The randomized controlled trial has long been held up as the gold standard for testing new drugs. But the nation’s top drug evaluator, Janet Woodcock, believes they aren’t necessary for all new experimental treatments. Randomized trials are long, expensive to run, and ultimately produce limited answers, she said at a medical conference last week.
The ability to use genetic information to classify patients and match them to potential therapies opens up new possibilities for evaluating drugs. As these capabilities increase, Woodcock says, the FDA should adjust its approach to reviewing drugs.
“People have been very happy with the use of the traditional standard randomized controlled trial,” Woodcock said last Thursday at the Precision Medicine World Conference at Duke University. “People know how to interpret that evidence. Yet that may not be appropriate for some of these diseases.”
The FDA has shown such flexibility with two recent approvals based on better genetic insights. Last week, the FDA approved Merck’s (NYSE: [[ticker:MRK]]) cancer drug pembrolizumab (Keytruda) for all solid tumors with a specific genetic signature, regardless of where in the body the cancer started. That decision came days after the regulator expanded use of Vertex Pharmaceuticals (NASDAQ: [[ticker:VRTX]]) cystic fibrosis drug, ivacaftor (Kalydeco), so more patients with a particular genetic mutations could get treatment. The additional approvals for both drugs did not require the companies to conduct more randomized controlled trials. Woodcock described the approvals as “landmarks for precision medicine.”
Pembrolizumab was already approved to treat cancers of the skin, lung, and bladder, among others. The data supporting the latest approval for the Kenilworth, NJ-based company’s drug came from open-label “basket trials” that simultaneously tested pembrolizumab on a variety of tumors that all share a specific genetic alteration. Patients were selected for the studies based on genetic tests that identified that signature, a predictor of whether they would respond to the Merck therapy. The FDA’s ruling was an “accelerated approval,” meaning Merck must gather additional evidence to confirm the earlier studies. Woodcock said that this type of flexible approach is particularly important for diseases that have no treatment alternatives.
Genetic information has also played a role in the development and approval of Vertex’s cystic fibrosis drug, ivacaftor. The drug was initially approved to treat patients who have specific mutations that indicate they would respond to the drug. On May 17, the FDA expanded the approval from 10 mutations to 33. Woodcock said the FDA based this decision on several factors, but the main evidence was a laboratory test that showed the drug could also help CF patients with more gene mutations. Woodcock said that this decision opens a pathway for drugs in cystic fibrosis and other diseases that have similar signs and symptoms. After a drug is first approved, a drugmaker could get additional approvals for additional patient subsets by using the lab test, rather than conducting a randomized clinical trial for each group.
The FDA and drug companies have been talking about adding new approaches to clinical trials for years, and that effort is now getting a nudge forward under federal law. Among the provisions of the wide-ranging 21st Century Cures Act, signed into law last year, are requirements that the FDA hold public hearings and issue guidance to help drug companies use new clinical trial designs to test their drugs. The law also calls on the FDA to use real-world evidence to support applications for new uses of already approved drugs. (Regulatory Affairs has a good breakdown of what the new federal law means for the FDA.)
Woodcock didn’t reference the Cures Act in her remarks. But she said that for some drugs, different trial designs are warranted. “Platform trials” might be useful to evaluate multiple drugs and drug combinations simultaneously, with the ability to adjust the studies on the fly by adding or dropping arms. This flexibility allows
