FDA’s Rare Disease Evidence Principles (RDEP): What We Know So Far
Authors:
Karen Sturgeon
Principal Consultant
Nohman Mohammad
Consultant
Introduction
The FDA has announced a new review process for rare diseases based on a molecule’s “plausible mechanism” which would allow the FDA to consider approval on a conditional basis. This initiative is designed to help speed up the approval of drugs to treat rare diseases and provide clear guidance on how evidence of efficacy can be demonstrated with a small patient population, removing the challenge of substantial safety and efficacy requirements.
Eligibility
The FDA’s Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) have jointly implemented a new regulatory pathway called the Rare Disease Evidence Principles (RDEP). To be eligible:
The investigational product’s indication must be for an ultra-rare genetic condition affecting fewer than 1000 patients and
Targeted at either replacing or correcting the genetic defect responsible for the disease
The disease should be severe enough to progress to significant disability or death
There should be no alternative therapies available that are able to divert the trajectory of the chosen condition
Requirements
Those programmes suitable will meet with the agency to help elucidate what data will be acceptable and discuss expectations for future engagement at significant milestones during development.
While drugs will still need to meet the usual safety and efficacy standards detailed in 505(d), RDEP allows one robust well-controlled study along with confirmatory evidence to be used for approval. Additional data considered as confirmatory may include:
Evidence of the drug’s treatment effect on the direct pathophysiology of the disease
Evidence from a relevant non-clinical model
Therapeutically relevant clinical pharmacodynamic data
Other clinical data including case reports and expanded access data
Appropriate selection of external controls or natural history studies
Sponsors seeking review under the RDEP programme must submit their request as part of a formal meeting application prior to launching a pivotal trial. If no IND exists, a Pre-IND meeting will be held to review the development plan prior to a formal IND being opened.
Additional Information
To keep uniformity between CBER and CDER, FDA review teams will refer with the Rare Disease Policy and Portfolio Council (RDPPC) before deciding if a drug qualifies for this process. Drugs approved through RDEP may need to provide additional data as a post marketing requirement after approval.
RDEP requests are independent of orphan-drug designation under section 526 of the Federal Food, Drug & Cosmetic (FD&C) Act. A drug reviewed under RDEP does not automatically qualify as an orphan drug, and sponsors must apply separately for orphan designation under the applicable statutory and regulatory procedures.
Single-arm trials are already being approved by the FDA for oncology conditions, so Sponsors developing oncology treatments are advised to liaise with the FDA’s Oncology Center of Excellence or the relevant review divisions before deciding if the REPD is the most appropriate drug development path for their asset.
Those not eligible for the specific criteria of the RDEP programme may be able to use the FDAs Accelerated Approval Program. This can be used for therapies for serious or life-threatening conditions and allows for earlier approval based on a surrogate endpoint, therefore shortening the time required for approval. Studies to confirm clinical benefit are still required and those that do not demonstrate efficacy may result in a change in label or withdrawal.