Compared with developing drugs for common prevalent diseases or conditions, developing drugs for rare diseases comes with unique challenges. The United States Orphan Drug Act of 1983 defined a rare disease as one that affects fewer than 200,000 people in the United States.

Developing drugs for such small patient populations often comes with uncertainties with regards to the natural history of the disease or condition as well as difficulties in enrolling a sufficient number of patients in clinical studies of the therapy during development.

Following the passage of statutes in the US, Europe, and elsewhere that provide incentives for developing drugs for rare diseases, there has been a resurgence of interest in the pharmaceutical and biotechnology sector to bring forward new therapies to help patients who suffer from rare diseases.

In February of 2019, the US Food and Drug Administration (FDA) issued a draft guidance on common issues that arise when developing new drugs for rare diseases. An FDA guidance sheds light on the Agency’s current thinking on a given topic.

The FDA frequently shares a draft guidance with the public to invite comments before finalizing them. This draft guidance on rare disease drug development is an update to a previous draft guidance issued in August of 2015.

This updated draft guidance begins by iterating that approval of any new drug treatment for a rare disease must meet the same requirements as a new treatment for a common disease—namely, the new drug must demonstrate substantial evidence of the drug’s safety and efficacy under the intended prescription labeling.

But the FDA acknowledges that these requirements may be more difficult to address in the case of a rare disease. Given these challenges, FDA regulations provide flexibility in applying these standards when considering treatments for rare diseases.

A thorough understanding of natural history is essential to understanding how a rare disease develops.

Natural history studies can provide a wealth of information with regards to entry criteria for clinical trials, endpoints in clinical studies, duration of clinical studies as well as help identify important biomarkers that may provide evidence of efficacy, guide dose selection, or even allow for enrichment for patients who are more likely to respond to the investigative drug therapy.

The natural history of many rare diseases, however, is often poorly understood; thus, sponsors should strongly consider initiating a natural history study early on in order to inform their pivotal clinical trials later in development.

A natural history study is not required by the FDA; however, it stands to reason that since rare diseases often vary in their presentations and can affect multiple organ systems with different rates of progression, a well-done prospective natural history study could enable a more efficient drug development program and avoid unanticipated findings in the later stages of development.

A prospective natural history study could also bring other benefits. Such a study provides an opportunity to further understand disease pathogenesis and identify factors that account for variations in disease presentation.

Furthermore, a study could also help identify new disease biomarkers that could predict how clinical manifestations develop over time. These disease biomarkers could also be used to inform the effects of the treatment in question.

In the draft guidance, however, the FDA points out that a surrogate biomarker does not qualify as a measure of clinical benefit per se. This also applies to other laboratory measurements and radiographic endpoints even though these measurements could be predictive of positive clinical benefits.

In special cases of rare diseases that are serious or life-threatening and have no available therapies, the draft guidance mentions that the Agency may consider an accelerated approval pathway based on a surrogate endpoint that is likely to predict a clinical benefit.

But in most cases, clinical outcomes from well-controlled clinical trials will be required to provide the evidence of efficacy required for FDA approval.

With regards to safety, health authorities will often require a sufficiently-sized safety database that helps establish the safety of the treatment under consideration.

This safety data is typically acquired by analyzing the safety of the treatment against a comparator arm in clinical studies where patients are administered a placebo or an active comparator.

For rare diseases, it could be challenging because of the smaller number of patients or because the patients themselves are less motivated to enroll in a study where there is a chance they could be randomized to a placebo group.

The draft guidance weighs in on several alternative options that sponsors could consider. This includes collecting data on a safety cohort that runs parallel to the registrational study that includes patients who do not meet all eligibility criteria.

Another option is to collect safety data in patients who receive the drug under an expanded access program. If the sponsor has started prospective natural history study as part of the development program, the draft guidance states that in special circumstances, a well-designed and conducted natural history study can provide an external control group for interventional trials.

With regards to the use of historical controls, the draft guidance states that this approach should generally be reserved for restricted cases since any comparisons are difficult to interpret when treatment groups are not run at the same time under the same conditions.

The use of historical controls can only be considered for special cases where the rare disease has a high unmet need, the disease has a highly predictable disease course, and where the drug effect is large and self-evident.

A new section to the draft guidance on developing drugs for rare diseases includes a call for sponsors to involve patients, their caregivers, and patient advocate groups in the drug development process.

Engagement with these groups can provide invaluable insight into the disease as well as the needs and priorities of the patients affected. This engagement can often be accomplished through direct contact in the form of advisory committees.

Finally, the draft guidance includes a section on pediatric considerations. More than half of those affected by rare diseases are children. Thus, it is critical to consider pediatric development plans early on in order that information on prescribing the therapy to this population can be included in the prescribing label as early as possible.

Rare diseases can have a severe impact on patients and their families. There are an estimated 7,000 rare diseases that affect 25 to 30 million individuals in the US. As physicians and researchers increasingly use tools such as genome sequencing to advance our understanding of rare diseases, there will be a growing opportunity to develop new therapies for rare diseases that target the underlying molecular pathophysiology.

Disclaimer: “I am an employee of Vertex. All opinions are my own and do not necessarily represent the views of Vertex.”