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Massachusetts Institute of Technology Company Response Letter

Elazer R. Edelman, M.D ., Ph.D ., F.A.C.C.
Thomas D. and Virginia W. Cabot Professor
Director, Biomedical Engineering Center
Harvard-MIT Division of Health Sciences and Technology 77 Massachusetts Avenue, 16-343
Cambridge, MA 02139
Phone: (617) 253-1569 Pager (617) 732-5700 #11586
Fax: (617) 253-2514 Email: ere@mit.edu

July 6, 2004

Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
Program Enforcement Branch I (HFZ-311)
2094 Gaither Road
Rockville, Maryland 20850
Attention : Kevin M. Hopson, M.B.A., Consumer Safety Officer

Re: Warning Letter to Elazer R. Edelman, Director of MIT-BMEC

Dear Mr. Hopson:


In response to the Warning Letter issued on July 15, 2004; we understand the scope and magnitude of the issues raised, and are committed to ensuring that the Test Facility is fully compliant with Title 21, Code of Federal Regulations (CFR), Part 58 - Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies. This letter details responses to specific observations cited in the Warning Letter, corrective actions the Test Facility taken, and further measures and practices that have been implemented or are in progress. We are pleased that you found our "written responses on February 12, March 10, and March 12, 2004 to the Form FDA 483 . . . [that] describe the efforts taken by your testing facility management to address and correct violations observed during the inspection' acceptable, and that you found that our... actions, which include new and revised SOPs, employment and training of key personnel, and dispensing additional resources to critical areas, will provide greater consistency, reliability, and accountability in your GLP program.". We hope that this response will address the remainder of the outstanding issues. After you have had time to review our response, we respectfully request to meet with you in person to discuss our proposed actions.

Allow us to address specific issues 1-5 directly, and then describe the other general procedural changes implemented. The citation from the Warning Letter is provided verbatim [Enclosed document section 1.5], followed by a specific response and actions taken with reference to the appropriate supporting documentation keyed by number to the documents in the enclosed response binder.

1. The testing facility management failed to establish standard operating procedures (SOPs) adequate to ensure the quality and integrity of the data generated during the course of a study, to limit unauthorized and undocumented procedural deviations, and to establish controls to ensure accountability of SOPs (21 CFR 58.63(b), 58.81(a), 58.81(b), 58.81(d), 58.83, 58.90(t), and 58.107).

Example: There is no suitable SOP to track the handling of test and control articles that would preclude error in the receipt and distribution of each batch documented.

Response Handling of each test and control article is performed in accordance with manufacturer's or sponsor's instructions at receipt of test articles as detailed in SOP [redacted] implemented in May 2003. In accordance with this SOP the Test Facility employed new forms to ensure appropriate maintenance of receipt, distribution and retention of the test articles. The Test Facility recently revised the SOP to enhance further procedures for the receipt, distribution and retention of the test articles . The most recent revision is attached ([Enclosed document section 1.6]). In addition to the SOP revision, we will continue to retrain Test Facility staff along these lines, and review procedures to ensure compliance.

Supporting document

The Test Facility enclosed the revised SOP and test article log that deals with these issues

  • Revised SOP [redacted] [Enclosed document section 1.6]
  • [redacted] [Enclosed document section 1.6]
  • [redacted] Enclosed document section 1.6]

Example: There are no SOPs for the laboratory tests specifically required by study protocols.

Response Since May of 2003, specific laboratory tests to be performed, including the blood work-cited during the audit, are described in respective protocols for each GLP study. The revised SOPs and other documents are under revision in draft form. These documents should be available for issuance, staff retraining where appropriate and implementation on or before November 2004. These documents include:

  • SOP [redacted]
  • [redacted]
  • [redacted]

Example: There are no SOPs to determine the acceptability of reagents and solutions.

Response The revised SOP is under revision in draft form. These documents should be available for issuance, staff retraining where appropriate and implementation on or before November 2004.

  • [redacted]
  • [redacted]

Example: There is no suitable SOP for the collection and handling of specimens shipped to contractors for analyses.

Response The requisite SOPs and other documents are under revision in draft form. These documents should be available for issuance, staff retraining where appropriate and implementation on or before November 2004. These documents include:

  • SOP [redacted]
  • [redacted]
  • [redacted]


Example: There is no suitable SOP established for the testing and maintenance of autoclave located in the surgical room.

