Summary

FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) propose a new process under Rare Disease Evidence Principles (RDEP) to facilitate the approval of drugs to treat rare diseases with very small patient populations with significant unmet medical need and with a known genetic defect that is the major driver of the pathophysiology. Drugs in this process will continue to be reviewed under the statutory marketing approval standard of safety and efficacy pursuant to 505(d) of the FDCA. What the RDEP offers is the assurance that drug review will encompass additional supportive data in the review. To ensure consistency between CDER and CBER, drug review teams will consult with the Rare Disease Policy and Portfolio Council (RDPPC) in the decision to accept a drug for review under this process. Drugs approved after participation in this process may be subject to additional postmarketing requirements. Because of frequent use of non-randomized trials and well-established early clinical endpoints (e.g., response rates, response durations) leading to multiple “rare” oncology indications, sponsors should first consult the Oncology Center of Excellence or the CDER/CBER oncology review divisions to determine if the below procedures are applicable to their development plan.

Background

It is well understood that drug development for rare disease has challenges not experienced by larger disease populations. The smaller the population or subpopulations in the rare disease being studied, the more difficult it is to generate evidence to meet statutory requirements for demonstrating efficacy through traditional trial designs (e.g., placebo-controlled) and quantity of clinical studies. To address this challenge, CDER and CBER propose a new process that provides greater clarity as to the kinds of evidence that can be used to demonstrate substantial evidence of effectiveness for diseases of known genetic defect.

Eligibility

Sponsors may apply for the RDEP process at any time prior to the launch of a pivotal trial if the investigative therapy is specific to the correction of the genetic defect in question (i.e., either correcting the gene or is a replacement of an essential physiological protein that is otherwise deficient due to the gene defect) and meets the following criteria:

the drug is for a very small, rare disease population or subpopulation (e.g., generally less than 1,000 persons in the United States);
the drug is intended to treat a known, in-born genetic defect that is the major driver of the pathophysiology;
the clinical course of the disease is progressive deterioration in function leading to rapid and/or significant disability or death in a relatively short period of time; and
there are no adequate alternative therapies that alter the course of the disease.

Proposed Process

For drugs that meet the criteria above, FDA expects that substantial evidence of effectiveness may generally be established based on one adequate and well-controlled study that may be a single arm trial, together with robust data that provides strong confirmatory evidence of the drug’s treatment effect. Such data 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; and
other clinical data including case reports and expanded access data.

FDA will also consider confirmatory evidence provided through the appropriate selection of external controls or natural history studies.

A determination of substantial evidence of effectiveness based upon one adequate and well-controlled study with confirmatory evidence may be found in some circumstances as described in the Draft Guidance for Industry: Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (September 2023). 

Review Process

A request should be submitted to a sponsor’s existing investigational new drug (IND) prior to the launch of a pivotal trial for each protocol the sponsor wants reviewed under the RDEP; the request should include reasonable evidence that the eligibility criteria are met and that the safety and efficacy of the drug can be demonstrated by one adequate and well-controlled study with confirmatory evidence. A request for participation in this process should be accompanied by a formal meeting request appropriate for the sponsor’s stage in the drug development process. A request should not include more than one protocol. If there is no IND for the product, FDA will assign a pre-IND number so that a meeting can be scheduled to fully inform FDA of the overall development plan for the product. The sponsor can subsequently open an IND after the meeting and then submit a request to the IND. The relevant center review team would issue a decision on acceptance following a consultation with the CDER/CBER RDPPC.

Accepted sponsors will have an initial meeting with the appropriate FDA review team to determine what data will be used to substantiate safety and effectiveness. The Agency’s concurrence on study design and qualifying confirmatory evidence would not necessarily indicate that the Agency expects to determine that the drug is approvable. FDA and sponsors would be encouraged to incorporate patient experience data, including by leveraging separate patient listening sessions where appropriate. At this initial meeting, the agency and the sponsor may discuss the need for future engagement at significant milestones in the drug development and/or application process, touchpoints between the agency and the sponsor at critical points of determining relevant evidence, etc.

Sponsor requests for review under the RDEP process are separate from and independent of requests for orphan-drug designation under section 526 of the Federal Food, Drug & Cosmetic (FD&C) Act. A drug that is reviewed under the RDEP process does not necessarily qualify as a drug that has orphan-drug designation, and the RDEP does not bear on the Agency’s determination whether a drug may be eligible for orphan-drug designation. A sponsor that wishes to seek orphan-drug designation for its drug must follow the procedures set forth under section 526 of the FD&C Act and 21 C.F.R. Part 316.