Regulatory Focus™ > News Articles > Is a Drug Unsafe or Just Unprofitable? How a Lack of Data Clouds Regulatory Classifications

Is a Drug Unsafe or Just Unprofitable? How a Lack of Data Clouds Regulatory Classifications

Posted 14 November 2014 | By Alexander Gaffney, RAC

Is a Drug Unsafe or Just Unprofitable? How a Lack of Data Clouds Regulatory Classifications

Regulatory professionals are frequently concerned with getting pharmaceutical products approved for use and available to consumers. But as a new paper in the Journal of the American Medical Association (JAMA) explains, the way in which drug products are withdrawn from the market can have significant implications for both regulators and patients as well.


Writing in JAMA Internal Medicine, Vinay Prasad, an official associated with Johns Hopkins University and the National Cancer Institute (NCI), explains that in the US, many drugs are eventually withdrawn or removed from the market.

"In the United States, among all new molecular entities approved from 1980 to 2009, 118 drugs were withdrawn from the market," he noted. However, of those drugs withdrawn from the market, only 26 (22%) were done so explicitly for safety reasons. The implication is that the remaining 78% of products were withdrawn for commercial reasons. That's a considerably higher percentage than in the UK, where between 1972 and 1994 just 59% of products were withdrawn for commercial reasons.

While those high-level statistics frame the outline of Prasad's piece, the bulk of his analysis focuses instead on just one drug, GlaxoSmithKline's Bexxar (tositumomab), as a microcosm of how regulatory officials should grapple with how to characterize drug withdrawals from the market.

Bexxar as a Case Study

As Prasad recounts, the drug, originally approved by FDA to treat non-Hodgkin's lymphoma, was withdrawn by GSK in February 2014 "for marketing reasons."

But that information is only the bookend to a more interesting story. As Prasad explains, the drug was first approved in 2003 based on data from a relatively small single-arm study assessing responses from 40 patients. A second single-arm study formed the basis for an expanded indication in 2004.

After approval, GSK was supposed to conduct a clinical trial to compare Bexxar with the standard of care for Hodgkins lymphoma, Rituxan (rituximab). However, that study suffered from poor enrollment, and was never finished. A similar trial comparing the two drugs was concluded in 2011, but failed to show any advantage for Bexxar over Rituxan, Prasad explained.

How Effective is the Drug?

Critically, "at neither the time of approval nor since has any trial shown that tositumomab improved survival for the patient groups for which it was approved," Prasad said.

That raises an interesting question for the purposes of regulatory classification: If Bexxar never showed a proven benefit over existing therapies, was its withdrawal truly for commercial reasons, or could regulators make the case that it was for a lack of efficacy, or even safety reasons?

Explained Prasad: "Although tositumomab’s benefits are unknown, its potential harms are clear. Tositumomab can cause severe allergic reactions at the time of infusion and prolonged and severe cytopenias. Secondary malignant neoplasms were reported in 10% of the patients enrolled in the clinical trials leading to its approval and in 3%of patients in the extended-access program. Safety concerns may have contributed to the drug’s dwindling use."

The consideration of these factors cast some doubt on this seemingly "unremarkable" drug, Prasad added. "Was tositumomab a good drug that improved outcomes in specific groups of patients? All that is known is that tositumomab improved a surrogate end point in one population and failed to show a survival benefit in two other populations."

In other words, without more conclusive data, it's difficult to make any definitive statements about Bexxar.

An Important Question for Regulators

The withdrawal of the drug also raises important questions for regulators, Prasad argues.

"With the approval by the FDA of more drugs in oncology and other specialties based on surrogate end points such as response rates, not overall survival, it is more important than ever to collect data on the ultimate efficacy of treatments," he said. And the story of Bexxar, he added, "is a reminder of the weaknesses of our current system for approving drugs and adequately continuing to study them after approval."


JAMA Article: The Withdrawal of Drugs for Commercial Reasons


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