Response The Test Facility revised the SOP for autoclave testing and maintenance and specifically made reference to appropriate elements in the autoclave manual, and the Test Facility identified the individual responsible for documentation, autoclave maintenance and testing, and weekly validation via biological monitor. The Test Facility retrained staff regarding appropriate testing, maintenance and documentation procedures, and have reviewed procedures to ensure compliance. The subsequent SOP [redacted] is under revision in draft form. These documents should be available for issuance, staff retraining where appropriate and implementation on or before November 2004.

Supporting document

The revised SOP and sterilization log are appended in the attachments as:

  • Letter from [redacted], regarding staff training [Enclosed document section 1.1]
  • Revised SOP [redacted] Enclosed document section 1.7]
  • [redacted] [Enclosed document section 1.7]

Example: There is no suitable SOP established to address the inspection and maintenance of the defibrillator located in the operating room of the surgical unit.

Response An SOP has been generated describing use and maintenance of defibrillator and procedures reviewed to ensure compliance. Staff will be retrained in use, inspection, and maintenance of the defibrillator.

Supporting document

New SOP [redacted] [Enclosed document section 1.8]


Example: Deviations in a study from SOPs were not always authorized by the study director and documented in the raw data.

Response/Action According to the GLPs Roles and Responsibilities of the Study Director, all SOP and protocol deviations will be documented at time of occurrence by the observer and communicated to the Study Director in a timely fashion . New processes have been implemented for the Study Director to review and assess the impact of those deviations on revised SOP on Deviation Reporting . Test Facility staff have been retrained, and procedures reviewed to ensure compliance.

Supporting Document
Revised SOP [redacted] [Enclosed document section 1.9]
[redacted] [Enclosed document section 1.9]
[redacted] [Enclosed document section 1.9]
[redacted] [Enclosed document section 1.9]

  • Re-Training Presentation performed on May 12, 2004 [Enclosed document section 1.3]

Example A historical file of SOPs and all revisions including dates of such revisions was not maintained.

Response As per the Test Facility 438 audit response of March 12, 2004, a historical file was maintained in the Quality Assurance Unit since July 2002 and after revision in May 2003. Further modification to Test Facility procedures will enhance inspection of historical records. The Test Facility revised all relevant SOPs, retrained our staff, and reviewed our procedures to ensure that new revisions of existing SOPs are issued at the appropriate times, and that there is compliance with and control over issued SOPs.

Supporting Documents

  • Revised SOP [redacted] [Enclosed document section 1.4] and Sample format
  • Revised SOP [redacted] [ Enclosed document section 1.10]
  • Revised SOP [redacted] [Enclosed document section 1.11].
  • [redacted] Copies of Logs from vendor [redacted] from Feb-June 2004 [Enclosed document section 1 .12].
  • Revised SOP [redacted] [enclosed document section 1.13],
  • [redacted] [Enclosed document section 1.13]
  • [redacted] [Enclosed document section 1.13]
  • [redacted] [Enclosed document section 1.13]
  • Revised SOP [redacted] [Enclosed document section 1.14]
  • [redacted] [Enclosed document section 1.14] and
  • [redacted] [Enclosed document section 1 .14]

2. Failure to conduct studies per approved protocol (21 CFR 58.130).

Example: In Study [redacted] the Study Director did not adhere to the protocol by executing procedures outside of specific requirements for temperature and humidity.

Example: In Study [redacted] the Study Director did not adhere to the protocol by executing procedures outside of specific requirements for temperature and humidity.

Response The deviations from the specific requirements for temperature and humidity were transient, and reported to the building maintenance staff, Sponsor and Study Director at the time of occurrence. New procedures have been implemented to assure proper documentation and assessment of the impact of deviations by the Study Director. In the specific case cited, the Study Director concluded that there was no impact on the scientific integrity or results of the study. A letter to the sponsor was generated and the Final Report amended. Other issues relevant to control and recording of temperature and humidity have been addressed in staff training and revision of SOPs.

Supporting Documents

  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1]
  • Revised SOP [redacted] [Enclosed document section 1.9]
  • Revised SOP [redacted] [Enclosed document section section 2.2]
  • [redacted] [Enclosed document section 2.2]
  • [redacted] [Enclosed document section 2.2]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report [Enclosed document section 2.3]

3. Failure to retain reserve samples from each batch of test and control articles from studies longer than four weeks (21 CFR 58.105(d))

The testing facility does not maintain reserve samples for required studies. It was determined that the testing facility did not retain reserve samples for [redacted] and in, at least eight other studies conducted since 2001.

