Inspections, Compliance, Enforcement, and Criminal Investigations
Hohmann, Elizabeth L., M.D. Response Letter
|Massachusetts General Hospital||
|55 Fruit Street GRJ 504
Boston, Massachusetts 02114-2696
Tel: 617-726-3812 Fax: 617-726-7416
Infectious Disease Division
Department of Medicine
July 17, 2006
Ms. Bhanu Kannan
Ms. Mary A. Malarkey, Director, Office of Compliance and Biologics Quality
Division of Inspections and Surveillance (HFM-664)
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
l401 Rockville Pike Suite 200N
Study 1: Safety and Shedding of Attenuated Listeria monocytogenes actA/plcB-deleted; [redacted]
Study 2: Safety and Immunogenicity of Attenuated Salmonella typhimurium expressing HIV-1Gag [redacted]
Dear Ms. Kannan and Ms. Malarkey,
I am writing in response to your warning letter dated July 10, 2006, which i received on July 13, 2006, A point-by-point response is provided. I have restated and in some instances summarized the comments from the warning letter briefly for ease of reading in bold font and then provide a response in regular font. For clarity, 1 have added the notation of what organism was under study following your notation of the projects as "Study 9 (Listeria monocytogenes) and "Study 2 (Salmonella typhirrturium)
1. You failed to submit an IND) application to the FDA for your clinical investigation. In Study 1 (Listeria monocytogenes) you administered an unapproved attenuated strain of Listeria vaccine [redacted] to at least 20 subjects between October 14, 1999 and December 2001 and continuedthis study until August 2, 2004, without submitting an IND to the FDA. During the inspection you explained that in 2001, after you had dosed the last subject with the Study 1 investigational vaccine, you sought FDA guidance for the need for an IND. An representative told you that youneeded an IND to conduct the study. Nevertheless, you failed to submit an IND to FDA, and continued to follow the subjects from this study through August 2004 when you informed the IRB that the study was closed.
As noted in my letter of May 16, 2006, I acknowledge and accept responsibility for this violation. All studies I have undertaken since December 2001 involving investigational organisms have been submitted to the FDA for review. I have carefully responded to all comments the FDA has made on my studies to date, most recently under INDs [redacted]
With respect to Study 1 (Listeria monocytogenes), as described in my response dated May 16, 2006, I sought the advice of the FDA in December 2001 by submitting a letter to Dr. Paul Richman of CBER (December 12, 2001; I note that the letter to Dr. Richman was previously submitted to you; I copy it again now, for ease of review as Attachment A). As a sub-investigator under another principal investigator at Massachusetts General Hospital I had previously conducted vaccine studies on live attenuated organisms without IND submission. I had also subsequently submitted these data as published reports to the FDA as part of an IND submission (BB IND [redacted] and received no comments or questions, leading me to believe this was acceptable to the FDA. My letter to CBER of December 12, 2001 referenced discussions with Dr. David LePays office noting the changing climate of research related to unfortunate events at other institutions, absence of written guidance on this matter, my own increasing knowledge of FDA regulations, and requested explicit guidance from CBER. When I did not receive a written response to my letter, I followed up and inquired by phone. In the brief conversation I had with Dr. Paul Richman, when I called him in follow up of my December 12, 2001 letter, I asked whether INDs should be submitted for future studies. He agreed with this statement; I said I would comply, thanked him for his time, and the conversation concluded without further direction. I did not understand from this conversation that the FDA desired that I submit an IND for a study in which no additional subjects would receive an investigational vaccine. I indicated in my letter that the study was being written up for publication. If I had understood that 1 needed to submit an IND at that time related to the 20 subjects who previously received an attenuated Listeria monocytogenes vector, I certainly would have done so. I did not receive this instruction from Dr: Richman, either verbally or in writing. No subjects received investigational vaccines without FDA review after I was directed to submit this type of clinical investigation to the FDA. As described in my earlier letter of May 16, 2006, subjects enrolled in Study 1 (Listeria monocytogenes) after December 2001 were healthy volunteers and patients with listeriosis whose participation included only provision of small blood samples. These latter subjects had always been included in the project as immunological controls, since inception. The study file was continued in this fashion to keep immunological data together. For completeness, I note the following points:
1) 20 subjects received the investigational inoculum in Study 1(Listeria monocytogenes).
