On March 28, the FDA issued a notice (here) informing pharmaceutical companies that have submitted in vitro and in vivo bioequivalence studies in applications that were conducted by Raptim Research Pvt. Ltd., a contract research organization (CRO) based in Navi Mumbai, India, that it has “identified significant data integrity and study conduct concerns” in certain studies in NDA and ANDA applications.

The notice states, “The agency has notified sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) that in vitro studies conducted by Raptim are not acceptable, and when those studies are essential for approval, they must be repeated at study sites that do not have data integrity concerns.”

Additionally, the notice states that “[a]pplications with in vivo studies conducted by Raptim will be handled on a case-by-case basis during the course of a standard submission review. Study concerns can be addressed by the applicants with appropriate steps, which may include providing additional information to justify how the data from the studies can still be relied upon, re-analyzing the study samples and re-conducting statistical analysis to demonstrate bioequivalence, or conducting a new study.”

This is reminiscent of relatively recent incidents (2021) with two other CROs from India, Synchron Research Services and Panexcell Clinical Lab.

The FDA requests that firms with NDA or ANDA applications that have in vitro studies that were performed by Raptim to respond to the Agency within thirty days regarding their plans to either:

  • reconduct the studies at study sites that do not have data integrity concerns in order to submit a supplement within the next year; or
  • voluntarily request withdrawal of approval of the affected ANDA or NDA.

The FDA plans to revise the ratings in the Orange Book for certain approved and marketed drugs from “A” to “BX,” which means that the data that has been reviewed by the Agency is currently insufficient to determine therapeutic equivalence. The FDA won’t change the ratings back to “A” until the requested information is submitted to the FDA and found acceptable. The FDA notes that “[a] drug with a “BX” rating is still approved and can be prescribed but is not recommended as automatically substitutable at the pharmacy (or by a pharmacist) for the brand-name drug.”

Additional information is provided in the notice regarding how the FDA came to these conclusions over the course of time as well as answers to questions such as:

  • How do I know if these data integrity violations affect a drug that I am taking?
  • What is the FDA asking Raptim to do to rectify the data integrity issue?
  • Will this issue result in any drug shortages?

Resolution of these issues could take applicants a significant amount of time. In the meantime, the FDA advises that patients should discuss appropriate next steps with their healthcare providers.