Response In accordance with GLP regulations and Test Facility revised SOP [redacted] [Enclosed document section 1.6]) reserve samples for studies whose duration is longer than four weeks shall be retained. As two of the three studies examined were substantially shorter [redacted] and [redacted] non-survival study of less then 24 hours duration) samples were not retained for these studies. In study [redacted] where the client only manufactured enough test articles for the animals in this study, the sponsor was informed at the time of implant of this issue that no sample could be retained and that a deviation would be filed with the Final Report.

Action To ensure that this matter will not recur, the Test Facility now request of each client in advance of the study adequate reserve articles from each lot to the testing facility for archiving in accordance to FDA regulations. The Test Facility now inserts into each protocol preceding the initiation of a study the following paragraph:

. . .Sponsor will provide at time of or prior to procedure one(1) reserve test article sample for each Lot# utilized in this study for Test Facility archiving per 21 CFR 58.105(d). Copies and/or originals of reports, data collection forms, and raw data may be retained by the research and pathology institution . All original raw data, data forms, resultant reports, histology, and used/unused devices will be submitted to and maintained by [SPONSOR] except where specified by the testing facility SOP's.

Supporting Documents

  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1]
  • [redacted] [Enclosed document section 1.6]

4. Failure to prepare the reporting of non-clinical laboratory study results (21 CFR 58.185)

Examples of this failure include but are not limited to the following :


Example: The final report for Study [redacted] does not not indicate the date when the study was initiated.

Response: The Test Facility has amended the final report to include the proper date the study was initiated and have presented this report to the study sponsor.

Supporting Documents:

  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1]

Example: The final reports for Studies [redacted] and [redacted] do not describe all circumstances that may have affected the quality or integrity of the data.

Response: Final Report Amendments have been issued by the Test Facility . The Study Director has determined that the deviations had no impact on the integrity of the scientific data or the interpretation of the results.

Supporting Documents:

  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.3]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 4.1]

Example: The final reports for Studies [redacted] and [redacted] do not have the names of scientists or professionals other than the study director, and the names of all supervisory personnel, involved in the study.

Response: Final Report Amendments have been issued by the Test Facility to include the names of scientists or professionals other than the study director and issued to the study sponsor but have also revised SOPs to ensure that these individuals be identified on all subsequent reports . The Test Facility will retrain staff along these lines, and review procedures to ensure compliance.

Supporting Documents:

  • Enclosed Letter from sponsor of study [redacted] [Enclosed document section 4.1]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.3]
  • Enclosed Letter to sponsor --- [Enclosed document section 2.3]
  • [redacted] [Enclosed document section 4.3]

Example: The final reports for Studies [redacted] and [redacted] do not include the signed and dated reports of each individual scientist or professional involved in the study

Response: The Final Report was amended to include the names of scientists or professionals other than the study director and issued to the study sponsor . The Test Facility has also revised SOP to ensure that these individuals be identified on all subsequent reports . Staff will also be retrained along these lines, and procedures reviewed to ensure compliance.

Supporting Documents:

Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.3]
Enclosed Letter to sponsor of Study[redacted] and amendment to Final Report. [Enclosed document section 4.1]
Enclosed Letter from Sponsor of Study [redacted] Contributing Scientists. [Enclosed document section 4.2]


Example: The final reports for Studies [redacted] and [redacted] do not identify the locations of all specimens, raw data, and records to be stored.

Response Amendments to the final report have been issued citing the location of specimens, raw data and final reports for studies [redacted] and [redacted]

Supporting Documents:

  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.3]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 4.1]
  • Enclosed Letter to sponsor of Study [redacted] [Enclosed document section 4.3]

5. Failure to have protocols that clearly contain information to conduct the non-clinical laboratory studies (21 CFR 58.120(a)(7))

Examples of this failure include but are not limited to the following:

Example: Protocols [redacted] and [redacted] do not contain a description and identification of the diet used in the non-clinical laboratory studies.

Response Current and future practice includes the description and identification of the diets used in both protocols and Final Reports. Specific diet brands are listed in protocols, and the ingredients with food analysis are included in the amendments to the Final Reports as well.