2) These 20 subjects were not actively followed between 2001 and 2004. They were all discharged from the study successfully, as described in the protocol. After IRB approval was obtained, several volunteers who received the attenuated organisms were contacted years later for optional, repeat blood samples; those who were residing in Boston and able to be contacted agreed to provide blood samples.
Again, I accept full responsibility for the noted violation but wish to emphasize that no subjects received investigational vaccines without FDA review after I was directed to submit these types of clinical investigations to the FDA. I sought out advice from the FDA, and now understand the FDA's position with respect to this issue and will continue, as I have since December 2001, to submit all such studies to the FDA for review and respond to all questions and requests promptly. INDs [redacted] on file at the FDA, support this.
2. You failed to ensure that informed consent was obtained according to the provisions of 21 CFR 50.
Deficiencies in the consent process were noted for 8 subjects as described in the table in the FDA warning letter dated July 10, 2006 [for Study 1 (Listeria monocytogenes)]. I again accept responsibility for these violations . These violations included using a form with a change made, before the 1RB had approved that change, or an accurate version of the form which was not stamped with the IRB approval stamp. Using these forms were errors on the part of one of my co-investigators, and I understand that I am responsible for them. I understand the importance of using the approved, stamped form, after IRB approval has been granted. It is noted in the warning letter that I explained that the IRB did not require any additional changes in the forms, but that 1 could have no way of anticipating whether the IRB would require additional changes after its review. It was not my intent to indicate anything other than to demonstrate that the subjects signed a form that, though it lacked formal IRB approval, included the relevant text that was ultimately approved by the IRB. I do fully understand that I could not know what the IRB would require in advance, and should not have used these forms in advance of their formal approval. As described in my earlier letter of May 16, 2006 my laboratory has developed a system of tracking consent forms, and will use colored pastel paper for current forms, to ensure that only approved, current consent forms are utilized. As suggested by FDA inspectors during their visit to my laboratory, earlier response, all our future studies will have an initiation visit by the [redacted] Quality Improvement Program to be sure all record keeping systems are in place before the study starts. A notice of a recent visit is enclosed (Attachment B) to demonstrate that I have implemented these changes.
3. You failed to maintain adequate and accurate case histories (21 CFR 312.62). It is noted that the administration dates are discrepant in subjects' case histories in subjects [redacted] and [redacted]. The hospital discharge summaries and the dates on a letter to the IRB do not match (3/28/00 in discharge summaries vs. 4/01/00 on the IRB letter). Due to these discrepancies the FDA is not able to determine whether these subjects were hospitalized for 14 days to monitor for safety as required by the protocol.
I accept responsibility for this violation, a failure to retain accurate records in connection with Study 1 (Listeria monocytogenes). I believe this inaccuracy is a result of a typographical error I made on an adverse event report form I submitted to the IRB. I am unable to find a letter with an incorrect date in my files. The hospital discharge summaries, dictated and signed by me with the medical record in hand, shortly after subjects left the hospital are correct. Review of study files, including admission no study labs, hospital temperature charts and daily progress notes on subjects [redacted] and [redacted] show that both of these subjects were admitted on 3/28/00 and discharged on 4/10/00, completing the protocol-specified 14 day hospital stay, I include as Attachment C study source documents which demonstrate that subjects were inpatients 3/28/00 through 4/10/00, and having study samples collected during their hospitalization. These source documents were completed independently by General Clinical Research Center nurses, not by me or my study staff, so they provide reasonable independent documentation, along with the formal hospital discharge summaries and other hospital documents in the complete medical records (not attached) that these subjects completed the specified inpatient stay. All of these study documents and the complete hospital record and were on site for review at the time of the FDA inspection. Every effort will be made to avoid this kind of error in the future.
