Commissioner Makary and Center Directors Tidmarsh and Prasad Announce 2 New Programs for Ultra-Rare Disease Therapies: RDEP and Bespoke

Commissioner Makary’s pronouncement in April of a new pathway for rare disease therapies based on a plausible mechanism of action or biological plausibility generated enormous excitement. The Commissioner’s general statement found meaningful expression in twin announcements this past Wednesday: one by Dr. Tidmarsh of a new program for ultra-rare genetic diseases, the Rare Disease Evidence Principles (RDEP) initiative, and one by Dr. Prasad of a program for bespoke therapies that will be outlined in an upcoming New England Journal of Medicine article from Drs. Makary and Prasad.

Therapies for Ultra-Rare Disease

Rare disease drug development has always been associated with certain unique risks not as prominent in larger populations. In addition to basic operational challenges such as diagnosis, recruitment, and retention, the impact of which are all magnified with smaller numbers, there are also typically additional challenges related to demonstrating substantial evidence of effectiveness. These challenges can be derived from interpatient differences in baseline characteristics (known and unknown), heterogeneity of disease progression and symptomatology, statistical powering, a dearth of medical literature and natural history data, and a lack of well-understood and recognized endpoints. Additionally, the funding for such programs is always a challenge to secure. Typically, the rarer the disease, the greater these challenges are. For ultra-rare diseases, these challenges can be extremely formidable.

Despite these challenges, there have been some success stories, even with ultra-rare disease populations. For example, Xuriden (uridine triacetate) was approved for the treatment of hereditary orotic aciduria based on a study with 4 patients. Kebilidi (eladocagene exuparvovec-tneq) was approved for aromatic L-amino acid decarboxylase (AADC) deficiency based on a study in 13 patients. Mepsevii (vestronidase alfa-vjbk) was approved for MPS VII based on 23 patients (17 of whom were evaluable for efficacy). Brineura (cerliponase alfa) was approved for CLN2 based on a study in 24 subjects (22 of whom were evaluable for efficacy).

However, the existence of a few success stories does not show the full picture, as many other programs have fallen short because there simply was no available regulatory approach they could fit into, resulting in lost opportunities for rare disease patients. We see on a regular basis the challenges these sponsors face, where they are often asked to develop programs in the same manner as non-rare diseases, including with placebo-controlled trials, which are extremely challenging, if not impossible, to successfully conduct in such contexts. To address ultra-rare diseases, one of the co-authors, as Chair of the Everylife Foundation for Rare Diseases, helped organize the only public workshop yet held on ultra rare diseases in May 2024, at which time the co-author called on FDA to publicly embrace the pathways FDA had used for approvals such as those listed above. This public recognition by FDA of the ability to approve therapies for ultra-rare conditions based on such precedents would hopefully reset the stage for all stakeholders just as the co-author’s 2010 testimony at the FDA’s first public hearing on rare diseases and his follow-up paper cataloging FDA’s use of flexibility has ushered in a whole new approach whereby FDA began to publicly embrace its exercise of flexibility.

As mentioned above, Commissioner Makary has been previewing a “new pathway” to help address these challenges in ultra-rare populations for the past few months, and we have been eagerly awaiting announcements. The “pathway” described by Commissioner Makary is based on biological plausibility, where what is known about the condition and the genetic defect driving it, as well as the mechanism of action of the product, can be leveraged to reduce the evidentiary burden.

On Wednesday, September 3, FDA announced the “CDER/CBER Rare Disease Evidence Principles” or “RDEP” process as a more fleshed-out embodiment of what Commissioner Makary articulated. This announcement was initially rolled out at FDA’s first Rare disease Innovation, Science and Exploration (RISE) workshop convened by the FDA Rare Disease Hub. For drugs accepted for review under the RDEP process, 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.” RDEP does not alter the statutory standard for approval for qualifying drugs, but does “offer[] the assurance that drug review will encompass additional supportive data in the review.” The confirmatory data may include the treatment effect on the direct pathophysiology of the disease, data from a non-clinical disease model, pharmacodynamic data, other clinical data (e.g., case reports, expanded access data), natural history data, or data from external controls.

Ever since Congress passed FDAMA 115 in 1997, it has been clear that FDA may approve a drug based on “one adequate and well-controlled clinical investigation and confirmatory evidence.” However, the law did not specify when such evidence might be appropriate, leaving it to FDA discretion. FDA subsequently published guidance on the topic in 1998, 2019, and 2023, describing in successively greater detail what kind of evidence might serve as confirmatory evidence if FDA approved a drug based on the FDAMA 115 pathway. However, none of these guidance documents clearly articulated when such approach would be appropriate (e.g., from the 2023 guidance: “Disease- or condition-specific considerations (e.g., unmet need, size of the patient population) may be relevant to whether such an approach is appropriate.”).

As such, it has remained within the discretion of review divisions whether a FDAMA 115 approach is available. While this has led to regulatory flexibility enabling efficient development for certain programs, it has also been clear that this flexibility is applied unevenly. The challenges of ultra-rare drug development have been on full display in the ongoing elamipretide saga, as Stealth Biotherapeutics again seeks approval for its Barth syndrome drug based on a randomized, placebo-controlled study in 12 subjects. Our firm has experience with several other examples where flexibility seems not to have been featured in the interactions with the Agency on ultra-rare condition therapies.

This RDEP announcement appears to establish a subset of the most clearly appropriate programs for which FDAMA 115 is likely to be available, although this does not mean that approval itself is guaranteed. To us, the most exciting component of RDEP so far made public is that the adequate and well-controlled trial here “may be a single arm trial.” This is extremely helpful in an ultra-rare disease setting where randomization may be exceedingly challenging.