Supporting Documents:

  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.3]
  • Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 4.1]

GENERAL COMMENTS
Citation We acknowledged your written responses on February 12, March 10, and March 12, 2004 to the Form FDA 483. Your written responses describe the efforts taken by your testing facility management to address and correct violations observed during the inspection. We find that your actions, which include new and revised SOPs, employment and training of key personnel, and dispensing additional resources to critical areas, will provide greater consistency, reliability, and accountability in your GLP program. Other improvements and changes to your GLP program were verbally communicated to our office on May 18-20, 2004. Please provide a status report of the changes proposed and implemented to date, a timetable of when they will be completed, and an explanation for any rescission of corrective actions proposed in your February 12, March 10, and March 12, 2004, letters.

Response The Test Facility is committed to GLP and as described above has attempted to address all deficiencies cited. In particular the Test Facility implemented three major areas of improvement regarding: 1) generation and maintenance of SOPs; 2) closure of outstanding studies and amendment of final reports for studies that utilized cited SOPs; 3) staff training.

SOP Generation and maintenance As described above, the Test Facility made every effort to ensure that SOPs are in place for every procedure performed. While the Test Facility responded to each specific citation above, the Test Facility also implemented a program to review and update all SOPs. The details of how this is performed are described in SOP on preparing procedures. In general, the Test Facility is pursing the following .

All new SOPs will adhere to the SOP Enclosed Letter to sponsor of Study [redacted] and amendment to Final Report. [Enclosed document section 2.1] [Enclosed document section 1.4]

As described in the SOP on Maintenance of SOPs ([redacted] [Enclosed document section 1.10]) the Test Facility revised the schedule of SOP review, and the Unit Managers have begun a review of all existing SOPs on an accelerated basis in critical areas.

Master Schedule The Test Facility Master Schedule is now current and up to date. Significant progress has been made in closing outstanding studies and finalization of reports . The Final Reports of other closed GLP studies listed on the Master Schedule which may have been affected by audit findings will undergo a re-audit by QAU to assure compliance with 21 CFR 58 requirements . Final Report amendments will be issued and forwarded to Sponsors if appropriate . The Test Facility will strive to accomplish this in a timely fashion but will likely extend beyond November 2004.

Supporting Documents

  • [redacted] [enclosed document section 5.1]
  • [redacted] [enclosed document section 5.2]

Training As discussed in far more detail below, the Test Facility are committed to training as the essential element of GLP adherence and have implemented a regular education program which instructs staff as to their specific requirements and importance of SOPs. The Test Facility management has already met on this topic with Test Facility staff on two occasions (February and May 12, 2004) and presented the enclosed presentation (Enclosed document Sections [1.1-1.3]).


HISTORICAL PROTOCOL DEVIATIONS With regard to your response to the FDA 483, Observation 3 (protocol deviations), we believe that the actions to notify the building maintenance and the study sponsor after each deviation are appropriate. Resolution should be documented in the study records and described in the final report. If the deviations are permanent and they change the requirements described in the approved study protocol, documentation of the changes and the reason for the changes are best accomplished by issuing a formal protocol amendment. If exceptions from laboratory's SOPs apply for the study, then those exceptions should be described in the protocol. In cases where it is impossible to issue an amendment prospectively, an amendment should be issued as soon as possible.

Response As described above, the Test Facility documented all protocol deviations in amended final reports which have been submitted to sponsors with an appropriate notification letter . In the instances cited, there was no reason to issue a protocol amendment. The Test Facility however implemented all of the other safeguards with regard to SOP maintenance, and staff training to deal with these matters. As described above, the Test Facility changed the deviation reporting process and retrained staff along these lines.

  • Revised SOP [redacted] [Enclosed document section 1.9]

PERSONNEL TRAINING There is a need for personnel to understand GLP requirements; especially the testing facility management. This familiarity helps to assure that the study personnel are aware of the requirements set forth in the regulation which may alleviate future violations. If the testing facility decides to conduct a nonclinical laboratory study subject to GLP requirements, then the management of the testing facility must assure that the nonclinical laboratory study complies with these requirements . Although the testing facility management requires the quality assurance unit to maintain a master schedule, there is no assurance that all nonclinical laboratory studies conducted at the testing facility and subject to this regulation are included in the master schedule.