4.A) You failed to promptly report to the IRB all changes to the research activity and failed to promptly report all unanticipated problems involving risk to human subjects. (21 CFR 312.66). A.) You failed to notify the IRB that Study 2 (Salmonella) was on hold. In your absence; a co-investigator notified the IRB that the study was placed on clinical hold, and FDA sent you a letter dated 10/17/03 listing the clinical hold issues. You did not inform the IRB about the clinical hold until 1/2/04, when you submitted a protocol amendment and revised consent form.
I apologize for and accept responsibility for this violation, which was not intended to deceive, delay or otherwise obfuscate the review of this study by the IRB or other oversight body. It was not clear to me that my laboratory would be able to address the scientific issues identified by the FDA in their clinical hold letter dated 10/17/03 related to Study 2 (Salmonella typhimurium). The FDA hold letter required additional laboratory and animal studies . As no human subjects were yet recruited or contacted, and 1 had committed in writing not to recruit or enroll subjects until all issues raised by required reviews, including the FDA's, were completed, it seemed acceptable to me as a scientist to attempt to address the issues and then provide identical information to the FDA and IRB concurrently. There was no intent to delay notification of the IRB, as evidenced by [redacted] notification by email in my absence, something I directed her to do as I was out of the country at the time. The intent was simply to provide the questions and the relevant responses and actions in one unit, for ease of review. I have since become aware that it is a requirement that the FDA letter be submitted promptly upon receipt and will do so in future . I do wish to reiterate that no subjects were enrolled into Study 2 (Salmonella typhimurium) until:
1) all FDA concerns identified in hold and "non-hold" letters were fully addressed, and the FDA agreed they were acceptable
2) the IRB received complete copies of all our responses to the FDA comments and amended consent forms in response to these changes
3) the N[H, Biosafety, and General Clinical Research Center reviews were completed and concerns were addressed and,
4) final IRB approval of submissions covered by items 1) to 3) was received and acknowledged by the IRB.
4.B) You failed to promptly report to the IRB all changes to the research activity and failed to promptly report all unanticipated problems involving risk to human subjects. (21 CFR 312.6b). You failed to promptly report the unexpected adverse events (primarily related to mild liver function test abnormalities) experienced by the study subjects to the IRB within time frames specified by the institutional policy.
I acknowledge and accept responsibility for these violations with respect to Study 1 (Listeria monocytogenes), as previously noted in my response dated May 16, 2006. I have since developed, with the assistance of our Quality Improvement Program, a log for tracking of adverse events, and their submission to the IRB and other regulators (Attachment D). I and my co-investigators and study staff will pay special attention to timely submission of all unanticipated problems and adverse events per the institutional policy and federal regulations. Additionally, we will retain a log for meetings of the investigative team, and appropriate checklists, accessible to all study team members, to ensure that all activities are undertaken in a timely fashion, in compliance with the approved protocol. As principal investigator, I have always been, and will continue to be in close contact with co-investigators and study staff on a daily basis about subjects in our studies.
With respect to Study 2 (Salmonella typhimurium), the IRB was notified within the time frame specified by institutional policy (30 days). As noted in my previous letter of March 16, 2006, the FDA form 483 did not accurately reflect the timing of reporting, and I will provide it again for subject [redacted] and [redacted] with supporting documentation as Attachment E. Please note that the second subject with liver function test abnormalities in this study was [redacted] not [redacted] as noted in the warning letter. All of these documents were in my study files an available to FDA inspectors at the time of their visit to my laboratory with the exception of the computerized lab sheets with liver function tests chronologically charted, which were generated for this letter.
Subject [redacted] developed mildly abnormal liver function tests on study day #4, 6/11/04 (labs attached).
The DSMB was notified on 6/30/04 (report attached).
The IRB was notified on 7/6/04 (submission attached): 25 days after the event occurred, with submission of the detailed DSMB report and detailed commentary on this subject and the study to date. This in within the 30 day window.
