FDA is adopting whole-heartedly at least one of Iowa Republican Senator Grassley's new de facto rules for drug approval reviews: the agency is not going to risk its public credibility by continuing to consider for approval applications where there is even a hint of a data integrity problem.That's one of the lessons of the Ketek investigation and one that Theravance experienced painfully late last month. On March 3, Theravance explained more about the last-minute cancellation in the planned February 27 FDA advisory committee review for its injectable antibiotic, telavancin.
The delay stems from FDA's unwillingness to review the application after the removal of data from one study site. Theravance said that the agency asked the company to remove the data from the site on January 30, twenty-seven days before the scheduled Anti-infective Drugs Advisory Committee and nineteen days after the agency first announced its intention to hold the advisory committee review of the drug.
Theravance maintains that the "removal of these data had no material impact on the overall efficacy and safety results or conclusions of the study previously reported, and we believed the site issue had been adequately addressed by the data removal."
In that case, the company was too focused on its own application and not paying attention to the overall environment and the pressure on FDA from Grassley's intense oversight -- focused in particular on the agency's willingness to overlook some questionable data to keep an applicaiton on track for approval.
Grassley sent FDA a letter on December 19 in his continuing review of FDA's handling of the Sanofi-Aventis Ketek (telithromycin) application that created a de facto standard: a sponsor cannot resolve a data integrity issue by just removing the results from the questioned center or investigator.
In his mid-December letter, Grassley made it very clear that he expects FDA to halt the approval process on applications if the agency finds any problems with data integrity. (See here for our previous coverage of Grassley's Ketek rule.)
Grassley's letter coming right before the Christmas holiday break was probably ignored by much of the financial community. It was also overshadowed by Theravance's December 27 announcement that it was getting ready for an imminent advisory committee review.
FDA tried to work around questionable data before. It asked an advisory committee previously to review the Ketek application with some suspect data from a clinical investigator removed. Based on the heat it has taken from Grassley for that review, FDA was unlikely to repeat that process of a quick fix for the data in the case of another drug, especially another antibiotic.
Theravance says it is "committed to working with the FDA to resolve outstanding issues related" to the telavancin clinical trials for complicated skin and skin structure infections, the "ATLAS program." The company reports that FDA wants to "further evaluate study site monitoring and study conduct to ensure data integrity in the ATLAS Phase 3 program." The agency wants to look into monitoring at other sites and not just take the word of the contract research organization.
Other NDA sponsors would be well advised to pay more attention to all pending data integrity issues for products nearing the review stage. The agency's division of scientific investigations is clearly emboldened and carrying more weight within FDA from Grassley's attention (See here).
Theravance's follow-up statement, however, at least begins to peel back the cover from the mystery of the recent wave of meeting cancellations. For a while in February, it looked like FDA did not want to bring any products to advisory committees. The agency canceled three meetings last month (see here).
