FDA Officials Offer Advice on Efficient Orphan Drug Development

Posted 17 October 2017 By Michael Mezher

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A group of top US Food and Drug Administration (FDA) officials shared insights on how drugmakers can be more efficient when developing treatments for rare diseases, according to comments on Tuesday at the National Organization for Rare Disorders' (NORD) Summit in Washington, DC.

Speaking via video, Center for Drug Evaluation and Research (CDER) Director Janet Woodcock said that despite the growing number of new therapies in development for rare diseases and approved each year, relatively little is known about many rare conditions.

"Unlike common diseases, there's a lot of information lacking when you want to develop a drug or other intervention for a rare disorder," Woodcock said, noting a lack of information about the natural history of a disease or its impact on patients' daily lives.

Efficient Clinical Trials

Robert Temple, deputy center director for clinical science at CDER, said that one of his long held interests at FDA has been making clinical trials more efficient.

"This is particularly important in orphan territory because there are often few patients in total and there are usually very few near the centers that want to do the studies," Temple said.

Because of the challenges inherent in identifying and enrolling patients with rare disorders in studies, Temple said that having detailed natural history data "can make a tremendous difference in identifying the manifestations you want to try to treat and identifying the patients you should include" in a study.

Another important consideration, Temple said, is whether there are design features that can be built into a trial to make it more efficient.

For instance, Temple said that cross-over studies could be done in situations where enrolling patients is difficult and the disease being studied has a transient effect.

This isn't a new idea, Temple said, pointing to a 1976 cross-over study of the synthetic steroid danazol to treat hereditary angioedema that enrolled only nine patients. In that study the patients were randomized to the drug or a placebo until they had an attack, at which point they were moved to the other study arm.

Temple also said that FDA has seen some success with doing randomized withdrawal studies, particularly in situations where a placebo-controlled arm is not feasible.

"Sometimes in the course of development you'll have a lot of people who for one reason or another have been put on the drug because it's the only game in town…with a lot of people on the drug you can sometimes, if they're willing, do a randomized withdrawal study," Temple said.

But Temple emphasized that these types of studies are only appropriate in certain circumstances, and stressed that sponsors should consider approaches early on.

Billy Dunn, director of CDER's division of neurology products, said that especially for rare diseases FDA and industry need to look at novel approaches to studying drugs.

"We're not the cardiovascular division, we're not accustomed to having these multi-thousand patient trials…many things that might seem controversial or unusual in other settings, sometimes—not always, but sometimes—those can be more run-of-the-mill for us," Dunn said.

Dunn also said that different considerations must be made for studies of progressive diseases, where different stages or forms of a disease can vary considerably. In such situations, Dunn said that sponsors need to consider progression when determining enrollment criteria and, "while difficult to operationalize, having patient individualized outcomes where we attempt to assess, for a given stage or form of a disease, those aspects…that are most impairing."

Wilson Bryan, director of the Office of Tissues and Advanced Therapies at the Center for Biologics Evaluation and Research (CBER), said that one of the challenges for his office is working with academic sponsors and small biotech companies that do not have extensive experience in drug development.

This is an especially challenging issue in the rare disease space, Bryan said, because there are very few patients with a particular disease to begin with and any inefficiency in a study can waste precious time and resources. This is also true for advanced therapies as many are disease modifying and have prolonged or permanent effects, making it difficult for patients to enroll in additional studies in the future.

"Too often we have folks come in with [investigational new drug applications] INDs and they haven't started their natural history study yet, and they haven't started thinking about what their outcome measures are going to be for Phase III," Bryan said.

When should sponsors begin thinking about these things? According to Bryan, at the very early stages of drug development and well before a product is set to begin human studies.

"When I say early on in drug development I don't mean at Phase I, I mean when you first start to do preclinical studies, think about what is the target. The target is not getting into clinical trials … the target is getting a product on the market that's of use to patients," Bryan said.

Julia Beitz, director of CDER's Office of Drug Evaluation III, said that sponsors should also make sure to establish a baseline for patients' clinical, cognitive and developmental status before beginning a study and take repeat measurements of those features throughout the trial.

Beitz also said that sponsors should try, "to the extent that is possible," to stabilize patients' conditions before starting them on a drug, especially when patients are expected to need another intervention, such as surgery or a medical device.

"If these measures are instituted during the trial it becomes difficult to assess the independent effect of the new treatment on the patient," Beitz said.

One audience member asked the FDA officials how a company should handle a new product being approved for a disease studied in an ongoing pivotal trial.

Temple said this can be a thorny issue: "If the newly approved drug is very critical, it modifies the disease and would be useful to the people in the trial, it's very hard ethically not to provide it, and the trial may need to be designed to become an add-on study."

But Dunn added that sponsors should generally be aware of other therapies being developed in the field and should plan for situations like that in their protocol.

Photo courtesy of the National Organization for Rare Disorders (NORD).

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