The IRB approved this submission (approval letter dated 9/22/04 attached).
Subject [redacted] developed mildly abnormal liver function tests on study day #10, 8/13/04 (labs attached).
The DSMB was notified on 8/18/04 (report attached).
The IRB was notified on 8/31/04 (amendment 21, attached) 18 days after the event occurred, with submission of the detailed DSMB report and detailed commentary on this subject and the study to date. This is within the 30 day window.
The IRB approved this submission (approval dated 7/15/04 attached).
The purpose of this reporting timeline was to provide to the IRB the additional expertise of the independent DSMB on the matter of the mildly abnormal liver function tests in these 2 subjects who were otherwise asymptomatic. The intent was to provide the IRB with more information, not less. As the events were reported within the relevant time frame, and were mild in degree, this seemed acceptable and of utility to the IRB. The IRB accepted our reports and had no further direction with respect to additional reporting, nor did they indicate that the reports were untimely. Subsequently, as a result of an investigator-requested site monitoring visit, our Quality Improvement program auditors suggested for additional completeness we ALSO submit a formal adverse event report form on each of these events, which we did on 9/27/06. These duplicate reports dated 9/27/06, submitted in an effort to be complete, unfortunately appear instead to have been a source of confusion . I note that the IRB also accepted these additional reports without any further requests . In sum, the information was submitted in a timely fashion, in the requisite time frame, with the advice of the DSMB, and auxiliary reports were submitted as a result of investigator-initiated study monitoring - an effort to improve. Nevertheless, in order to prevent any misunderstandings in the future, the logs (Attachment D) and processes described immediately above will be followed going forward.
4. Based upon our review of Study 1 (Listeria monocytogenes) we request further explanations for the discrepancies between the amount of monetary compensation to subjects provided an the consent form approved by the IRB [redacted] and [redacted] vs. the amount of monetary compensation calculations in the protocol [redacted] and [redacted] respectively).
The compensation calculated for the consent forms was the accurate number, and what was actually paid to subjects for their participation in this prolonged study requiring multiple visits and 2 weeks in hospital . These rates were based upon a fixed amount per outpatient visit, and another fixed amount per inpatient period of 24 hours, and also included a bonus for subjects who made all follow-up visits in a timely fashion without a need to reschedule. These amounts fluctuated over the course of the study as additional visits for blood draws were added, and approved by the IRB after initial approval. I failed to accurately update the formal protocol to reflect these changes and apologize for this oversight and accept responsibility for it. Going forward, every effort will be made to update our protocols completely at continuing review, to reflect changes made over the preceding continuing review interval . The IRB submission logs described above and included as Attachment D will serve as a checklist so that I will be sure that every amendment can be formally added at the time of continuing review to the detailed protocol and protocol summary, as is currently required by the [redacted] IRB.
I very much appreciate the opportunity to respond to these concerns, and I understand the importance of the violations identified and my responsibility, as principal investigator, to address them and be sure they do not happen again. I do again note that my laboratory has improved over time, a point acknowledged by FDA inspectors at the time of their visit. As described above, two of the items identified as problematic for Study 2 (Salmonella typhimurium), were an effort to provide complete, accurate, and understandable information to the IRB.
I wish to proceed in full compliance with all federal and institutional policies and will respond immediately to any requests or suggestions for further actions or remedial efforts. No subjects have been enrolled in studies administering investigational vaccines since the FDA inspection of my laboratory. As is our primary goal, there have been no serious medical sequellae or complaints from subjects in these studies over the past decade, and we continue to make the safety of volunteers who participate our highest priority . All subjects who participated in these studies were fully informed of the risks and lack of any personal health benefits in the course of detailed discussions with me and/or my physician co-investigators.
I am providing a copy of the warning letter dated July 10, 2006 and this response and attachments to all of the institutional representatives and regulators listed below, and shall promptly attend to any additional requests made by the FDA or any of them. Thank you for your attention to this response.
Elizabeth L. Hohmann MD
Associate Professor of Medicine