Efficient orphan drug development - clinical trial designs in rare disease area

For a long time, drug development in rare diseases is a niche area for biotechnology companies. With the rapid advanced in genetics and ‘-omics’ and in the precision medicine era, researchers are continuously identifying new diseases or disease variants. A prevalent disease can be dissected into many small pieces, each subset could become a rare disease.

Rare diseases pose challenges in clinical trial designs. Some of the challenges are:

• Small number of patients affected
• Small number of patients for clinical trials
• Heterogeneity of the disease
• Limited understanding of the disease’s natural history
• Lack of well-defined study endpoints
• Limited early phase clinical trial data

There are several initiatives in US and in European countries that are focusing on the clinical trial designs and methodologies in rare disease area.

In US, the NORD (National Organization for Rare Disorders) is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them.  NORD, along with its more than 260 patient organization members is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services. NORD’s visions include a culture of innovation that supports basic and translational research to create diagnostic tests and therapies for all rare diseases and a regulatory environment that encourages development and timely approval of safe, effective diagnostics and treatments.

This week, Nord’s Rare Diseases and Orphan ProductsBreakthrough Summit was held in Washington DC. During the meeting, FDAOfficials Offered Advice on Efficient Orphan Drug Development:

“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.

In the social media era, it is important to have a platform for patients and caregivers to communicate and engage. INSPIRE is such an organization and provides the most authentic platform for patient engagement.

A group of people are forming a DIA working group called NEED (the Nature and Extent of Evidence Needed for Decision) engaging in the discussions about the clinical trial design in rare diseases including the natural history study, historical control, innovative study designs such as adaptive design and Bayesian design,…

In European countries, there are several initiatives focusing on the clinical trial design aspects of the rare diseases or small population group trials.

• IDEAL (Integrated Design and Analysis of Small Population Group Trials)
• ASterix (Advances in Small Trials dEsign for Regulatory Innovation and eXcellence)