Response The Test Facility management and staff understand that training is the linchpin of GLP adherence and have placed great emphasis on providing Test Facility staff with access to all guidelines, experts in Quality Control/Quality Assurance and formal training. Selected management staff have, since 2002, and will continue to attend regular meetings of the Society of Quality Assurance Annual Training Conference. Additional management personnel are scheduled to attend the SQA Annual Training Conference in February of 2005. After each of these visits, the attendees will conduct internal training sessions. The Test Facility is currently in the development phase of an internal training program and seeking external sources for additional training of all staff in both GLP and technical tasks.

As an extension of our commitment, the Test Facility hired [redacted] as a part-time quality assurance/quality control consultant. [redacted] spends two full days per week in the Test Facility . He works with the Quality Assurance Unit to ensure compliance with regulations and to respond to the audit observations. [redacted] has a long history in the field. His curriculum vitae is attached. In addition to graduate work in the field of Quality Control, more than 35 years of industrial experience and tenure as a Professor at Boston University and Suffolk University Schools of Business [redacted] is a Fellow of The American Society for Quality (ASQ), and former Chairman of the Electronics Division of the Society. As an active and voting member of committee Z1 of ASQ, he reviews and comments on Quality System documents of the ISO 9000 and ISO 14000 series . He was a Technical Expert of the US National Committee, and was Assistant Secretary of Technical Committee 56, of the International Electrotechnical Commission (IEC) for 10 years. Additionally, he is a Senior Member of the IEEE, and former Chairman of the Reliability Definitions and Standards Committee[redacted] brings invaluable experience and insight to the issues of GLP, QA and QC. As [redacted] he will have
no responsibility for or in any way be involved in any study being conducted at or in the operation of the lab. His principal responsibility will remain support of the BMECI organization's procedure system to assure corrective action based on the audit findings.

[redacted] and [redacted] have created a formal educational program to add to the routine GLP seminars that is presented to the Test Facility staff. This now includes a PowerPoint presentation that is enclosed that reviews the audit and its findings as well as the audit and Warning Letter response.

Supporting Documents

  • [redacted] [Enclosed document section 5.3]
  • [redacted] [Enclosed document section 1.3]
  • [redacted] Enclosed document section 1.2]

FINAL REPORTS Additionally, management should address the preparation of the final reports. Reports from professionals and scientists involved in the study should be finalized and included in the report before it is signed and dated by the study director. Any changes in the report must be in the form of an amendment which meets the requirements of 21 CFR 58.185. To avoid the necessity for many report amendments, the report should not be signed by the study director until it has been reviewed by the scientists involved in the study, has been audited by the quality assurance unit, and after all changes and corrections occasioned by that review and audit have been made.

Response The Test Facility closed a significant number of outstanding studies with final reports, and submitted amendments to final reports for studies cited as non-adherent to SOPs or using deficient SOPs. Final Report generation has now been changed. As part of that SOP, it is now made clear that "the report should not be signed by the study director until it has been reviewed by the scientists involved in the study, has been audited by the quality assurance unit, and after all changes and
corrections occasioned by that review and audit have been made.

  • [redacted] [Enclosed document section 4.3]

SPONSOR NOTIFICATION The sponsor should be informed of the noncompliance conducted in the analyses and services directly involved in their sponsored studies. Generally, sponsors are required to report whether nonclinical laboratory studies intended to support an application submitted to FDA were conducted in compliance with Part 58. See e.g. 21 CFR 812.27, 21 CFR 312.23(a)(8)(iii), 21 CFR 314.50(d)(2)(v), and 21 CFR 814.20(b)(6)(i) for Investigational Device Exemptions, Investigational New Drugs, New Drug Applications, and Premarket Approval Applications respectively.

Response All sponsors affected have been notified in writing of the Warning Letter and have received amendments to the Final Reports.

  • Support in Documents Enclosed Letters and amendments to sponsors from Study Director [redacted] [Enclosed document sections 2.1, 2.3, and 4.1]

Once again we appreciate the opportunity to respond to the issued Warning Letter and to inform the FDA of the changes the Test Facility implemented to ensure compliance with Good Laboratory Practice standards . Adherence to GLP is important to us. Our written response, revised SOPs and internal educational program are testimony to this commitment. We respectfully request a face-to-face interview to review our responses and to determine if they are adequate and complete. Finally, we are receiving inquiries regarding the Warning Letter as it is now posted on the FDA website. We are eager to learn when might our response be posted so that we can refer inquires to the web site as well?

Sincerely yours,

/s/
Elazer Edelman