When the European Medicines Agency approved Myozyme in 2006, Genzyme’s enzyme replacement therapy for the lysosomal storage disorder Pompe’s disease, it involved an 18-month randomized, placebo-controlled trial study of 90 patients with the late-onset form of the condition.

But the study also included a separate arm of nine children with the infantile-onset Pompe’s disease. Because there was already evidence of a beneficial effect of the drug and the fact that the infantile-onset Pompe’s disease progresses rapidly and is fatal, it was considered unethical to conduct a randomized, placebo controlled-study for the late-infantile form of the disease. Instead, a single treatment arm was used and data from a registry of patients who matched the inclusion criteria of the study served as a control group.

That is just one example of how patient registries can play an important role in bringing new therapies for rare diseases to market. But if the right data doesn’t exist in a patient registry, then it can’t help address some of the challenges involved in developing treatments for these conditions.

There are many challenges in developing therapies for rare diseases. Among those is the lack of information about a specific disease, uncertainty about how a given disease progresses, the variations in the way the disease may manifest itself in patients, and the small patient populations. Rare disease registries can play a critical role in laying a foundation for understanding a disease. They can also provide critical insights into trial design and fleshing out meaningful endpoints for studies.

A new study in the Orphanet Journal of Rare Diseases from researchers involved in the Asterix consortium, a European Union funded partnership that focuses on the development of research methodologies for rare disease drug trials, examined the possible applications for disease-specific, rare disease registries to aid in drug development and suggests data elements that should be collected by registries for that purpose.

While rare disease patients will want to know about treatments as soon as they are diagnosed, the reality for roughly 95 percent of rare diseases is that there are no approved therapies. The path to developing treatments is long and costly, often beginning with the need to understand the biological mechanisms underlying the disease.

Rare disease registries represent a critical tool for the development of therapies and can accelerate that process, even if there a long financial, scientific, and clinical gulf to bridge.

“Designing a registry with a future clinical trial in mind can considerably reduce the time needed for the clinical development phase of a long-awaited drug,” the authors wrote. “One of the first steps in making a disease-specific [rare disease registry] applicable to inform a drug trial for market authorization is to think of the research question and endpoints of that future trial. It is pivotal to consider what could be appropriate outcome measures in a very early stage, even when a trial is still far away.”

That requires considering what a possible clinical trial in the future would look like to understand what information should be collected today. It also will be important to think about the use of validated measurement instruments if they exist, or validating promising instruments, as well as standardizing how measurements are taken to increase the chances that they could be useful in a future clinical trial and withstand the scrutiny of regulators.

The authors provide a checklist of the types of information that should be included in a rare disease registry to inform clinical trial design. This includes elements that provide basic characterization of the patient (patient characteristics, demographic characteristics), disease aspects (diagnosis, co-morbidities, treatment), and outcome variables (mortality, life impact, pathophysiological manifestations).

The authors also note the importance of obtaining patient input on quality of life and daily functioning measures that matter to them as a way to improve the design of a registry and its utility in a clinical trial. For instance, the authors point to a Duchenne muscular dystrophy advocacy group that had identified the need to develop a scale to measure motor function of the upper limb to be able to include children who were unable to walk in new registration studies.

The key is to think ahead. The better rare disease registries can anticipate the clinical trials for a therapy for a given disease, the greater utility they can provide. As the American philosopher and Yankee Hall-of-Famer Yogi Berra said, “If you don’t know where you are going, you’ll end up someplace else.”

September 18, 2018
Photo: Yogi Berra