Why FDA Supports a Flexible Approach to Drug Development

By: Margaret A. Hamburg, M.D.

We all know that just as every person is different, so too is every disease and every drug.

Margaret Hamburg, M.D.And so we weren’t surprised by the results of a new study published in the Journal of the American Medical Association. The study found that FDA used a range of clinical trial evidence when approving 188 novel therapeutic drugs for 208 indications (uses) between 2005 and 2012. These results are entirely consistent with our regulatory mandate. We believe varying approaches to clinical studies to support drug approval is good news, not bad.

Data to support the approvals studied were based on a median of two pivotal trials per indication. A pivotal trial presents the most important data used by FDA to decide whether to approve a drug.

But when the authors looked more closely, they found that more than a third of these drugs were approved on the basis of a single pivotal clinical trial, while still other trials involved only small groups of patients for shorter durations. Of the approvals studied, the new drug was compared with existing drugs on the market only about 40 percent of the time.

The authors concluded that, based on these results, the ways in which FDA arrived at those approvals “vary widely in their thoroughness.” Or, in the words of one study author, “Not all FDA approvals are created equally.” Although I don’t think it was actually the author’s intent, a number of commentators framed this as criticism. But I would be more troubled if FDA used a rigid, “one size fits all” approach.

People with serious or life-threatening illnesses, particularly those who lack good alternatives, have told us repeatedly that they are willing to make some trade-offs in order to gain access.

And, of course, “thoroughness,” such as whether a clinical trial is large enough, is in the eyes of the beholder. There is no reason to expect drugs to be tested on similar numbers of patients, regardless of the disease.

Variation in approach to clinical studies demonstrates FDA’s innovative and flexible approach to drug development and approvals. Such an approach was specifically adopted by Congress in the Food and Drug Administration Modernization Act in 1997 and, most recently, in the Food and Drug Administration Safety and Innovation Act in 2012.

The FDA of today works with sponsors of new drugs to design a development and review pathway for each drug that best reflects the disease and patients it is intended to treat, the drug itself, and other treatment options. Some of the factors that enter into our calculus include whether the drug treats a rare or serious disease or addresses an unmet need and any previous knowledge we might have about the drug.

Thus, for example, FDA approved Imbruvica (ibrutinib), a treatment for mantle cell lymphoma, last year based on an “open-label, single-arm trial,” which means that every patient received the treatment and both patients and researchers knew they were receiving it. The results were compared to how well the 111 participating patients had responded to previous treatment for their disease.

And Elelyso (taliglucerase alfa) – for Gaucher disease – was an orphan drug approved in 2012 based on two trials with 56 patients.

In contrast, some trials require large numbers of patients to demonstrate a drug’s effects. This is often the case in studies in patients with a chronic condition such as cardiovascular disease, where larger populations are studied to capture treatment effects.

No matter what clinical trial design is chosen, the Agency always applies the same statutory approval standards of safety and efficacy to all drugs seeking to be marketed in the United States.

Increased flexibility does not mean abandoning standards, and it certainly does not mean abandoning science. Just the opposite. We need to employ the best science in ways that will increase efficiency, productivity and our shared ability to find creative solutions to the challenges that confront us.

At the end of the day, that is just smart regulation – ensuring that patients can more rapidly have access to the best that science has to offer.

Margaret A. Hamburg, M.D., is the Commissioner of the Food and Drug Administration

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