Released by FDA:  4/26/04.  Posted by FDA:  5/7/04

Gilbert Godin, B.Eng., M.B.A.
Group Vice-President, Early Stage Development
MDS Pharma Services
2350 Cohen Street
Saint-Laurent (Montreal) Quebec H4R 2N6 Canada

Dear Mr. Godin:

Between July 7 and 9, 2003, Allen F. Hall, Martin K. Yau, Ph.D., and Sriram Subramaniam, Ph.D., representing the Food and Drug Administration (FDA), inspected the following bioequivalence study conducted by your firm:

Study [deleted by FDA] "Comparative, Randomized, Single Dose, Four-Way Crossover, Fully-Replicated Bioavailability Study of [deleted by FDA] and Schering (Claritin®) 10 mg Loratadine Tablets in Healthy Adult Males Under Fasting Conditions Following a 40mg Dose," performed for [deleted by FDA]

This inspection is a part of FDA's Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research, to ensure that the rights, safety, and welfare of the human subjects of the study have been protected, and to verify compliance with Title 21 of the Code of Federal Regulations (CFR), Part 320, Bioavailability and Bioequivalence Requirements.

At the conclusion of the inspection, our personnel presented and discussed with [deleted by FDA] Ph.D. the items listed on Form FDA 483, Inspectional Observations. Following our review of the establishment inspection report and related documents, including the letter from Drs. [deleted by FDA] and [deleted by FDA] dated July 10, 2003, in response to the items listed on Form FDA 483, and the letter from [deleted by FDA] Ph.D. dated October 2, 2003, we conclude that you failed to demonstrate that the analytical method used in this in vivo bioavailability study was accurate to measure the actual concentration of loratadine and its metabolite, descarboethoxyloratadine, achieved in the body, as required by 21 CFR 320.29(a).

Your analytical method for determining loratadine and descarboethoxyloratadine concentrations in subject plasma samples for this bioequivalence study used [deleted by FDA]

It is our understanding that during your analysis of plasma samples, it became apparent that at least 32 subject samples were contaminated because the samples contained unexpectedly high analyte concentrations.  To assure accurate data when this occurred, you should have conducted a thorough and systematic evaluation to determine the extent and source of the contamination.  Instead, you assumed that the contamination was limited to those samples with anomalous results.  Based on this assumption, you selectively reassayed only the samples you assumed were affected, representing less than 1% of the total subject samples.  We conclude that the limited steps you took to investigate and address the source of contamination failed to provide assurance of the accuracy of your analytical method as it was utilized in this study, as required by 21 CFR 320.29(a).

In your initial response to FDA Form 483 (letter dated July 10, 2003), you provided additional data and calculations that you claimed supported the validity of the original plasma sample analysis, notwithstanding the presence of contaminated samples.  We note the following deficiencies in your analyses:

Your subsequent response (letter dated October 2, 2003) described your post-FDA inspection efforts to evaluate the potential role of the [deleted by FDA] in the contamination of plasma samples.  This response included the results of the [deleted by FDA] experiments you conducted using [deleted by FDA]  You indicated that your investigation did not identify the source of contamination and acknowledged that "there are numerous places where contamination might have occurred."  You concluded "that it is extremely unlikely that cross well contamination in the instrument caused or contributed to the few random high concentrations observed" and that your initial assumption about the source of contamination "was erroneous."  However, notwithstanding your failure to identify the source of contamination, you maintained that your original data were "solid and valid."

In your October 2, 2003, response, you reconsidered your original position concerning the need to reassay samples, and concurred with the agency's position that all of the subject samples should have been reassayed.  You subsequently re-analyzed the entirety of the subject samples, and the sponsor submitted this data to the agency on December 22, 2003.  The agency conducted a follow-up inspection at your facility on February 9-13, 2004, to inspect the data from your reanalysis.  Our audit found, among other things, that the data related to [deleted by FDA] experiments were missing.  You claimed that these data could not be found.

As discussed above, your approach to investigating sources of contamination in bioequivalence studies is inadequate and has resulted in the submission of invalid data to the agency.  You should have conducted a systematic and thorough evaluation to identify and correct the source of contamination when it was first observed.  Our inspections indicate that your facility lacks adequate policies and procedures to address such contamination issues.  The manner in which MDS Pharma investigated the contamination problem in this study causes FDA to have concerns with the validity of other bioequivalence data generated by MDS Pharma.  Because of these concerns, the agency intends to determine on a case-by-case basis what additional steps may be necessary to assure the accuracy and validity of the analytical method for bioequivalence data generated by MDS Pharma in pending and future applications.  Such steps could include, among other things, additional inspections, third-party audits, and rejection of data where circumstances warrant.

If you have questions or concerns about the issues raised in this letter, please reply to:

C.T. Viswanathan, Ph.D.
Associate Director, Bioequivalence
Chief, GLP & Bioequivalence Investigations Branch
Division of Scientific Investigations
Office of Medical Policy
Center for Drug Evaluation and Research
7520 Standish Place, Room 116
Rockville, MD 20855
Telephone: (301) 827-5460

Sincerely,

Joanne L. Rhoads, M.D., MPH
Director
Division of Scientific Investigations
Office of Medical Policy
Center for Drug Evaluation and Research