The FDA Needs a Conditional Approval System

The Food and Drug Administration has long shunned the concept of conditional approvals – the granting of approval to market safe drugs with some indicia of activity for a period of time while additional studies are conducted to support full approval.

The Food and Drug Administration (FDA) has long shunned the concept of conditional approvals – the granting of approval to market safe drugs with some indicia of activity for a period of time while additional studies are conducted to support full approval.

The FDA’s Accelerated Approval Program allows for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need, based on a surrogate endpoint. And, if mandatory subsequent studies that provide substantial evidence of clinical effectiveness are not positive, the drug is taken off the market.

At the eteplirsen advisory committee meeting last week, the panel voted seven to three against full approval and seven to six against accelerated approval for Sarepta’s drug for patients with a type of Duchenne Muscular Dystrophy (DMD). The FDA maintained that substantial evidence of effectiveness was not provided, and the panel agreed.

DMD is a rare disease (there are approximately 45,000 patients per year in the U.S.) that results from a lack of dystrophin in muscle cells. Since the dystrophin gene is found on the X chromosome, DMD affects boys almost exclusively. Symptoms of muscle weakness are apparent between the ages of three and five and 90% of DMD patients age 15 to 24 are confined to a wheelchair. Eventually, the disease weakens the heart and the muscles involved in breathing, leading to death often before the patient’s 30th birthday.


The European Medicines Agency (EMA) instituted Conditional Marketing Authorization (CMA) procedures in 2006 for products where:

 (a) benefit/risk balance is positive;

(b) it is likely that comprehensive clinical data will be provided;

(c) unmet medical needs will be fulfilled; and

(d) benefit to public health of immediate availability outweighs risks that additional data are still require.

The approvals require annual renewal and can be converted to full marketing authorization upon review of definitive data generated during the conditional approval period.

In 2014, the EMA granted conditional marketing authorization of PTC Therapeutics’ ataluren (Translarna) for DMD, stating in the European public assessment report:

"Despite the limited data available, and the fact that no benefit was demonstrated at a higher dose of 80 mg/kg daily, the CHMP considered that there is some evidence that Translarna 40 mg/kg daily slows the progression of the disease and that its safety profile is not of major concern. The Committee also acknowledged the seriousness of Duchenne muscular dystrophy and the unmet medical need of patients with this condition."

In February 2016, the FDA rejected the ataluren New Drug Application without even convening an advisory committee panel; according a press release from the company:

"PTC was notified in the letter that, in the view of the FDA, both the Phase 2b and Phase 3 (ACT DMD) trials were negative and do not provide substantial evidence of effectiveness,’ PTC stated. ‘The FDA also characterized certain of the company’s adjustments to the ACT DMD study as post hoc and therefore not supportive of effectiveness. In addition, the FDA noted that the NDA did not contain adequate information regarding the abuse potential of Translarna, a requirement for new molecules that cross the blood-brain barrier."

BioMarin’s drisapersen (Kyndrisa), which acts similarly to etepliersen, was rejected by the FDA in January following a negative advisory committee review in November 2015. The panel voted 15-2 that there was not enough evidence that the drug was able to improve the ability of children with DMD to walk.  It was accepted for review by the EMA in June 2015, and an opinion from the Committee for Medicinal Products for Human Use (CHMP) EMA is expected imminently. Perhaps, it too will receive CMA. 


At the Sarepta advisory committee panel, data were presented on 12 patients who took eteplirsen for four years. The company compared the results to closely matched historical controls from patients in Italy and Belgium because it did not feel that a randomized study was ethical since one group of patients would be receiving placebo, yet, undergoing repeated muscle biopsies with absolutely no possible opportunity of benefit. 

The boys in Sarepta’s study could walk on average 162 meters (almost two football fields) further during the six-minute walk test than the boys in Italy and Belgium. Ten of the 12 boys on the drug were still able to walk after four years, versus only three of 13 in the control group. FDA staff stated, “Know that if these results were from a well-designed and interpretable trial, there likely wouldn’t be much to talk about,” meaning, the data were quite compelling, but from the wrong kind of study in FDA’s view.

“Fifteen-year-old boys like Billy don’t maintain ambulation by accident,” Dr. Jerry Mendell, director of the center for gene therapy at Nationwide Children’s Hospital in Columbus and lead investigator in Sarepta’s study, told the committee, after showing a video of one 15-year-old on the drug.

 Aaron S. Kesselheim, AdComm member and associate professor at Harvard Medical School in Boston, said “The studies provided by [Sarepta] were not adequate and well controlled.” But he acknowledged that it remains an “open question” whether Eteplirsen produces a clinical benefit to patients who take it. Dr. Bruce I. Ovbiagele, chairman of neurology at the Medical University of South Carolina, voted against approval but said, “Based on all I heard, the drug definitely works, but the question was framed differently.” 

Family members made impassioned pleas for the drug after recounting anecdotes pertaining to the drug’s effects. One panel member remarked, ”Unfortunately, what I would consider meaningful evidence from the testimony of the families is not properly measured in the study.”

It seems that if the eteplirsen trial data were more robust and if qualitative measures of the drug’s effects on the lives of patients were obtained in clinical trials, the panel would have been swayed to vote in favor of its approval. But, isn’t that what accelerated approval is all about—allowing safe drugs with some indication of effectiveness in debilitating diseases on the market while definitive data are collected later? No, that is what CMA in Europe is about. For the FDA, accelerated approval demands substantial evidence of effectiveness, at least on a surrogate marker.

For eteplirsen, that surrogate is dystrophin—the faulty protein in DMD patients that the therapy is designed repair. Patients’ average dystrophin levels on eteplirsen rose from 0 to 0.9% of normal levels, an increase that was “very disappointing,” said FDA staff.

What is disappointing to DMD patients and their families, and to millions of other Americans, is that the FDA does not have a real conditional approval system. Perhaps, the eteplirsen debate will finally impel the FDA or Congress to establish such as system, akin to the EMA.