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U.S. Department of Health and Human Services

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Matthew P. Malcolm, PhD, OTR - Warning Letter Response 6/4/12


Department of Occupational Therapy
College of Applied Human Science
Port Collins, Colorado 80523-1573
(970) 491-6253
FAX: (970) 491-6290

June 4, 2012

Kathy Weil
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3566
Silver Spring, Maryland 20993-0002

Dear Ms. Weil:

This letter is in response to a warning letter for CTS# G070098/E001 dated May 22, 2012 from the FDA, which I received at my office on May 24, 2012.  I want to respond to the issues raised in the warning letter, in order to provide clear information on corrective actions and any appropriate preventative actions we have taken or will undertake in the future.  We remain very committed to maintaining the safety of research participants and to limit all study-related risks to the greatest possible extent.  Importantly, this study is closed to enrollment and we are now in the process of data dissemination.  Accordingly, some requests for future planning and preventative actions will not be applicable.  I would like to request that this response to the warning letter is posted on the FDA website.

1. Failure to ensure that informed consent was obtained in accordance with 21 CFR Part 50 [21 CFR 50.25(a)(2) and 812.100].

FDA COMMENT: “Your response is inadequate in that you do not fully explain your procedure for ensuring that site staff will access the correct lCD version in future situations. Please provide a description of this procedure and documentation of staff training on the procedure.”

RESPONSE:  As previously mentioned, we have not enrolled any participants within the last year and have closed the study to future enrollment.  Accordingly, staff training on ICD procedures is not applicable for this investigation.  In future studies, however, we will ensure proper procedures, training, and documentation for correct ICD use. 

FDA COMMENT: “…since hearing risks were not provided to subjects as a result of receiving the wrong lCD. Please provide us with copies of any communications to subjects and the results of your follow-up attempts.”

RESPONSE:  We want to address two points raised in this issue.  First, we agree that insufficient written information was provided in the original ICD regarding our methods to protect hearing.  However, even though the most current version of the ICD was mistakenly not used, subjects were provided with the exact same information regarding hearing risks in both the original and revised ICD’s.  The below sections of the original and revised ICDs describe hearing risks and methods around this. 

The original ICD stated the following:

Other risks that could occur with TMS include dental pain and mild hearing loss (we will have you where ear plugs to limit this risk).

The revised, FDA-approved ICD indicates the same information regarding hearing-related risks, but explicates our methods for protecting hearing in written form as follows:

Other risks that could occur with TMS include dental pain and mild hearing loss.  To limit the risk of hearing loss, we will provide you with earplugs which we will ask you to wear during delivery of TMS.  We will frequently re-check the earplugs to make sure they are staying in your ears.  If you feel the earplugs become loose or fall out, please let us know immediately.  We will stop TMS to correct the earplug placement.  We will also stop TMS if we notice that the earplugs become loose.

CORRECTIVE ACTION:  In regards to the second point raised, i.e., follow-up attempts with subjects, we have documented recent follow-up phone conversations with subjects regarding any hearing changes.  This information has been recorded on the Case Report Form (copies of these forms are provided in Appendix).  We have spoken with 12 of the 16 subjects.  We learned that one subject had since passed away sometime around (b)(6).  In the case of the remaining three subjects, we were unable to reach two after three phone attempts and another individual’s phone has been disconnected.  All three of these individuals were sent a letter by certified mail to their last known address requesting them to contact the PI.  These letters specifically ask that the subjects provide contact information with a request for the individual to contact the PI by mail or phone.  Copies of these letters are included in the Appendix.

During these post-study follow-up phone calls, we noted four reportable (non-adverse) events that we deem as unrelated to study procedures.  One subject had an episode of internal bleeding related to being on a blood thinner.  One subject had apparent bladder problems.  One subject passed away.  One subject had a traumatic liver injury.  In each of these cases, the health event occurred 2 to 3 years following their participation in the study.  Each of these events were reported to the local IRB on June 4, 2012.  We have included a an expanded summary of information obtained in these and the ‘unremarkable’ phone calls in the Appendix.   

2. Failure to maintain accurate, complete, and current records relating to all relevant observations, including anticipated and unanticipated adverse events [21 CFR 812.140(a)(3)(ii)].

FDA COMMENT:  “In your response letter, pg. 8, Corrective action for Observation 5i and ii, you stated that you will report adverse events to the IRB and FDA in accordance with reporting requirements. Your response is inadequate in that you did not tell us how you rectified the adverse event deficiencies listed above, or provide us with your future process for obtaining and reviewing adverse events and with documentation of staff training. Please provide this information in writing.”

