More data integrity issues, this time a CRO based in India. FDA issued an untitled letter to Semler Research Center Private Limited located in Bangalore, India on April 19, 2016. The firm conducts BA/BE studies in support of drug approval. The inspection in question ended October 9, 2015 and resulted in a 3-page form 483. Briefly, FDA found evidence that the firm substituted samples and data from one patient group for another as demonstrated by a spreadsheet found on one of the firm’s servers.
FDA indicated that the firm’s response was inadequate because it did not address:
- “Why your firm had documentation indicating that subject samples were substituted or manipulated in order for studies to meet the bioequivalence criteria;
- If any other bioequivalence or bioavailability studies conducted at your firm had subject samples substituted or manipulated;
- What impact the sample substitution and manipulation had on Studies ,[b] , and [b], respectively; and
- How each of these studies could have multiple instances of overlapping subject sample concentrations.”
FDA further indicates that the deficiencies raise “…significant concerns with the reliability and validity of all bioequivalence data generated by Semler.” In light of this concern, FDA evaluated post market serious adverse events for drugs which were approved on the basis of data provided by Semler. They did not identify any specific safety concerns. FDA, however, is taking three actions on the basis of the inspection observations:
- The therapeutic equivalence rating for any product approved that relied on data from Semler Research is changed to ‘BX’, indicating that there are insufficient data to determine whether the product is therapeutically equivalent to the Reference Listed Drug.
- All sponsors of approved applications that relied on data from Semler Research must repeat the BA/BE studies at a different firm, and
- All sponsors of applications under review that rely on data from Semler Research must repeat the BA/BE studies at a different firm.
HERE is an example letter sent to sponsors regarding the need to repeat BA/BE studies. This is not an inexpensive venture for the firms involved. The Semler Research website identifies a variety of inspection success with FDA, EMA, Chile, Turkey and WHO. It will be interesting to see if EMA and WHO revisit their inspections and decisions.
This is yet another example of data integrity problems identified at CROs in the past few years. Most recently it’s been an EMA initiated review of clinical studies conducted by Alkem in India. Reuters provides additional information including a link to the notification of referral that identify some of the problematic conditions observed during an inspection by the German authorities. Some of the data in question are ECG data. These type of data were also implicated in the earlier data integrity findings at India’s GVK Biosciences based on an EMA inspection. In 2015 WHO issued two Notices of Concern to CROs, Quest Life Sciences and Svizera Labs Private Limited. And in 2011, FDA issued an untitled letter to Cetero Research in Houston, Texas for data integrity concerns. This resulted from two inspections, one ending May 2010 and one in December 2010. The forms-483 are provided HERE and HERE respectively. Similar to the consequences for Semler identified above, FDA took action against those who used data from Cetero to support product approvals. For those who want to do a deep dive into the topic of enforcement actions for firms that conduct bioequivalence studies they may be found on the FDA webpage devoted to the GCP/GLP area
[UPDATE April 25, 2016]: The Economic Times reports that WHO issued a Notice of Concern to Semler Research on April 12, 2016. Two inspections were conducted in January 2015 and December 2015. The FDA and EMA inspections were conducted in December 2014. It would be interesting to know whether those two inspections prompted WHO to evaluate the site. The WHO Notice mentions that this includes products from Lupin, Strides Ltd, Micro Labs and Mylan.
These actions provide evidence that the GCP/GLP area is not being ignored by global regulatory authorities when it comes to data integrity. Unfortunately, we’ve probably only seen the tip of the iceberg in this area. Clearly, firms that outsource any activity should perform a detailed due diligence evaluation and provide ongoing oversight of their contractor or risk expensive consequences. These consequences can include the need to repeat studies, changes in bioequivalence category that will impact sales, and delays in product approval. While firms can outsource activity, they cannot outsource responsibility and accountability for data and results produced by others under a contractual relationship. Don’t be overly impressed by successful regulatory inspections in the past. Conduct your own, rigorous evaluations and ongoing oversight including a deep dive into the issue of data integrity.