by Craig Klugman, Ph.D.

In a surprising move, the Food and Drug Administration approved Exondys, a drug that has not been proven to work, did not have a randomized control trial, and that recommended against by an independent expert panel. The approval was via the accelerated pathway “which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatment. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients.” You just need to show a likelihood of benefit, not proof that it works.

The drug targets a genetic mutation that is the cause of 13% of Duchenne muscular dystrophy (DMD) cases. The disease is rare, affecting approximately 20,000 boys in the U.S., aged 5 – 24 years. Most patients die in the 20s or 30s.

Approval was based on a study of 12 boys with the disease who took the drug. There was no control group. The expert advisory board voted against approving the drug, citing a lack of meeting FDA study requirements such as sample size and controls. Usually, the FDA follows the recommendation of the advisory boards.

In this case, approval went against the advisory board recommendation because of pressure from patient and advocacy groups. There simply are not any other good treatments for the disease. The FDA is requiring a future confirmatory trial, after approval. Proof after approval is the opposite of how the FDA usually works. Though in the case of emergency approvals for Zika drugs and vaccines, this process is becoming more common.

One expressed concern is that this action creates a precedent for the FDA to approve drugs simply on advocacy of patients and drug companies, instead of being based on good science. Rigor has given way to speed in approving some drugs. Sarepta Therapeutics, after all, did not prove that Exondys worked. This follows a state-by-state push for right to try laws that allow patients to petition drug companies to use experimental drugs that have not yet been approved by the FDA. The danger is that one bad outcome could lead to bad publicity that forces a company to shelf a promising drug. This is the opposite of a public health approach in that it prioritizes the individual above the group good. There is also a highly likelihood of patient harm since there is no significant proof the drug works or even knowledge of the side effects. Without studies, there is no answer as to whether the drug actually helped or if the idea of the drug helped (placebo effect) nor can we know how much it helps (or hurts) without a comparison group. Instead, one must rely on historical case studies, a far less accurate method.

Might this approval represent a new standard where drugs are passed based on popularity or encouragement of drug companies rather than the result of rigorous trials? The move toward popular involvement with approval began in the 1980s with the emergence of AIDS where advocacy groups pushed for early access to experimental drugs. A populist approval method may be the natural result of those humbler beginnings. As I and others have written, there is no obligation for anyone to provide materials for people to self-experiment.

Orphan drugs and drugs targeted to a low patient population also tend be very expensive. Exondys will cost $300,000 per year. The company has to recoup its cost and make its profits with a small potential customer base, so they charge a lot more.

On other hand, it is very expensive and difficult to gain attention for drugs to treat rare diseases. This process may be a way to get drugs to market when the patient population is too small for a statistically significant trial. These patients have no other options and desperation can create demand and a willingness to undertake risks that provide no benefit, perhaps even harm. The answer is a call for more proper studies and for finding alternative models for testing (computers, animal) that can give an approximate answer. However, patients may feel a lot of pressure to participate in studies when the population is small. That pressure can compromise consent and autonomy. If one person does not participate in these trials, or does not adhere perfectly to the regimen, then the data is compromised and results are skewed and/or invalid.

For those who suffer with this disease and see few options, they may see this news as good, providing some hope. That hope is shallow though and not supported by science. The approval also sets up a situation where in the future, if the FDA does not approve other drugs, advocacy groups can yell foul. The effectiveness of the FDA protecting us from fraud and harm may have been irrevocably compromised.