The first drug approval by FDA for treating Duchenne Muscular Dystrophy (DMD) - who win, who lose?

Early this year, I wrote an article about “Race for the first drug approval by FDA for treating Duchenne Muscular Dystrophy (DMD)”, now came a great news for DMD patients and the biotechnology company Sarepta Therapeutics. This week, FDA approved Sarepta’s Eteplirsen for treating DMD patients – the first drug approved by FDA for treating DMD. Approval of Eteplirsen is a great example of a drug approved for treating rare disease where FDA’s flexibility and sensitivity to the obstacles of drug development for rare diseases has brought forth a successful treatment.  

However, this approval has a lot of controversies. In April, 2016, FDA’s advisory committee voted against the approval citing that there was not sufficient evidence demonstrating the efficacy. It is rare that FDA did not following advisory committee’s recommendations. On the other hand, we can clearly see that there are a lot of pushes from the patient advocate groups orchestrated most likely by the company. FDA tends to bow to the public pressure in approving drugs where there may not be substantial evidence. It is shown in the approval of Eteplirsen for DMD in this case and in the approval of Flibanserin (Addyi or so-called female Viagra) last year for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD).  

Food Drug and Cosmetic Act says:

…the term ‘‘substantial evidence’’ means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

The adequate and well-controlled investigations should have the following features:

1.      A clear statement of the objectives of the investigation and a summary of the …methods of analysis

2.      The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol…should describe the study design precisely.

3.      The method of selection of subjects provides adequate assurance they have the disease or condition being studied.

4.      The method of assigning patients to treatment and control groups minimizes bias and …assure(s) comparability of the groups.

5.      Adequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data.

6.      The methods of assessment of subjects’ response are well-defined and reliable.

7.      There is an analysis of the results of the study adequate to assess the effects of the drug.

Based on FDA’s briefing document for advisory committee meeting, there were a lot of issues that were against these principles for an adequate and well-controlled investigations. The primary efficacy endpoint was not statistically significant. The assay and assessment were not reliable. There was inadequate handling of missing data in analysis. There was inadequate use of the historical control. There were a lot of fishing expeditions - searching for the positive signals in largely negative studies.  

As mentioned in an article in Boston Globe "For a mother, a bittersweet victory as a long-sought drug is finally approved":

In approving the drug — called eteplirsen, it’s made by Cambridge-based Sarepta Therapeutics — the FDA overruled its own staff and advisers, who concluded there was not enough evidence it worked. Even if it does, it’s expected to help only 13 percent of the estimated 20,000 people in the United States with Duchenne.

But advocates like Christine McSherry begged the FDA to approve it, arguing it was their only hope

Studies to Support the Approval of Eteplirsen

Studies	Phase	Sample Size	Study Design	Protocol title
Study 28	Phase 1	7	Single arm, no concurrent control	Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy
Study 33	Phase 1/2	19	Open label, dose-ranging study	Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients
Study 201	Phase 2	12 (4 patients per arm)	Randomized, controlled study with two active dose groups versus placebo	Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients
Study 202	Phase 2	12	Open label extension	Extension study of Study 202

• FDA Faces Sensitive Challenge With Review of DMD Drug
• FDA Panel Votes Against Approval for Sarepta DMD Drug
• Sarepta Wins Controversial FDA Approval for First DMD Drug
• FDA Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee (PDF - 4.2MB)
• Sarepta Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee (PDF - 1.7MB)
• Sarepta Guest Speaker Presentation for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee (PDF - 145KB)
• Minutes for the April 25, 2016 Meeting of the Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee (PDF - 91KB)

Right after FDA’s advisory committee voted against the approval of Eteplirsen, the Catch-22 for FDA was clear:

Does the agency approve a generally safe but possibly ineffective DMD treatment based on limited data, and then rely on post-marketing data to see if the treatment is really effective, possibly raising false hopes of families and young boys that believe the drug is working?

Or

Does FDA reject eteplirsen, wait for more data to prove its effectiveness and possibly deny access to the treatment (for up to three years) until more concrete evidence of the treatment’s effectiveness?

FDA decided to go with the first option to approve eteplirsen. Eteplirsen is approved under accelerated approval regulatory pathway and Sarepta is required to conduct a confirmatory study after the approval. Theoretically if the confirmatory study cannot show the efficacy, the drug should be withdrew from the market. However, it will be extremely difficult or unlikely to withdraw the drug from the market even if the evidence about the efficacy is not substantial from the post-marketing study. FDA bows to the public pressure now and will face even more daunting pressure then. 

The approval of eteplirsen is the win for drug developer, for DMD patient advocate group, and for orphan drug development. The approval of eteplirsen is also the loss for FDA who approves a drug largely due to the public pressure.  

As for DMD patients, on the surface, it seems to be a victory to have a drug available, however, it is a drug with unproved benefit that may give the patients the false hope. Hopefully, the fight for efficacious treatment for DMD will continue and the approval of eteplirsen will not impede the further pursuit of DMD treatment by other companies.