial staff is unable to complete the preparation of minutes in a timely manner, we will utilize the services of temporary professional typists.
(b) OHRP finds that IRB actions were not documented separately for each individual protocol. As noted above, the system will now require separate documentation for each individual protocol in both the file and the minutes. Documentation of required changes in research protocols will be prepared. The IRBs will not take action to re-approve or approve protocols until documentation is in the record to confirm that required changes have been made. Minutes will reflect this confirmation.
(11) OHRP found that there were "several protocol applications in which the IRB failed to receive or consider sufficient information for the IRBs to make the determinations " In our response of 12/28/00, we detailed changes in our review form to consider additional safeguards for vulnerable populations. Nevertheless, a checklist will be used in the review process to assure that information is provided on "(a) subject recruitment and enrollment procedures; (b) the equitable selection of subjects; (c) provisions to protect the privacy of subjects and maintain the confidentiality of data; and (d) the local context for research conducted in international settings." We will document consideration of all of these criteria by using a checklist.
(12) OHRP found that IRB records failed to demonstrate consistently the consideration of additional safeguards for vulnerable populations. We disagree with this statement. Nevertheless, the IRBs will develop and use checklists to determine that all required considerations are made. Each protocol involving vulnerable populations will be discussed at a convened meeting, and the minutes of such meetings will show that additional safeguards were considered.
(13) OHRP found instances in which IRB members inappropriately participated in the initial and continuing review of protocols for which they had a conflicting interest. It has been the long-standing policy of the Institutions that members should abstain in accord with 45 CFR 46.107(e). We will provide additional education of IRB members and staff to address this point. In addition, at convened meetings the Chairs of the IRBs will review the agenda for protocols that may involve members to assure that their votes are not recorded. We agree to have conflicted members leave the room and return after the deliberations on protocols in which a member has an interest.
(14) OHRP found that the IRBs routinely employed expedited procedures to review changes that exceed the regulatory limitations. We will develop a checklist based on 45CFR 46.110 (b)(2) that permit use of expedited procedures for review of minor changes to previously approved research.
(15) (a) OHRP states that it found multiple instances where required elements were omitted or inadequate in consent documents. We respectfully request that OHRP identify the specific cases on which this finding was made, which will assist us in understanding this basis for this finding. The detailed consent form checklist previously discussed in this response will be provided to those designated to review the consent form. The records will reflect this review. Convened meeting minutes will note that consent form elements were reviewed as part of the process. In addition, in addressing staffing levels, we will identify a staff member who will be designated as a consent form reviewer to aid in the review process and be available to investigators in developing consent forms. This individual will assist the IRBs in determining that finding 15 (a)(ii) is addressed. The individual will be responsible for assuring that there are no discrepancies between the protocol application and the consent document statements regarding the purpose, risks, and benefits of the research.
(b) OHRP is concerned that the IRBs encourage investigators to limit the length of informed consent documents. We will eliminate any directive with respect to the length of informed consent documents.
(16) OHRP found that elements at 46.116(b)(2), (4) and (5) were additional elements of consent that were frequently overlooked by the IRB in its review of consent documents. We respectfully request that OHRP identify specific cases giving rise to this finding was made which will assist us in understanding this basis for this finding. As stated in the response to OHRP's finding (5), both the 8 basic elements of informed consent will be rigorously considered by the IRB, as well as all additional elements stated in the regulations. The consent form checklist will reflect all of these elements. Investigators will be provided with guidance on the required and additional elements. The consent form reviewers referenced in response to finding (15) will also be used to ensure that elements are not overlooked.
(17) OHRP is concerned that the informed consent documents approved by the IRBs often appeared to include complex language that would not be understandable to all subjects. We note that consent form language and complexity is a significant problem for all IRBs nationally. We request OHRP guidance on one possible plan which would include a required element in the application for IRB review to state the grade level of the text of the consent form and the program used to determine that level. We will also explore the use of special consultants and computer programs for the purpose of eliminating unnecessary complexity in language. IRB members reviewing the application will determine whether the language at that grade level is appropriate for the study.
(18) OHRP has expressed concern that the boilerplate informed consent document is difficult to understand and contains information that may be irrelevant for certain research projects. We are revising the boiler plate language. We will educate members as to which information is relevant for particular research projects. The written guidelines for writing consent forms will be revised to further address this concern.
(19) (20) (21) OHRP expressed concern with the current membership of the IRBs, the large volume of research reviewed by the IRBs, and the level of staffing for the IRB functions. We have been actively addressing issues of staffing and, as discussed with OHRP representatives, recently expanded the number of IRBs. The Institutions have been absolutely committed and supportive of the IRBs and their functions. Hopkins is committed to constituting a third IRB at the East Baltimore Medical campus as soon as possible. A detailed analysis will be performed to determine what additional changes should be made in composition of the IRBs, membership, and staffing. The results of thisanalysis will be reported to OHRP.
We wish further to advise you that we are considering and will make an effort to expand the ethnic diversity of IRBs being mindful of the protocols involving foreign cultures abroad.
(22) (23) OHRP expressed concern that IRB records do not reflect that specific findings were made regarding research involving children or research involving prisoners. We will implement as part of the review process additional checklists to those we already employ to assure that documentation in these two categories of research verify that specific relevant findings were made by the IRBs in the review process.
(24) OHRP expressed concern that the IRBs issue approval letters to investigators prior to receiving and confirming the adequacy of revisions required by the IRBs. In the past, the IRBs have approved projects with stipulations and issued letters so stating this fact. In those cases, a valid approved consent form was not issued before all stipulations were agreed. To address any perceived deficiency in our procedures for receiving and confirming the adequacy of revisions required by the IRBs, we will no longer issue approvals with stipulations. Only when final documents are approved by the IRBs will an approval notice be provided to an investigator.
