When Regulators are Ignored

By: John Roth

In my last FDA Voice post, I explained the Office of Criminal Investigation’s (OCI) role within FDA as using our top-flight federal agents to protect the public health in unique ways. Not every one of our cases involves undercover agents investigating shadowy overseas drug counterfeiters. Sometimes, illegal behavior leads us to high-profile instances of non-compliance right here in the United States.

Now, the good news is that the vast majority of the FDA-regulated entities respond to FDA’s ordinary regulatory tools. The concerning news, however, is that lapses in compliance do occur and the criminal remedy is available to gain compliance for that small portion of the industry that fails to respond to ordinary regulatory tools. 

Before selecting that remedy, OCI will look to see whether the entities have demonstrated a resistance to other regulatory efforts, including requests for voluntary cooperation and FDA formal warning letters or inspection reports, and instances in which entities fail to comply with judicial orders. We are particularly sensitive to circumstances in which it appears that the regulated entity engages in fraud or other deceptive conduct, either in relation to the FDA or the public at large.  

One area of particular OCI focus is the deceptive conduct by those who manufacture and market pharmaceuticals. It’s nothing less than a life-threatening problem for millions of Americans who rely upon safe medications. 

Moreover, it’s a category that has involved our OCI professionals in a number of fairly high-profile criminal prosecutions involving a range of criminal behavior. Take the investigation of Abbott Laboratories, for example. Abbott applied for FDA approval to use its drug Depakote for additional indications, including treating dementia and schizophrenia. Healthcare providers using the drug for approved uses were required to balance the potential benefits against the significant risks associated with the drug. Indeed, the drug carried three “Black Box” warnings — the most serious warning the FDA can require — as a result of the adverse side effects associated with the risk of the drug.  

The FDA denied the application because even after a number of clinical trials, Abbott could not demonstrate that Depakote was effective for the new indications. Notwithstanding the FDA rejection, Abbott trained its sales force to aggressively market Depakote for dementia and schizophrenia, claiming advantages over several competing products, and failing to disclose the previous negative studies. Moreover, after two of Abbott’s own studies failed to show that Depakote was effective in treating patients with dementia and schizophrenia, Abbott waited nearly two years to notify its own sales force about the study results and another two years to publish those results. Abbott ultimately pleaded guilty and paid $700 million to the U.S. in fines and forfeitures.  

A similar fact pattern occurred in the investigation into the biotechnology company Amgen. In that case, the manufacturer sought FDA approval for additional indications for its anemia drug Aranesp. The company wanted to add patients with chronic kidney disease or those receiving much larger, less frequent, doses of chemotherapy than those currently approved by the FDA for these patient populations. FDA rejected the application after determining that Amgen had failed to show that Aranesp was safe and effective for these expanded indications. 

Despite that decision, Amgen aggressively marketed the drug as more effective than its FDA-approved competitor for the unapproved indications. Amazingly, the Amgen sales force was trained to provide physicians with studies to demonstrate Aranesp’s effectiveness — studies that the FDA itself had rejected as insufficient to support the safety and efficacy of the drug for those off-label uses. And in fact, for one of the off-label uses — the treatment of anemia caused by cancer, irrespective of whether the patient had undergone chemotherapy — the FDA later determined that its use caused an increased risk of death and issued a “Black Box” warning on the drug for that use. Amgen ultimately agreed to pay the U.S. over $700 million in criminal and civil penalties to resolve these claims. 

In the next post, I’ll detail another aspect of OCI’s work. In the meantime, consider the nearly $1.4 billion in fines against these two firms – it’s an outcome that underscores the severity of the public health challenge and what happens when regulators are ignored. 

John Roth is Director of FDA’s Office of Criminal Investigations

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