The FDA CDER/CBER Rare Disease Evidence Principles Approval Process – More of the Same, or More than Meets the Eye?
In this article, Eric Hardter examines the FDA’s newly proposed Rare Disease Evidence Principles (RDEP), questioning whether they mark a genuine step forward in rare disease drug approvals or a reframing of existing approaches.
In a recent communication from the United States Food and Drug Administration’s (US FDA) Rare Disease Innovation Hub1, the general framework of a proposed process for facilitating approval of drugs to treat rare diseases (termed the Rare Disease Evidence Principles, or RDEP) was unveiled. The broad reaction is likely universally shared – any novel paradigm that helps expedite the provision of safe and effective medicines to patients with no other options, as is often the case with rare diseases, is a step in the right direction. But even with the acknowledgement that there will be additional granularity to follow, the question remains – how big of a step is it really?
Understandably, rare disease drug development often necessitates novel regulatory practice. A “phase 1, phase 2, and two, large phase 3 trials” approach is ill-fit in a clinical space that will have far fewer participants, and where it may be unethical to include healthy patient volunteers, or comparator cohorts. My colleague Harriet Edwards and I touched on some of this nuance in a prior Conversations in Drug Development podcast (entitled “The Regulatory Challenges of Rare Disease Drug Development”)2.
Correspondingly, the FDA has proven malleable in their approach to the rare disease space. Further, as technology and science have advanced (e.g., cell and gene therapies, genome editing), the FDA has adapted. Examples of previously released guidance and programs typifying this include but are not limited to:
- Rare Diseases: Considerations for the Development of Drugs and Biological Products (December 2023)3 – This guidance document provides advice throughout the duration of investigational medicinal product (IMP) lifecycle development, including discussion of nonclinical, manufacturing and clinical issues. This includes potential clinical design options where a randomized, controlled, double-blind study may not be practicable.
- Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (September 2023)4 – This draft guidance describes scenarios where a single, pivotal clinical trial may suffice in providing for the acceptability of an IMP’s risk/benefit profile. Further, it details specific alternatives to further clinical scrutiny (e.g., Natural History study data, or data obtained from nonclinical investigation in a relevant animal model).
- Rare Diseases: Natural History Studies for Drug Development (March 2019)5: This draft guidance document discusses when Natural History study data may be used as supportive clinical evidence, including potentially as a comparator arm of an unblinded clinical trial, as well as best practices for data obtainment and analysis.
- Human Gene Therapy for Rare Diseases (January 2020)6: This guidance details considerations specific to gene therapy IMPs, including treatment populations, dose-finding exercises, and staggering of IMP administration and dose escalation to best ensure safety. It also touches on the potential need for accelerated manufacturing to mirror a truncated clinical program, with a need to validate a quantitative potency assay earlier in development.
- FDA’s Rare Disease Endpoint Advancement Pilot (RDEA)7: This program signified FDA’s understanding that certain rare diseases may be best profiled by unvalidated biomarkers (e.g., increase or decrease of a biomarker could describe disease progression or treatment). Commensurately, the RDEA affords selected drug developers the opportunity for additional liaison with FDA stakeholders, thereby derisking novel endpoint development.
To some extent, the RDEP program appears to pull from each of these. Additionally, it speaks to the need to meet with FDA for discussion prior to the launch of a pivotal clinical trial, under the Sponsor’s existing Investigational New Drug (IND) application. However, prudent developers of novel therapeutics for rare and ultra-rare diseases were likely doing this anyhow, with a goal of a one- or two-trial clinical development program. Therefore, discussion should have been held as early as a pre-IND (or INTERACT) meeting to best gauge the FDA’s appetite for an accelerated IND phase, with more substantive discussion occurring at an end-of-phase (or other) meeting.
Given this, it’s fair to wonder if the RDEP program represents a novel step towards licensure for IMPs meeting specified criteria, or if it’s more of a repackaging of previously provided information? Further, does it add any further incentivization for drug developers who, outside the benefits of Orphan Drug Designation, still may not see financial benefit through IMP licensure? We will need to wait for additional FDA commentary on RDEP to firmly ascertain these answers, but in there interim there may be some signal in the noise.
Firstly, the RDEP idea was born from the FDA Rare Disease Innovation Hub8, a recent FDA initiative. Importantly, the Innovation Hub is a collaborative effort between stakeholders from CDER and CBER, best ensuring a “single source of FDA truth.” Drug developers working on multiple IMPs spanning both drugs and biologics, especially in the rare disease space, have undoubtedly received varying guidance from CDER and CBER stakeholders (e.g., during formal FDA meetings). Having FDA stakeholders across drugs and biologics aligned under the Innovation Hub, and subsequently RDEP, should help provide transparency, and consistency of messaging.
Secondly, though some of the RDEP criteria are common in rare disease drug development (i.e., the drug treats an in-born genetic defect; the disease results in quick, progressive clinical deterioration or death; and, there are no available therapies to treat the disease), one condition is more notable: “the drug is for a very small, rare disease population or subpopulation (e.g., generally less than 1,000 persons in the United States).”
Per the Orphan Drug Regulation (21 CFR 316), a rare disease is described as one that affects fewer than 200,000 people in the US. Compared to more widespread diseases, this is indeed a relatively small number. But RDEP appears to take this a step further, speaking to the less prevalent diseases affecting fewer than 1,000 people.
To provide perspective, the National Human Genome Research Institute within the National Institutes of Health runs a number of Natural History studies to best understand rare genomic defects. One such example is a Natural History study of propionic acidemia9, an inborn error of metabolism estimated to affect 1 of every 243,000 live births in the US. The study’s goal is to enroll just over 1,000 participants over the course of 14 years – not only is this a small number, but the patients profiled who may subsequently be eligible for a clinical trial (factoring out exclusion criteria such as age, disease progression, comorbidities, and receipt of solid organ transplantation) will only be a fraction of the National History study’s total enrollment.
While only one disease, it serves as an example of the practical issues drug developers face with ultra-rare indications. For FDA to highlight this, and define it as an immense unmet need is a massive step in the right direction, and may ultimately define the niche area in which the RDEP program will operate. Stakeholders in this space are undoubtedly waiting for additional detail to accompany the initial announcement, but even if the early returns show redundancy with other FDA initiatives, the RDEP program as currently understood does appear to have the potential to advance treatment options for the most vulnerable in our society.
References
1 CDER/CBER Rare Disease Evidence Principles (RDEP) | FDA
3 Rare Diseases: Considerations for the Development of Drugs and Biological Products | FDA
5 Rare Diseases: Natural History Studies for Drug Development | FDA
6 Human Gene Therapy for Rare Diseases; Guidance for Industry
7 Rare Disease Endpoint Advancement Pilot Program | FDA