(25) OHRP found that IRB documents reveal no evidence that the IRB consistently satisfies the requirement to find and document four specific criteria when approving waiver or alteration of some or all of the required elements of informed consent. However, the IRB application was changed in 2000 to require submission of information to justify a waiver of consent. IRB reviewers will verify that the application provides such documentation. We currently present each waiver of informed consent application individually at full convened meetings along with a list of the 4 criteria for approval. Nevertheless, we will create an additional checklist of the required findings, and the record will note that the findings were made and documented.
(26) OHRP expressed concern that the Chairs and members of the IRBs appear to lack a detailed understanding of the specific requirements of the HHS regulations for the protection of human subjects and that, as a result, IRB determinations have sometimes deviated from these requirements. While we believe that any deviations in no way detract from the commitment of Chairs or members to the requirements of the regulations, we will provide updated copies of both DHHS and FDA regulations to IRB members so that they have available the material needed for consultation. In addition, copies of the regulations will be taken to each meeting to allow consultation on the regulatory requirements. Education efforts will be implemented to address OHRP's required actions. (See page 10, item (1)(c).)
(27) OHRP found at 27(a) that the IRB did not have adequate procedures for (a) determining which projects need verification from sources other than the investigators that no material changes have occurred since previous IRB review. Hopkins' audit process is described in item 3 and will be used to address this finding. OHRP found at 27 (b) that the IRBs did not have procedures for ensuring prompt reporting of (i) any unanticipated problems involving risks to others and (ii) any suspension or termination of IRB approval. The IRBs have had policies in place concerning reporting of serious and unexpected adverse events. The policies will be amplified to include specific reference to the regulatory requirement referenced in the findings.
(28) OHRP expressed concern about "the adequacy of the IRB's present procedures for ensuring prompt reporting, review, and evaluation of unanticipated problems". Hopkins will include in the policies referenced in item 27(b) above, policies for review and evaluation of unanticipated problems involving risks to subjects or others.
Additional OHRP Guidance
(29) OHRP recommends that documentation for initial and continuing reviews conducted utilizing an expedited review procedure include the specific permissible categories. As stated in response to finding #14, Hopkins will use a checklist for each project that is reviewed through an expedited review process.
(30) OHRP strongly recommends that all required findings be fully documented in the IRB minutes, including protocol-specific information justifying each finding. As stated in previous paragraphs, we will document in the minutes of the IRBs deliberations the issues as required by federal regulations.
(31) OHRP recommends that the minutes of IRB meetings clearly reflect determinations regarding approval period (review interval) based on degree of risk. Our current review form asks members to comment on this specifically. To assure proper documentation, IRBs will use a checklist showing consideration of the appropriate approval period. Minutes will reflect the documentation to satisfy 45 CFR 46.103(b)(5) and 46.109(e).
OHRP Required Actions:
(1) JHUSOM, JHBMC, and all other Institutions covered by the MPA M-1011 must develop corrective action plans as a condition for OHRP consideration of reinstatement of the MPA. The detailed responses to the specific findings enumerated by OHRP noted above state what actions have been taken and will be taken.
(a) The plan includes confirmation that convened IRB review will be done for all research protocols not eligible for an expedited review.
(b) As noted earlier in our response, the Institutions will undertake a detailed and thorough review of its IRB processes. We take exception to the implication that the Institutions are not committed to human subject protections. Our commitment to human subjects' protections will be further strengthened by the addition of one IRB at the East Baltimore Medical campus as soon as possible, including sufficient staffing and the previously described additional staff for audit and consent form review. In addition, we have committed to study these issues as specified in items (19)(20)(21).
(c) The Institutions will develop an education plan for all IRB members, all IRB staff, and all research investigators. On Monday, July 23rd, we will by telephone solicit the assistance of Dr. Jeffrey Cohen, of OHRP's Education Division, to request his immediate assistance in planning and putting on an educational program directed to our IRB members and staff. We believe this to be the most expeditious way to provide our faculty and staff with this service and we would appreciate your intervention with Dr. Cohen to ensure his ready availability for this. In addition, we will contract for sessions of IRB 101 offered through PRIM&R and require attendance of all IRB members and staff. It is our understanding that you think highly of the quality of training provided by PRIM&R.
(2) By August 10, 2001, the Institutions will provide to OHRP a complete list of all federally supported research protocols that were suspended, including the project title, principal investigator name, IRB project number, and the federal department or agency project number. The list will identify those projects for which it has been determined that research activities involving previously enrolled subjects may continue because it is in the best interest of the individual subjects. The material will describe the procedure used to make the determination that the protocol may continue.
* * * * * *
We appreciate OHRP's availability to assist us in the development and implementation of the corrective action plans. Please identify for us the OHRP staff member(s) who are available to us for this activity. Please be assured that we are committed to changes in our system that will strengthen the review of human subjects research in a fashion that will lead to increased protection while still allowing conduct of vital research.
We trust that this lengthy and detailed corrective action plan will be given your immediate attention pursuant to your generous commitment to do so, and that you will find it warrants immediate reinstatement of the Institutions' MPA.
Sincerely yours, Edward D. Miller, M.D.Dean and Chief Executive OffricerJohns Hopkins MedicineJohns Hopkins University School of Medicine__________________________________________
Chi Van Dang, M.D., Ph.D.Vice Dean For ResearchJohns Hopkins University School of Medicine__________________________________________ Gregory F. Schaffer, M.S.PresidentThe Johns Hopkins Bayview Medical Center