May 26, 2017
By Mark Terry, BioSpace.com Breaking News Staff
Charles Seife, a journalist, author and professor at New York University, filed a federal lawsuit against the U.S. Food and Drug Administration (FDA) related to documents over the approval of Sarepta Therapeutics ’s Exondys 51 for Duchenne muscular dystrophy (DMD).
In December 2016, Seife filed a Freedom of Information Act (FOIA) with the FDA for the documents, which they eventually rejected. According to the Boston Business Journal, “The documents sought by Seife include emails to and from top FDA officials, including former commissioner Robert Califf, that mentions Sarepta, Duchenne and other key words. Seife is also seeking correspondence between Califf and the editors of scientific journal Annals of Neurology, which published a study in 2013 attesting to the effectiveness of Exondys 51. Just days before the drug was approved, Califf called for a retraction of the study, which had been funded by Sarepta, describing it as ‘misleading.’”
The complaint filed yesterday states, in part, “It will shed light on the hotly debated issue of whether the FDA approved an entirely ineffective drug based on faulty clinical trials and undue industry influence, or whether an effective drug is being unjustly excluded from reimbursement in many prescription drug plans.”
The story of Sarepta and Exondys 51 was dramatic from the beginning. It started more or less, in January 2016, when the FDA postponed a review of the company’s New Drug Application (NDA) because of a pending snowstorm on the east coast. In February 2016, 109 members of Congress sent a letter to the FDA urging it to accelerate approval of a DMD drug, any DMD drug. In March 36, DMD experts signed a letter to the FDA urging it to approve eteplirsen.
The April meeting lasted 12 hours and had 52 public commentators, including families and DMD children. In May, the FDA delayed its decision, indicating it wanted more time and data. Then, on August 4, the clinicaltrials.gov website indicated that Sarepta’s Phase III ESSENCE trial for DMD had begun to recruit patients.
On September 14, investors noted that Ronald Farkas, who headed the clinical review team that oversaw the drug’s approval process, left the agency for a job in the private sector. Farkas was notably critical of the drug and the clinical trial data, but he wasn’t the only one.
DMD is a muscle wasting disease caused by mutations in the dystrophin gene. It is a progressive disease that usually causes death in early adulthood, with serious complications that include heart or respiratory-related problems. It mostly affects boys, about 1 in ever 3,500 or 5,000 male children.
Exondys 51 uses gene-skipping technology that allows the gene to produce a truncated version of the necessary protein. There are a number of questions about the drug. Part of the issue is that the clinical trial size was very small—12 children—and two of them were not included in the data because they were considered too old for the drug to be effective. There was no placebo control. One other issue is that one of the tests used to evaluate DMD and the drug is a walk test, where the patient walks for about six minutes, if they can, and the distance is evaluated. It’s a test that can potentially be strongly influenced by the placebo effect—essentially, if the patient feels they are doing better on the drug, they will manage to walk a bit further.
The controversy didn’t end there, however.
There was significant controversy over the approval of the drug within the FDA, which is what Seife appears to be investigating. Documents already released show just how much controversy there was within the agency.
There were at least three major opponents to approval within the FDA. Ronald Farkas, who left the agency, the agency’s acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation, strongly opposed approval, arguing that Sarepta did not provide substantial evidence of Exondys 51’s effectives.
But Janet Woodcock, director of the CDER, pushed it through, overruling her staff. The final decision then went to Robert Califf, the FDA’s Commissioner at the time. Evidence suggests that Califf had similar reservations as Borio and Unger, but sided with Woodcock.
The disagreements did not appear to be over whether the drug actually worked, at least not completely, but on whether Sarepta had actually proven that the drug’s effectiveness had met the bar set by the FDA for DMD drugs and any other drugs. Borio, for example, wrote a memo that has been released, where she stated, “To me, the crux of the disagreement is not whether there is an appropriate threshold, but whether such a minuscule amount of dystrophin is reasonably likely to predict clinical benefit.”
As part of its eventual approval, Sarepta is required to conduct a two-year, randomized controlled trial to verify the drug’s benefits. If it doesn’t, it’s conceivable that the FDA would withdraw approval.
Meanwhile, the price for the drug is $300,000 per year, based on a patient’s weight. That price point is based on a patient weight of 25 kg, which makes most analysts think the actual price for the drug will be $450,000 to $500,000. For the most part, insurers have agreed to cover the drug, particularly in light of a complete lack of alternatives. Anthem, which has 38 million customers, chose not to pay for it, arguing that it is “investigational and not medically necessary.” Humana agreed to cover it, but only for six months, at which point it will only cover the next six months if the patient continues to be ambulatory.
Seife’s legal filing also argues, according to Reuters, “that the FDA is required by law to grant expedited processing to the federal Freedom of Information Act request he filed last year because of its importance to the public.”
