Drugs Against Rare Diseases: Are The Regulatory Standards Higher?

Abstract

The US Food and Drug Administration (FDA) recently issued a draft Guidance for Industry for Rare Diseases: Common Issues in Drug Development (referred to as “Rare Diseases Guidance”). In our opinion, the FDA should consider: (a) explicitly acknowledging the standards are higher for rare diseases for the reasons presented in this article; and (b) illustrating innovative development pathways that may be acceptable for rare diseases, including case studies.

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A

“…This may cause imbalanced baseline disease characteristics due to potential biases in enrolling patients, and may therefore complicate determination of the dose–response relationship simply based on the observed data. However, in rare diseases with a limited number of patients available for study enrollment, conducting a series of adequately powered, randomized, controlled clinical studies throughout the development program, including a conventional dose-finding study, may not be feasible [ 44 – 47 ], especially in the presence of high unmet medical need where rapid access to new drugs is strongly desired. For dose–response characterization, non-linear mixed-effect (‘population’) modeling, which considers inter-individual variability and influential covariates, appears to be an appropriate methodology to analyze limited early-phase clinical study data [ 45 – 49 ].…”

Can the Government Deter Discrimination? Evidence from a Randomized Intervention in New York City

“…Power issues loom large when the behavior of interest, discrimination, is relatively rare and is itself estimated with uncertainty. In such cases relying on conventional standards of significance may be overly conservative-an issue that has been of concern also in the study of rare diseases and has led to calls to alter standards in such cases (Gobburu and Pastoor 2016). Rather than altering standards, we calculate appropriate beliefs that the intervention is effective using a Bayesian framework by estimating the probability of a hypothesis (that each messaging strategy is effective) given the data.…”

Challenges and Opportunities in Rare Disease Drug Development

“…Interestingly, the US Food and Drug Administration recently issued a draft guidance for industry for rare diseases . As Gobburu and Pastoor point out, there seems to be a disconnect between this document and current US Food and Drug Administration practice. They discuss, among other things, the following that can be found in the draft guidance “The statutory requirement for marketing approval is ‘substantial evidence’ that the drug will have its claimed effect.…”

“…Substantial evidence is based on the results of adequate and well‐controlled investigations.” It seems hard to imagine how drug development for rare diseases could take place if what this seems to imply is literal. What is interesting is that this does not seem consistent with current regulatory practice, which seems to be quite accepting of innovative approaches for therapeutics that treat rare diseases …”

“…What is interesting is that this does not seem consistent with current regulatory practice, which seems to be quite accepting of innovative approaches for therapeutics that treat rare diseases. 5 Innovation becomes important to contemplate and we are lucky that at the 2016 American Society for Clinical Pharmacology and Therapeutics Annual Meeting there was a session entitled "Don't Do Different Things. .…”