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Massachusetts Institute of Technology FDA Response Letter


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration

Center for Devices and Radiological Health

2098 Gaither Road

Rockville, MD 20850

Via Federal Express

OCT 5 2004

Elazer R. Edelman, M.D., Ph.D., F.A.C.C.
Director, Biomedical Engineering Center
Thomas D. and Virginia W. Cabot Professor
Harvard - MIT Division of Health Sciences and Technology
77 Massachusetts Avenue, 16-343
Cambridge, Massachusetts 02139

Dear Dr. Edelman:

The purpose of this letter is to acknowledge receipt of your July 6, 2004, response to the Warning Letter, which you received on June 15, 2004. Your correspondence will be made a part of our official files.

The corrective actions taken by Harvard - MIT Division of Health Sciences and Technology at the Biomedical Engineering/Experimental Cardiovascular Interventional Laboratory at Brigham and Women's Hospital and the Edelman Laboratory of the Biomedical Engineering Center at Massachusetts Institute of Technology-Histology Unit focus primarily on proposed and implemented changes that will affect its current operations to oversee nonclinical laboratory studies subject to Food and Drug Administration's Good Laboratory Practice (GLP) regulations, i.e., Title 21, Code of Federal Regulations, Part 58.

Your effort is a clear and formal indication that GLP compliance is being taken seriously at the testing facility. Your actions to develop written procedures, to amend or correct final reports, to audit GLP studies, and to train and hire current staff will provide greater consistency and accountability in this aspect.

We have reviewed your corrective action plan. We recommend that you consider our comments as means to facilitate improvement and communication at your testing facility.

The final reports of the FDA-audited nonclinical laboratory studies were amended to correct the reporting deficiencies. None of the subsequent changes made to the final reports were reviewed by the Quality Assurance Unit (QAU) to confirm the accuracy and completeness of the amendment or correction.

It follows that after the original report has been changed, the QAU should review the changes in the draft report, check it against the original report and audit record, and report its findings to the study director and management. The QAU must follow up on its activities to its satisfaction. In the event, the matter remains unsolved; the matter should be referred to management for consideration and final decision. The QAU assures management that the facilities, equipment, personnel, methods, practices, records, and controls used for a study complies with applicable rules and regulations. The testing facility must develop, implement, and conduct procedures that fulfill its quality assurance responsibilities.

The study director should also assure herself or himself that there was a QAU review of the amendment. If the study director is satisfied that the report is a complete, true and accurate representation of the study and its results, then and only then, should the study director sign and date the amendment to indicate acceptance of responsibility for the validity of the data.

As you devise requisite standard operating procedures and other documents, you should address services outsourced to other nonclinical laboratories. It is your responsibility to determine by periodic visits that the contract facility complies with GLP requirements. Your QAU should have SOPs that describe the quality assurance oversight and reporting when portions of the study are contracted --- whether the contractor has its own QAU or not. The QAU of the relevant facility should provide information concerning the work for which it is responsible. If the contract facility does not have its own QAU, your facility must perform all quality assurance functions and take whatever steps are required to promote the GLP compliance of the contract facility. In this scenario, the contractor's laboratory should be considered as an extension of your testing facility and subjected to equivalent requirements and monitoring procedures.

You mentioned that final reports of closed nonclinical laboratory studies, which might have been affected by the findings of the FDA inspection, will undergo an audit to determine compliance with GLP regulations and, if appropriate, final amendments will be issued and forwarded to the sponsors. Based on your supporting documentation, we cannot determine if final report amendments were prepared to address the observations of noncompliant activity.

The QAU report is a confirmation of what, if anything was found, and what actions were taken to correct any deviations. There is no documentation to support, such as the date of the notices to the facility management; in some reports, notices to the study director about the deficiencies in final reports, histology records, study protocols, and other records. See your QAU reports [redacted] in [redacted] and [redacted] on page [redacted] of response for noclinical laboratory studies: [redacted], [redacted], [redacted], [redacted],[redacted], [redacted] and [redacted]. There is no documentation that measures were executed by the study director and testing facility management to resolve the deviations observed by the QAU.

The QAU does not attest to the state of compliance or non-compliance in the study. The responsibility lies with the study director and the study sponsor. The QAU inspects the operational phases of a study, monitors actions taken in response to quality assurance reports, and reports those actions, issues, and other findings, including deviations to the study plan, to the testing facility management and study director. The GLP regulations mandate that the study director has the primary responsibility in assuring the conduct of the study meets regulatory requirements. The study director represents the single point of study control. The study director serves to assure that the scientific, administrative and regulatory aspects of the study are controlled. Lines of communication must be established to ensure that deviations from the study plans are rapidly transmitted and that issues arising from these deviations are documented and followed.

The sponsor directly submits the results to the regulatory authorities such as FDA. When the sponsor commissions a testing facility to conduct a nonclinical laboratory study, the sponsor must ensure that the testing facility is able to conduct the study in compliance with GLP regulations. As stated in the Warning Letter, the sponsor are obligated to notify FDA about the compliance of their nonclinical laboratory studies to the GLP regulations as part of their research or market application.

Your master schedule does not contain all nonclinical laboratory studies subject to GLP regulations. See 21 CFR 58.3(d). FDA knows of, at least, one sponsor whose application an Investigational Device Exemption) contains a nonclinical laboratory study [redacted] that is subject to GLP regulations conducted at this testing facility. [redacted] is identified as the study director. We are aware that the sponsor did not notify you of [redacted] on the necessity to conduct the study according to GLP regulations.

Testing facility management must take an active role in determining what nonclinical studies fall within the scope of the GLP regulation (21 CFR 58.1). Nonclinical studies intended to be submitted to FDA should be listed . FDA can inspect these studies under its authority to evaluate the test results of the studies designed to demonstrate product safety.

Management of a testing facility is responsible for ensuring that the facility operates in compliance with the Good Laboratory Practice regulations. It is in the best interest of the testing facility management to have written procedures for documenting their interactions with sponsors on these matters. If testing facility management believes the study is within the scope of part 58, they should resolve the matter with the sponsor. If the matter is not resolved, the testing facility management should decline the study. The effective date of the federal regulation is June 20, 1979. Nonclinical laboratory studies initiated on or after the effective date were to be done in full compliance with this federal regulation: See Federal Register, Volume 43, Number 247, page 60013.

This responsibility includes the appointment and effective organization of an adequate number of appropriately qualified and experienced staff throughout the facility, including study directors and quality assurance professionals who are designated as the Quality Assurance Unit. Management has the responsibility for support of the personnel to ensure that studies are carried out in compliance with the GLP regulations. The QAU must be aware of all nonclinical laboratory studies subject to this regulation so they can properly execute their duties. It is in the best interest of the testing facility management to maintain a SOP defining the procedures adopted for selection and appointment of study directors and other personnel. Failure to communicate adequately is the main factor leading to unsatisfactory conclusions in the conduct of nonclinical laboratory studies.

We recommend that you submit an update of any changes made since July 6, 2004, and a status report periodically as you implement your corrective action plan. FDA may verify if these changes have been properly implemented and determine if these changes have been effective to improve your testing facility's good laboratory practices through future site inspections.

Please direct questions concerning this matter to Mr. Kevin Hopson, M.B.A., at (240) 276-0125.


David R. Kalins
Chief, Program Enforcement Branch I
Division of Bioresearch Monitoring
Office of Compliance
Center for Devices and Radiological Health