Top FDA Compliance Official Notes 'Revival' Of Data Integrity Fraud

A top FDA compliance official warns the generic drug industry of a “revival” of data integrity fraud as a number of brand-name drugs go off patent and companies rush to be the first to file.

A top FDA compliance official said that data integrity problems are not going away any time soon as many brand-name drugs are now going off patent and the pressure to be the first to file intensifies with an “enormous” amount of money at stake, harking back to the days of the generic drug scandal.

Thomas Cosgrove, director of the Office of Manufacturing Quality in the Office of Compliance in FDA's Center for Drug Evaluation and Research, made these remarks at the Association for Accessible Medicines’ Chemistry, Manufacturing and Controls Workshop on May 24 in Bethesda, Md.

“There has been somewhat of a revival on the issue of data integrity," Cosgrove said. "What is old is new again.”

He noted that many of the same conditions that set the stage for the generic drug scandal are now in play today. “We have a rapidly changing industry, an industry that is becoming more global every day. We have an enormous number of patents that are expiring and an enormous amount of money at stake. … It is clear there are a lot of pressures being put on the system. And for those who are inclined to cheat and those that are inclined to cut corners, the conditions are ripe.”

Cosgrove said that the only difference is that the data integrity problems occurring today are not of the same ilk as those seen at the height of the generic drug scandal in 1989.

“On the FDA side I just don’t see that kind of behavior anymore. That kind of rank fraud or obvious fraud is less prevalent nowadays. What we are seeing now are low-level GMP violations such as switching data in and out and things that add up and have a significant impact on products and applications, but not quite to the level of what we saw in the generic drug scandal.”

In 1989, members of FDA’s Office of Generic Drugs were found to have taken illegal gratuities from industry and shown favoritism to certain applicants. In that crisis, FDA officials pleaded guilty to receiving bribes and generic companies admitted to providing false data.

Data integrity problems have been a common theme in drug GMP warning letters and these problems are increasing. Of the 26 warning letters to active pharmaceutical ingredient firms in calendar year 2016, 16 (61%) focused on data integrity issues (Also see "FDA GMP Warning Letters Review: Rate Soared In 2016 On Sterility And Data Integrity Concerns" - Pink Sheet, 25 Apr, 2017.). Data integrity problems surfaced in at least 13 (30%) of drug GMP warning letters in FY 2015 and in 17% the year before. (Also see "FY 2015 Drug GMP Warning Letters Hit Compounders and Foreign Sites" - Pink Sheet, 29 Jan, 2016.).

Cosgrove said that “we are seeing a lot of troubling behavior and we are doing a good job of spotting it but I am confident that there’s a lot out there that we’re not seeing.”

Cosgrove said that FDA investigators are seeing a lot of these data integrity problems in their inspections:

• Testing into compliance;
• Cherry picking data;
• Reusing data;
• Batch records that don’t match test results; and
• Audit trails and back-ups going on and off.

Cosgrove said that two recent warning letters reflect these data integrity trends. One was FDA’s warning letter in March 2015 to Hospira Inc. after the company was found deleting or altering raw data files. (Also see "Hospira’s Global Quality Compliance Strategy Questioned In FDA Warning Letter" - Pink Sheet, 7 Apr, 2015.) FDA said that Hospira’s high performance liquid chromatography software did not have sufficient controls to prevent the deletion or alteration of raw data files. Trial injections of stability samples were saved in the test folder and official samples were analyzed after trial injection.

In another case, a warning letter was sent to Tai HengIndustry in Shanghai, China, after personnel were found changing the time clock on their high-performance liquid chromatography equipment rather than investigating and correcting issues underlying the out-of-specification results obtained in batch release testing. (Also see "FDA GMP Warning Letters Review: API Supplier Warnings Surge On Data Integrity Concerns" - Pink Sheet, 26 Apr, 2017.)

Cosgrove said that in the past, FDA has used the Application Integrity Policy it developed after the generic drug scandal to target data integrity lapses.

Recently, the agency has come to rely more on Form 483 reports to combat data integrity failures. This was the tool the agency used in the Semler Research Center Private Ltd. data integrity fraud case. FDA gave Semler a Form 483 report of inspectional observations in April 2016 when it found that the company's clinical and bioanalytical studies were not acceptable as a result of data integrity concerns. Semler is a contract research organization that conducts bioequivalence and bioavailability studies for a number of pharmaceutical companies. FDA found evidence that the firm substituted samples and data from one patient group for another. (Also see "Indian CRO Inspection Fall-Out: Semler's Clients Have To Repeat Studies For US FDA" - Pink Sheet, 25 Apr, 2016.) (Also see "Semler Dirty Data: EMA Suspends Over 200 Products; Stings Indian CROs" - Scrip, 25 Jul, 2016.)

A Form 483 report that results in an official action indicated, or OAI, finding “really has the same effect that it would have had in the old days under an AIP,” Cosgrove said. “Fifteen to 20 years ago it could have been thought of as an AIP case, but we came to the same outcome.” Yet he said that “the policies behind the AIP are alive and well.”

Cosgrove said that it is in a firm’s best interests to have robust quality systems and to catch problems before FDA investigators walk in the door. “Even if you have done as good a job as possible in hiring and have the most moral upstanding folks on the planet, there are going to be folks within your company who are going to cut corners. Your job is to try to prevent that. It is your job to ferret that out. You need to prevent that and protect your patients.”

From the editors of the Gold Sheet.