Clinical Data Fraud Involving CROs Attracting US Justice Department Attention
Executive Summary
Submission of manipulated clinical data to support product approval is a ‘major concern’ for the DoJ, consumer protection branch director Gusav Eyler says, adding that some of the problems relate to outsourcing of trials. Also, DoJ and HHS OIG are using data analytics to identify outliers in prescribing and reimbursement claims.
The US Department of Justice is increasingly focusing enforcement attention on issues related to clinical trial data fraud, particularly where contract research organizations are involved.
Speaking at the Food and Drug Law Institute’s recent conference on advertising and promotion of medical products, Gustav Eyler, director of the DoJ’s consumer protection branch, said that in investigating potential cases involving false and misleading marketing, the department also is looking at whether the data intended to support a product’s use are manipulated or misleading.
“If there are problematic actors to whom the clinical trials are being outsourced, that creates problematic data.” – DoJ’s Gustav Eyler
In addition, the DoJ is looking at cases where manipulated clinical trial data may have been submitted as the basis for marketing approval.
“This is a major concern for us as it is for FDA,” Eyler said.
Some of the problems that DoJ sees “relate to the outsourcing of clinical trials,” Eyler said.
“This of course is a not uncommon practice, and I think that it can serve an important role … to expedite the conduct of trials and develop important data that is needed for drug approval or device approval,” Eyler said. “But at the same time if there are problematic actors to whom the clinical trials are being outsourced, that creates problematic data.”
If a product sponsor “is either knowingly relying upon data that is obviously manipulated or incorrect, and using that then to submit an approval for its drug or device or to use that improper or incorrect data in the promotion or advertising of its product, you’re going to have some real issues,” Eyler said.
However, if the outsourcing entity is hiding its misconduct from the product sponsor that contracted for the clinical trials, that “could also be a problem, an enforcement area for us,” he said.
“I think that we are seeing this and are focused on that area more as an area of potential fraud and one that can lead to real consumer risks, in that if the drug approval or device approval is founded on manipulated or sometimes just downright falsified data, I think we’d all agree that that’s a problematic instance.”
FDA Actions In CRO Fraud Cases
While there have been a few high-profile cases in recent years of pharmaceutical data fraud allegations involving CROs, they have resulted in regulatory action by the Food and Drug Administration as opposed to DoJ enforcement action.
In April 2016, the FDA notified drug product sponsors they would need to repeat bioequivalence and bioavailability studies performed by Semler Research Center Private Ltd. due to practices at the CRO’s Bangalore, India facility that resulted in the submission of invalid study data. (Also see "CRO Inspection Fall-Out: Semler's Clients Have To Repeat Studies" - Pink Sheet, 22 Apr, 2016.)
In January 2018, Semler sued the FDA, alleging its decision to make public what the CRO said were unfounded claims about data fraud destroyed its reputation and damaged its business. A federal court in California recently granted the agency’s motion to dismiss Semler’s lawsuit. (Also see "CRO Does Not Have Same Rights As Sponsor, Court Says In Tossing Semler Suit Against US FDA" - Pink Sheet, 24 Sep, 2019.)
In 2011, the agency notified sponsors of its findings that the CRO Cetero had falsified bioanalytical and bioequivalence study data and that the tests might have to be conducted again. (Also see "Cetero Fallout: Five Years Of Potentially False Data Creates Three Tough Options For Sponsors" - Pink Sheet, 27 Jul, 2011.)
The December 2012 approval of Bristol-Myers Squibb Co./Pfizer Inc.’s antithrombin Eliquis (apixaban) was delayed, in part, by reports of fraud involving sponsor and CRO employees at a clinical trial site in China. (Also see "Eliquis Approval Delayed By Fraud, Dispensing Errors In Pivotal Trial" - Pink Sheet, 18 Jun, 2013.)
CROs have not been publicly implicated in the recent data fraud cases involving Novartis’ Zolgensma and Kolon’s Invossa.
More recently, there have been two high-profile instances of data fraud in the cell and gene therapy space, although CROs have not been publicly implicated in those cases.
The FDA has said Novartis AG could face civil or criminal penalties for submission of manipulated preclinical safety data supporting the approval of the Zolgensma (onasemnogene abeparvovec-xioi), a gene therapy for spinal muscular atrophy. In this case, the data manipulation related to an in vivo murine potency assay. (Also see "Novartis' Zolgensma Had Manipulated Data In Application, US FDA Says" - Pink Sheet, 6 Aug, 2019.)
Novartis learned of the data manipulation by its AveXis Inc. subsidiary potentially as early as March but did not tell the agency until late June, after Zolgensma’s approval, because the company was conducting its own internal investigation. (Also see "Novartis CEO Explains Delay In Telling US FDA About Zolgensma Data Fraud: We Wanted To Understand It First" - Pink Sheet, 7 Aug, 2019.)
