Eteplirsen ‘Worrisome Model’ for Drug Approval: Authors

Harvard Medical School professors Aaron Kesselheim and Jerry Avorn say that FDA’s recent approval of eteplirsen (Exondys 51) as a treatment for Duchenne muscular dystrophy provides “a worrisome model for the next generation of molecularly targeted therapies: demonstrate a slight difference in a laboratory test, activate the patient community, win approval, and charge high prices, while relying on limited regulatory follow-up.” Writing in the Journal of the American Medical Association, the two review the history of the drug’s progression through the accelerated approval pathway, including the fact that an advisory committee voted narrowly not to recommend the drug’s efficacy and that approval was opposed by all of the agency’s medical reviewers, whose objections were overturned by CDER director Janet Woodcock. When the reviewers appealed to FDA commissioner Robert Califf, he upheld Woodcock’s decision, they write.

Kesselheim and Avorn note that FDA used a surrogate measure (muscle dystrophin levels) as the basis for approval. However, they write, the accelerated approval pathway it went through requires that a surrogate endpoint must be reasonably likely to predict a drug’s clinical benefit, and they argue that that standard is challenged by the minimal changes seen in the dystrophin levels. “Speeding drugs to market based on such biomarker outcomes can actually lead to a worse outcome for patients, even those with life-threatening diseases,” they say, “if a product confers no meaningful benefit and carries a risk of adverse effects and a high cost. Immediately after approval, the manufacturer (Sarepta Therapeutics) announced a price of $300,000 per year for eteplirsen. This approach also unfairly penalizes manufacturers that pursue a more rigorous course of development using more clinically relevant endpoints, while rewarding competition that submit trials that have less evidence supporting efficacy.”

The article says the drug’s approval also raises questions about how to integrate subjective and anecdotal patient experiences in the agency review process. Patient-reported clinical outcomes such as functional status can be of value in drug assessment, they say. But they caution that such outcomes can be misleading in very small, poorly controlled, or unblinded studies that don’t account for placebo effects. They also note that while the voices of patient advocates should be made known, many such groups are supported by drug manufacturers to help advance their goals.

With the growth of pharmacogenetics and precision medicine, Kesselheim and Avorn conclude, an increasing number of drugs are likely to be developed that alter laboratory tests or protein expression and are then tested in trials that assess such surrogate measures but do not show convincing clinical outcomes. “Approval by FDA on this basis will apply enormous pressure on public and private payers to cover the very high prices of these drugs and will impose substantial cost burdens on uninsured or underinsured patients,” they say. “Meanwhile more rigorous data from follow-up trials may be years away, or may never become available. This will further increase the nation’s growing expenditures for medications, even in the absence of clear patient benefit.”

One partial solution they suggest is adoption of novel regulatory models, such as limited approval with intensive collection of new clinical evidence before a drug becomes universally available. They also suggest that drugs that have not yet shown clinical outcome benefit could be made available at just the cost of production, or most profits could be held in escrow, until adequate trials are completed.