Developing a drug for patients with a rare disease is inherently challenging. There are a limited number of patients to participate in clinical trials and an even more limited number of sites with investigators experienced enough to conduct them.
In addition, most rare diseases are neither well known nor understood, and in many cases established endpoints do not apply. Sponsors must determine both the right endpoints and then be able to defend them to regulators.
Sponsors can increase their chances for bringing effective treatments to patients with the following strategic considerations at each stage of the rare disease drug development process:
1. Gather data on the natural history of the disease
For a rare disease, the pathogenesis and underlying biology is usually not well understood, making it hard to determine relevant endpoints. For example, the average patient in the United States waits about 7.6 years and visits 8 different physicians to confirm a rare disease diagnosis. Along the way, the patient receives an average of 2-3 misdiagnoses.
Often, the best way to identify good endpoints is to understand the natural history of the disease—from its pathological onset through recovery or death. But when there is a dearth of information about the disease, a company must gather data by:
Gathering the data and determining the endpoints can be done in parallel with early clinical development and later submitted as real-world evidence (RWE) with the clinical submission.
2. Listen to patients and patient advocates
About half of orphan disease patients are children. Consequently, rare diseases often are a family affair, and input from caregivers, including parents and extended family members, is important to designing feasible trials, and choosing suitable endpoints.
For many rare diseases, families and others have formed patient advocacy groups (PAGs). With only 5 percent of rare diseases having a form of treatment available, the rare disease community is eager to work with sponsors and Clinical Research Organizations (CROs) to help advance the development of new treatments. Involving PAGs can contribute to the successful design of research protocols, flagging feasibility issues and facilitating patient recruitment.
The recent (February 2019) FDA Draft Guidance on drug development for rare diseases notes that patients can provide “solicited consultation on scientific issues (e.g., clinically meaningful outcome measures).”
For example, patient advocates successfully have argued for regulators and payers to acknowledge the drawbacks of the standard “6-minute walk test” (6MWT) endpoint to measure the efficacy of drugs for Duchenne muscular dystrophy (DMD), a rare disease primarily afflicting young boys that leaves them wheelchair-bound. The 6MWT is a suboptimal tool to measure efficacy in the non-ambulatory phase of DMD, while other measures, such as time spent in a wheelchair, are more relevant to patients and caregivers.
In order to increase collaboration with patients, caregivers and PAGS, sponsors and CROs must demonstrate their commitment to the rare disease space. Some ways some CROs and sponsors have done this and others can too is to increase visibility by participating in and supporting key rare disease events, dedicating leadership focused on rare disease sponsor engagement, patient advocacy and patient/caregiver relations, and engaging patients in developing innovations that can support patient recruitment and retention by addressing barriers they often face.
3. Engage early with regulators
Regulatory agencies have been extremely flexible in their approaches to orphan drugs, offering expedited mechanisms, such as the FDA’s Breakthrough Therapy Designation and the European Medicines Agency’s (EMA’s) priority medicine (PRIME) program. But many companies don’t engage with regulators early enough to take full advantage of these programs.
A company considering non-standard endpoints should schedule a meeting with regulators as early as possible—and invite patient advocates to that meeting.
For example, the FDA’s Critical Path Innovation Meetings (CPIMs) offer sponsors, investigators, PAGs and regulators a chance to sit down at the same table and discuss relevant endpoints outside the traditional pre-IND or Type C meetings. And the EMA has long offered scientific advice (SA) meetings. For drugs that receive PRIME designation, a consultation can be requested at any time during development.
4. Understand the current and future therapeutic landscape
The pace of scientific advances, a crowded, competitive marketplace for therapeutics, and the need to win reimbursement from payers means sponsors must analyze the market they intend to enter, even for ultra-rare and orphan conditions.
A thorough landscape assessment can inform endpoints and answer the following questions:
5. Expand the product value story
Clinical data adds to the product value story at each stage of development, and endpoint selection is a key driver in that process. Sponsors must determine what type of clinical data will support the therapy during regulatory review and whether the therapy may qualify for an accelerated regulatory pathway such as the FDA’s Breakthrough Therapy Designation.
RWE—based on scientifically- and clinically-sound endpoints that are practical and meaningful to patients—is an increasingly important part of the value story and should support and enlarge the clinical dossier. When designing RWE studies, sponsors should consider:
By understanding the strategic considerations that impact rare disease drug development, sponsors can successfully and efficiently deliver new and better medicines to patients that very much need them.
Global Drug Development