RESPONSE:  We agree that information consisting of potential adverse events should be appropriately reported.  At the time, these occurrences were viewed as completely unrelated to study activities that had occurred one or more months prior.  Additionally, most of these are of a nature that does not relate to any of the known risks in our protocol.  On the other hand, we understand that some unknown risks may occur and therefore there exists some possibility that health-related events may somehow be related to participation in the study.  Further, we also appreciate that documenting individual events that appear unrelated to the study may establish a pattern of adverse effects that were unanticipated.  In the case of the events raised by the FDA, we do not believe that the health-related issues were resultant from participation in the study.

CORRECTIVE ACTION:  We submitted the events and observations noted by the FDA reviewers to the local IRB for review on May 29, 2012.  We have also reviewed the remaining phone logs for any additional adverse events or health-related observations.  We found no new adverse or problematic health events in any additional phone logs.  We did, however, note two health improvements in a subject who had been identified by the FDA reviewers on Form 483.  Specifically, subject BS001 reported during a 1/25/08 phone call that she no longer needed an eye patch and had not had headaches for the previous two weeks.  We want to bring this to the attention of the FDA, because as the FDA reviewers noted in their Form 483 report, there had been some negative health issues with the subject post-study intervention.  A copy of this phone log is provided in the Appendix.

PREVENTATIVE ACTION:  Because all subjects enrolled have finished the study protocol and no further subjects will be enrolled, we generally do not anticipate any further adverse events or health-related observations.  As reported under item #1 above, we are in the process of contacting these past subjects to follow up.  The four reportable events have been submitted to the IRB for review (on 6/4/12).  We are awaiting responses back for three past participants who were mailed a certified letter requesting them to contact us.  For these remaining three individuals, if we learn of any changes in health or adverse events, we will immediately report to the IRB.  

3. Failure to maintain accurate, complete, and current records relating to each subject's case history and all relevant observations, including records showing the dates and reasons for each deviation from the protocol [21 CFR 812.140(a)(3) and 812.140(a)(4)].

FDA COMMENT:  “In your response letter, Appendices 1, 2, 4, and 7, you provided copies of your revised Screening procedure, General Study procedure, Neurology Screen form, and your newly-created Case Report Form for documenting events not otherwise captured in the study documents. We also request that you provide documentation of staff training on these procedures and the use of these forms.”

RESPONSE:  As previously mentioned, we have not enrolled any participants within the last year and have closed the study to future enrollment.  Accordingly, staff training on these forms currently is not applicable for this investigation.  In future studies, however, we will use these forms (or something very similar) to ensure proper procedures, and will conduct and document training on the use of the forms.

4. Failure to prepare and submit progress reports to FDA at regular intervals and at least yearly [21 CFR 812.150(b)(5)].

FDA COMMENT: “In your response letter, pg. 9, Corrective action for Observation 7, you stated that you had incorrectly assumed that progress reports were no longer necessary because the study was no longer enrolling subjects. You sent a letter, dated February 24, 2012, to the FDA Document Mail Center explaining this situation, stating that you are now in the process of drafting the progress report. Please provide us with an update on the status of this progress report and an expected completion date.”

CORRECTIVE ACTION:  A progress report was sent to the FDA on May 3rd 2012 and received by the FDA on May 7th 2012 (verification of receipt of the progress report is included in the Appendix, i.e., in a letter from the FDA dated May 7th 2012).  Through email communications with the scientific reviewer, Dr. Bernard Berne, at the FDA, I and the reviewer determined that a termination of the investigation was appropriate given that we are done enrolling subjects.  Dr. Berne indicated in his email dated May 15th 2012 that the “FDA's response to your submission will acknowledge the termination of your investigation”.  Copies of the email communications are included in the Appendix.  After a teleconference with FDA representatives Adam Donat and Kathy Weil (meeting minutes in Appendix), I understand that I should also send a letter to the FDA to explicitly indicate our intention to close the investigation.  A copy of said letter is included in the Appendix and will be mailed the week of June 4, 2012. 

FDA COMMENT:  “In your response, pg. 9, Corrective action for Observation 8i, ii, and iii, you stated that you plan to expand the DSMC responsibilities to include review of all study forms and procedures to ensure compliance with the written protocol and Standard Operating Procedures, and reporting of all findings.  Please provide us with a complete monitoring plan including your proposed expanded procedures for monitoring.”

RESPONSE:  As previously mentioned, we have not enrolled any participants within the last year and have closed the study to future enrollment.  Accordingly, we will not be convening another DMSC meeting.  In future studies, however, we will form a DSMC with duties and procedures that align with the FDA’s Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. 

I am happy to provide additional information as the FDA may require.  I will also send a copy of this report to the FDA’s Denver District Office as requested in the warning letter.  I am the contact person for this application.  I authorize the FDA to contact me by email or fax regarding this application.



Matt Malcolm, PHD, OTR
Associate Professor
Colorado State University