In a rare move, FDA has sent letters to NDA and ANDA sponsors telling them that they will have to repeat bioequivalence and bioavailability studies conducted by the contract research organization Semler Research Center Private Ltd. for their approved products and pending applications.

The agency said that during an inspection of SRC's Bangalore, India, facility it found the company's practices had "resulted in the submission of invalid study data to FDA." As a result, the agency said it would not accept data generated at SRC as a basis to approve the sponsors' applications.

The notification highlights continuing problems in India's clinical trials industry, as well as FDA's focus on data integrity beyond the current good manufacturing practice arena. The agency said its investigators found "significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples."

In an April 20 announcement on its website, FDA said it has evaluated drugs that were approved based on data from Semler and has not identified postmarket reports that raise serious safety concerns about the products. However, it is changing the therapeutic equivalence rating for any approved ANDA that relied on data from Semler to "BX," which indicates data reviewed by FDA are insufficient to determine substitutability of the generic product to the drug it references. Companies must repeat their bioequivalence studies at a site other than Semler, or voluntarily withdraw their products from the market.

For pending applications, FDA's sample letter to sponsors says they must reconduct bioequivalence/bioavailablity studies (both bioanalytical and clinical) at an alternate contract research organization. They must submit an amendment to their application describing their plans within 30 days.

Semler said it understands the seriousness of FDA's notification and is in the process of reviewing the agency's concerns. "We have engaged a high quality consulting firm to review the data and we would be providing a detailed response to these concerns with appropriate steps undertaken as advised by the agency," Semler said in a statement.

Data Integrity Gaining Attention In Clinical Realm

It is unknown how many sponsors will be affected by Semler's data integrity problems. FDA said it could not say how many firms it sent letters to since the agency is prohibited from commenting on pending applications.

Consultant John Avellanet, managing director of Cerulean Associates LLC, said FDA would not be making the notification to sponsors public unless it was contacting a large number of firms. He thinks the notice is a positive development.

"It is a silver lining in the cloud" for companies, Avellanet said. "It gives them a heads up that if these guys are on your list [of CROs] you should remove them so you don't waste millions of dollars" in clinical studies.

Avellanet said the notice also shows that data integrity issues are not just GMP specific but are also a focus in good clinical practice and good laboratory practice.

"I believe that the main reason people can easily perceive that data integrity is just a cGMP issue, and forget about how critical data integrity is in the clinical world, is because so few FDA warning letters citing poor data integrity under cGCP (in comparison to cGMP) are written," he said. "Many clinical data integrity problem citations from FDA tend to get placed into complete response letters that are not made public."

Plasma Samples For Test And Reference Drugs Switched

FDA's untitled letter to Semler President and CEO Krathish Bopanna cites "objectionable conditions" observed during the agency's Sept. 29 to Oct. 9, 2015, inspection. The agency notes that investigators reviewed the conduct of four studies; the letter redacts the study details and sponsor names.

The agency emphasized that Semler "failed to demonstrate that the analytical method used in an in vivo bioavailability or bioequivalence study to measure the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, is accurate and of sufficient sensitivity to measure, with appropriate precision, the actual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), achieved in the body."

FDA cites instances of sample switching and poor documentation. It says FDA investigators found an Excel spreadsheet on Semler's server describing the substitution of plasma samples from a subject who received the reference product with the plasma samples from a subject who received the test product.

FDA's inspection report Form 483 also notes that in one study 19 aqueous humor samples were excluded from the PK analysis because they were contaminated with blood. It says that during the PK analysis in one study the 3.5 hour concentration for one subject was switched with the 3.5 hour concentration for another subject and there was no documentation of sample mix-up.

In addition, FDA said not all study-related correspondences were archived and not all raw data was maintained in the study folder. The report notes that bioanalytical data worksheets were found crumpled and torn in a trash pile on the floor. Inspectors also found that laboratory analysts had the ability to delete, copy and rename liquid chromatography-mass spectrometry instruments' raw data folders.

There is at least one other case in which FDA has notified sponsors that CRO data supporting their applications might be faulty. In 2010, FDA sent letters to sponsors following an inspection of Cetero Research's Houston laboratory, informing them that Cetero had falsified bioanalytical and bioequivalence study data and that they might have to do re-tests to support their applications Also see "Cetero Fallout: Five Years Of Potentially False Data Creates Three Tough Options For Sponsors" - Pink Sheet, 27 July, 2011..

Cetero subsequently filed for Chapter 11 bankruptcy, restructured and changed its name to PRACS Institute LLC, which in turned ceased operations and filed for Chapter 7 bankruptcy. Actavis, which has since become Allergan PLC, was one of the firms that was caught up in the CRO's data integrity problems.

FDA determined that its Watson subsidiary's generic bupropion was not therapeutically equivalent to GlaxoSmithKline PLC's Wellbutrin XL when Actavis was unable to rerun tests because it's CRO went out of business. The CRO was believed to be PRACS Also see "Watson’s Bupropion XL Undone By Outlier Patient, Bankrupt CRO" - Pink Sheet, 21 October, 2013..

WHO Finds Similar Problems

Semler's website notes that its clients are leading organizations in biopharma, devices and diagnostics from the US, Europe, UK, India and Canada.

The website also touts a January 2015 inspection of its Bangalore facility by the World Health Organization under the headline "SRC successfully completes 5^th WHO inspection!"

However, WHO issued an April 12, 2016 "Notice of Concern" to Semler saying that inspection and a follow-up inspection in December "revealed critical and major deviations from GLP and GCP." WHO cited some of the same issues that FDA did, including the manipulation of study samples. The notice says that in some cases the manipulation involved replacement of subject samples where test and reference had been swapped.

WHO recommended "an immediate stop for all submissions of dossiers relying in whole or in part on involvement from Semler until the underlying issues have been verified to have been adequately resolved."

WHO cited specific studies and sponsors impacted by its findings. It said the inspection raised questions about the validity of three studies performed for Mylan Laboratories Ltd.; five for Lupin Ltd., two for Strides Ltd., and one for Micro Labs Ltd.

The notice says that Semler appealed a draft Notice of Concern in February and March.

Semler's website also states that the European Medicines Agency inspected the facility and approved a bioequivalence study for one product.

Barbara Unger, a GMP consultant, said these types of inspections require training in how to find problems and one auditor may find a critical deficiency while the next may not.

"You're making a decision based on a snapshot in time and a snapshot of the data," Unger said. Auditors do not all have the same skill but they are getting more training, she added, "so I think we're only going to see more of this in the future."

There have been several other cases in which regulatory authorities have identified data integrity problems at CROs, particularly in India. Last year, the WHO issued a "Notice of Concern" to Quest Life Sciences over major deviations from good clinical practices involving data integrity, subject safety and quality. WHO found data changes to make it seem electrocardiograms were from different people when more than 67% were duplicates ([A#28150712001]).

And the European Union ordered about 700 generic drug products to be pulled from the retail market after EMA cited concerns about the reliability of studies conducted by the Indian CRO gvk bioSciences Private Ltd. The French regulatory agency ANSM had flagged GVK's alleged manipulation of electrocardiogram-related data ([A#28150728001]).

FDA came to a different conclusion following its inspection of GVK's Hyderabad site, citing only minor concerns about the data reports ([A#28150610001]).

CRO Inspection Fall-Out: Semler's Clients Have To Repeat Studies

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