MDS Inc sustained another blow to its reputation and finances as the US Food and Drug Administration asked a number of the Canadian company’s clients to re-evaluate pharmacokinetic studies conducted by MDS for approved or pending branded and generic medicines.

The FDA is sending out more than 1,000 letters to companies with drugs cleared or filed for marketing approval that may have used data from pharmacokinetic tests performed by MDS between 2000 and 2004. Although only a small proportion of these applications are likely to be affected, and the FDA has no evidence to date that any of the drugs pose a safety risk, the agency said it acting “as a precautionary measure” to ensure that data submitted and used in making approval decisions was “of the highest quality”.

MDS’ problems with the FDA date back to July 2003, when its MDS Pharma Services subsidiary received a Form 483 inspection report from the US agency following a routine audit of bioequivalence studies conducted by the company at its Canadian facility in St. Laurent, Quebec. A Form 483 ‘Notice of Inspectional Observations’ lists any regulatory discrepancies noted by an FDA field investigator in the course of a site visit.

Subsequent discussions with the agency and further inspections of the St. Laurent facility failed to resolve the FDA’s concerns, and in December 2004 it wrote to MDS asking the company to review five years of bioequivalence studies at the site. This audit started in March 2005. A year later, though, an FDA inspection of the bioequivalence operations at St. Laurent and another facility in Blainville, Quebec generated another Form 483 questioning the validity and effectiveness of MDS’ Retrospective Review.

The company’s efforts to bring the review up to scratch included suspending all commercial bioanalytical liquid chromatography/mass spectrometry testing at St. Laurent. The FDA’s concerns persisted, nonetheless. Last year some MDS clients received letters from the agency indicating that approval submissions containing bioequivalence data from the St. Laurent and Blainville facilities would not be approved until the issues raised by the FDA had been resolved.

Now the agency has expanded on this initiative by following up directly with all pharmaceutical companies whose marketed drugs or pending approval applications may have been affected by the observed discrepancies in testing at the Quebec facilities. These included failure to “conduct a systematic and thorough evaluation” that would identify and correct sources of contamination; lack of assay reproducibility between original and repeat results; and “biased manipulation of study data”, resulting in the acceptance of failed test runs.

While there was no sign of any problem with the efficacy, quality, purity or potency of the affected products, the FDA had identified significant deficiencies with MDS’ audit of its bioequivalence data at its most recent inspection of the Quebec facilities, it noted. Consequently, it informed the companies’ clients, “serious questions remain about the validity of bioequivalence data generated by MDS in studies during this time period [January 2000 to December 2004] that have not been inspected by FDA, including the studies you submitted in support of your applications”.

The agency has given MDS’ clients the choice of (preferably) repeating the affected studies; re-assaying the samples at a different bioequivalence facility; or commissioning a scientific audit from an independent expert, “selected by your company rather than MDS”, to verify the results obtained by MDS.

The FDA has also asked companies to compare the blood/plasma level results from these studies with any published literature or other relevant and publicly available information, as “one of the agency’s significant findings for the inspected MDS studies was the presence of anomalous results”. It has set a recommended timeframe of six months for completing whichever testing option is chosen.

Crisp path forward

In response, MDS said it would immediately scrap the Retrospective Review and redirect its efforts towards supporting clients with independent audit activities. While the company still believed its review could effectively determine the validity of the data under question, the FDA’s approach was “an efficient path to bring closure to this issue” for its clients, MDS added.

“While we are disappointed in the time and effort that it has taken to get to this course of action, we believe that it will benefit everyone involved to have a crisp path forward to resolve this issue,” commented president and chief executive officer Stephen DeFalco.

The company has also suggested it could contribute towards its clients’ retesting costs. The Retrospective Review has already taken a slice out of its finances: Can$31 million in direct costs for the last fiscal year ended 31 October 2006. Bioequivalence work for generic manufacturers has declined significantly while MDS has been addressing the FDA’s concerns, it noted. Revenues from the bioanalytical and early clinical research services business dropped by 9% to Can$305 million in fiscal 2006.

Reimbursing clients or covering the cost of additional testing could put a bigger hole in MDS’ balance sheet, although the company will be insulated by the recent Can$1.3 billion disposal of its Canadian diagnostics business to Borealis Infrastructure Management. On the other hand, the sale proceeds could encourage lawsuits from disgruntled customers. By Peter Mansell