Another day, another issue with data integrity. This time, however, the US Food and Drug Administration (FDA) is taking the issue one step further and notifying sponsors of New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) that clinical and bioanalytical studies conducted by Bangalore, India-based contract research organization (CRO) Semler Research are not acceptable as a result of data integrity concerns and need to be repeated.
Following its review of postmarket serious adverse events for all drug products which had studies conducted by Semler, FDA said Wednesday that it has not identified reports that raise serious safety concerns. However, the agency is requiring that sponsors of approved applications repeat the bioequivalence/bioavailability studies using a company other than Semler.
The concerns were revealed following an FDA inspection of Semler’s bioanalytical facility in Bangalore between 29 September 2015 and 9 October 2015, which resulted in a Form 483.
“The inspection found significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples,” FDA says, noting that the agency issued an Untitled Letter to Semler on Tuesday with detailed findings.
The untitled letter and letter to NDA and ANDA sponsors show how FDA is tightening its grip on data integrity issues, particularly among Indian drug and API manufacturers, as well as clinical trial researchers. The WHO and European Medicines Agency have previously taken issue with data integrity violations from two other Indian CROs.
On Tuesday, FDA released another warning letter for an Indian manufacturer over data integrity violations, which was preceded by at least 15 others for similar reasons. FDA also released new data integrity guidance last week to try to help manufacturers understand what it means when the agency finds such deficiencies.
Specifically, FDA took issue with Semler’s failure to demonstrate that the analytical method used in an in vivo bioavailability or bioequivalence study measures the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, and is accurate and of sufficient sensitivity.
The agency also said Semler's responses to the Form 483 were insufficient because they failed to address (1) why the company had
documentation indicating that subject samples were substituted or manipulated in order for
studies to meet bioequivalence criteria; (2) if any other bioequivalence or bioavailability
studies conducted at your firm had subject samples substituted or manipulated; (3) what impact
the sample substitution and manipulation had on three different studies; and (4) how each of these studies could have multiple instances of overlapping
subject sample concentrations.
Semler says on its website that it has conducted more than 750 drug studies ranging in size from 40-400 volunteers in various therapeutic areas for various regulatory submissions. The company, which also has offices in the US, did not respond to a request for comment.
FDA said it is also changing the therapeutic equivalence rating in FDA’s Approved Drug Product with Therapeutic Equivalence Evaluations (the Orange Book) for any approved ANDA that relied on data from Semler to “BX," which indicates that data reviewed by the agency are insufficient to determine therapeutic equivalence, i.e., the generic product can be a substitute to the drug it references.
FDA is sending letters to sponsors of applications that are currently under review that include data from studies conducted at Semler. The letter informs the sponsor that it must repeat the bioequivalence/bioavailability studies at an acceptable alternate study site.
Sponsors have 30 days to respond to FDA with an amendment to their NDA or ANDA.
FDA Notification to Pharma Companies
Untitled Letter to Semler Research