Improving R&D and Review Processes
Participants told FDA that they should be flexible when weighing approval of orphan drugs. Some advocates asked for a specific written statement of policy from the FDA explaining and affirming commitment to evaluation of probable benefit of orphan drugs in a more flexible, case-by-case, and scenario-appropriate manner compared to conventional drugs.
Multiple academic rare-disease experts argued that allowances in trial designs should be made for orphan drugs, for example, using probable prognosis as opposed to placebo or adjusting p-value thresholds to 0.10 from the 0.05.
Designing drug trials for orphan diseases has, historically, been challenging. Recruiting sufficient numbers of patients for adequate powering to reach FDA-mandated statistical thresholds can be difficult to impossible. Additionally, many rare diseases manifest very differently across patients. This heterogeneity makes determining optimal primary endpoints, composite endpoints, or surrogate endpoints in a trial unclear.
Finally, due to historically small patient numbers, the etiology and natural course of rare diseases are often poorly understood. Very rarely is the benefit of a short course of drug therapy so large that the benefit to patient is unequivocal. This further complicates trial design, as thresholds for meaningful clinical benefit have not been established.
FDA has traditionally stated that orphan drugs are held according to law and agency guidelines to the same clinical effectiveness bar as drugs for treatment of more common diseases. FDA has noted that orphan drugs must prove probable benefit and safety to the same degree as all other drugs. Due to the complexity of these diseases combined with FDA’s stance on approval, drug development for orphan diseases can be risky and unclear.
It is possible to utilize SPAs, but these negotiations are often a lengthy and bureaucratic process that can take up to a year or longer. Speakers at the hearing asked that FDA be more committed in facilitating rapid SPAs.
There were also multiple calls for development of comprehensive patient/disease databases to better characterize disease etiology, progression, and prognosis. Data from these projects, stakeholders argued, could potentially serve as acceptable historical controls for future drug development.
Biomarkers are another important topic in orphan drug development. Advocates argue that FDA should be more receptive to scientifically rational and accepted biomarkers or surrogate endpoints in orphan drug evaluation. Trials that use biomarkers instead of event data as primary endpoints are often more rapid, better powered, more economical, and more practically feasible.
Another topic was the seven-year data exclusivity period, which runs concurrent with Hatch-Waxman patent extensions, giving orphan drugs an incremental two years of patent protection. Orphan disease advocates suggest that the 12 years conferred on biological therapies may be appropriate for orphan drugs as well. In addition, some patient advocates proposed that companies be granted patent extension vouchers, which can be applied to any one drug patent of choice. This is similar to vouchers currently granted for development of drugs for tropical diseases that are thought to have limited commercial returns.
Some advocates contend that the threshold for orphan drug status also needs updating. The U.S. population in 1983, when the Orphan Drug Act was passed, was around 230 million but has since increased 35%. Meanwhile the patient count threshold for orphan diseases remains at 200,000 per the original 1983 act. This would prevent certain true rare diseases from receiving orphan status.