After the Zolgensma data manipulation came to light, FDA acting commissioner Ned Sharpless that although data fraud in medical product submissions is rare, it happens more than he would have expected. (Also see "Data Manipulation Not Common, But Happens "More Than I Would Have Expected," US FDA's Sharpless Says " - Pink Sheet, 5 Sep, 2019.)
Outside the US, South Korean authorities recently cancelled the approval of Kolon Life Science Inc.’s cell and gene therapy Invossa (TG-C) after concluding the company submitted false data at the time of approval. (Also see "Invossa Approval Revoked As Korea Confirms False Data Submission" - Pink Sheet, 28 May, 2019.)
The ministry of Food and Drug Safety confirmed that an active cell component of Invossa was derived from the human embryonic kidney cell and not from a cartilage cell, as stated in the data submission. A Phase III trial of Invossa in the US remains under clinical hold.
‘Refined’ Enforcement Approach On Off-Label Marketing
In discussing the DoJ’s enforcement priorities, Eyler sought to counter the perception that the department is not pursuing off-label promotion cases due to recent First Amendment case law that has been unfavorable for the FDA.
“I’ve heard a lot of talk about well the department is not really doing off-label promotion in cases anymore. I think that that’s a false perception,” Eyler said. “Rather what I would say is we have refined our enforcement efforts in this space to really focus in on marketing that is false and misleading, or/and that involves consumer harm or a substantial risk of consumer harm.”
“Our goal here is to employ our resources intelligently and most appropriately to address conduct that is of greatest concern to patients and most undermines the regulatory regime and the trust [and] faith that Americans have that the uses that they see for a drug or device are reliable and consistent,” he said.
The DoJ is especially focused on statements in promotional or marketing materials that are untrue because they are either inconsistent with scientific evidence and clinical data, or entirely unfounded, Eyler said.
A recent federal grand jury indictment brought against Indivior PLC alleged the company used promotional materials that contained false statements about reduced abuse and diversion with Suboxone (buprenorphine/naloxone) film that relied on survey results and other data that were false or misrepresented. (Also see "Indivior Knew Suboxone Film Did Not Have Greater Child Safety Than Tablet, Grand Jury Claims" - Pink Sheet, 10 Apr, 2019.)
“The other thing that we look to is whether the promotion of a drug outside of its approved uses can have an articulable or a real risk of patient harm because the use goes so far beyond that which was intended for that it causes other known side effects or known effects on the individual patient,” he said.
Growing Role For Data Analytics
Data analytics are playing are larger role in the affirmative or proactive enforcement activities of the DoJ and Department of Health and Human Services’ Office of the Inspector General.
The DoJ’s consumer protection branch has significantly increased in size in the last few years and now has approximately 75 prosecutors, Eyler said.
“Within the last two years our branch has nearly doubled in size in terms of the number of prosecutors," he said. "We have more than tripled in size in terms of our support staff, and we have substantially increased our data review and analytical capabilities, all of which I think has compelled us to be a much more robust actor in the space, and there’s a lot of activity going on.”
The bolstering of data analytics staffing and capacity has enabled the branch to develop more cases involving medical products on its own initiative.
“If there are outliers, it sounds to me like they’re going to probably catch the attention of folks at DoJ and HHS OIG.” – Skadden Arps’ Jennifer Bragg
“We basically have our own analytics lab and we have spent the past several years kind of amalgamating lead data, informational sources from across the government and other partners, and then applying fairly sophisticated analytical tools to that information to spot outliers, trends, which can really allow us to drive the initiative, instead of just being a reactive force that responds to leads and referrals that come in,” Eyler said. “It allows us … proactively to say … this is an area of harm, of risk, and devote resources to it.”
Similarly, the HHS OIG’s office is using data analytics to identify outliers in prescribing and reimbursement claims for medical products, senior counsel Mary Riordan said.
The OIG’s Office of Counsel now has an administrative litigation branch focused on enforcement actions for various kinds of false claims submitted to federal health care programs, she said. “One of the things that I know that branch does is really look at data analytics, and we have an internal data group at the OIG and we also are looking for anomalies in billing. We’re looking for outliers in terms of prescribing and claims submission in a variety of areas.”
“We have done a lot of work, and I think we’ll continue to do that sort of affirmative analytical work,” Riordan said.
Session moderator Jennifer Bragg, a partner in the Washington, DC office of Skadden, Arps, Slate, Meagher and Flom, identified a key takeaway for industry based on the comments by Eyler and Riordan.
“I’ve heard data analytics a lot today,” Bragg said. “The beauty of that is you should be able to figure out what the government is looking at if you’re in a company, you know your data, you can buy data, do data analytics.”
“If there are outliers, it sounds to me like they’re going to probably catch the attention of folks at DoJ and HHS OIG,” Bragg said.