Many programs meeting the RDEP criteria already receive FDAMA 115 flexibility, and a number of rare disease programs are also utilizing single arm studies (see our recent post on that topic here); alternatives are not typically feasible for such programs. Nevertheless, the RDEP is a huge step forward, as it provides clarity, reliability, and efficiency to ease the development and review process for both industry and FDA officials, while maintaining FDA’s gold standard regulatory authority. While selection for RDEP would not erase all of the challenges associated with rare disease drug development, we are hopeful that implementation of RDEP will alleviate some of them, including many of those that are the most vexing.

It is also exciting to one of the co-authors who has been involved with orphan drug development since the enactment of the law in 1983 to see FDA continually work to refine its regulatory systems to address the barriers to development of therapies for our sisters and brothers affected with rare diseases, and in this case, the subset of rare diseases that are ultra rare. It should be noted that as science and medicine evolve and discover new rare conditions, these new rare diseases are overwhelmingly ULTRA-RARE so the need for FDA to adapt its regulatory structures to meet these newly discovered conditions is critical, and it is so wonderful to see that FDA is seemingly aware of this and responding!

How does RDEP work?

Eligible programs for RDEP must meet the following criteria:

1. the drug is for a very small disease population or subpopulation (“e.g., generally less than 1,000 persons in the United States);”
2. the drug is intended to treat a known inborn genetic defect that is “the major driver of the pathophysiology;”
3. the drug must be specific to the correction of the genetic defect (“i.e., either correcting the gene or is a replacement of an essential physiological protein that is otherwise deficient due to the gene defect”) [note: although we have seen some trade press refer to this initiative as limited to gene therapies, this criterion would appear to include other treatment modalities, such as enzyme replacement therapies];
4. the disease results in progressive functional deterioration “leading to rapid and/or significant disability or death in a relatively short period of time;” and
5. there are no adequate alternative therapies that alter the disease course.

Sponsors may apply for RDEP any time prior to the launch of a pivotal trial for each protocol it wants reviewed under RDEP. The RDEP request should be submitted as part of a formal meeting request. If there is no IND, FDA will assign a pre-IND number to facilitate the meeting; the sponsor can open an IND after the meeting and submit a request to the IND. The request, which should include only one protocol, should also include reasonable evidence that the eligibility criteria are met and that safety and efficacy of the drug can be demonstrated by a single study with confirmatory evidence.

The relevant center review team would issue a decision on acceptance following a consult with the Rare Disease Policy and Portfolio Council (RDPPC), which was established in 2024 along with the Rare Disease Innovation Hub. The RDPPC’s role in this process is to ensure consistency between CDER and CBER.

Sponsors of programs accepted into RDEP will then meet with the appropriate review team to determine what data will be used to substantiate safety and efficacy, although the announcement is clear that FDA agreement “would not necessarily indicate…that the drug is approvable.” The announcement also encourages the incorporation of patient experience data, “including by leveraging separate patient listening sessions where appropriate.”

The announcement states that “FDA may require additional data as a postmarketing requirement” (emphasis in original).

Of note, in acknowledgement of the distinctiveness of oncology drug reviews, the announcement states that “[b]ecause 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 [of ultra-rare oncology drug programs] should first consult the Oncology Center of Excellence or the CDER/CBER oncology review divisions to determine” if RDEP is applicable.

Bespoke Therapies

At the same RISE workshop last Wednesday at which Dr. Tidmarsh announced the RDEP initiative, Dr. Prasad spoke of an upcoming New England Journal of Medicine article to be co-authored with Dr. Makary on bespoke therapies, or therapies that are individualized, often just for one individual or a handful with the same genetic mutation. Organizations like Dr. Stan Crooke’s n-Lorem Foundation (one of the co-authors is a Board member) have been working in this field for years and it is very encouraging to all involved in these efforts to see the FDA move forward with a program tailored to the unique regulatory challenges presented in such situations.

Our Final Thoughts

We heartily applaud FDA for this RDEP initiative and for its promise of announcing soon a program for bespoke therapies as well. As stated above, while we have had the privilege to be part of a large percentage of the successful development programs in rare, even ultra-rare, diseases, we have seen too many programs fail when even a modest exercise of flexibility may have permitted a promising program to ultimately reach patients in need. The FDA’s new RDEP initiative now seems to provide clear guidance as to when flexibility and what kind of flexibility (one adequate and well-controlled trial, single-arm trials) might be applied in certain ultra-rare disease programs that will be selected for RDEP.

We are also buoyed to see that the time to apply for RDEP is prior to the initiation of the pivotal trial and tied to an FDA meeting. This timing, as opposed to waiting until closer to the NDA/BLA review, should provide some amount of regulatory clarity to enable efficient development for qualifying programs, including from a fundraising perspective. Although there are no timelines associated with the RDEP announcement itself, there are timelines associated with FDA meetings. We hope that these meeting timelines will apply to the RDEP requests and not add additional delay to these programs, but this is an open question at the moment.

The formal meeting process and timelines were established via PDUFA negotiations, another round of which is now ongoing. Perhaps this new round of PDUFA negotiations will result in a new type of meeting: a Type R (for RDEP) meeting, which could be for meetings within the RDEP Initiative and which specifically would include appropriate FDA personnel experienced in dealing with rare disease issues and FDA’s rare disease programs.

It is noteworthy that, unlike with orphan drug designation, this RDEP announcement does not include a firm population threshold, instead referring to “generally fewer than 1,000 patients” in the U.S. This is likely to be particularly helpful for rare diseases, where epidemiological data are not always available or sufficiently specific, so some flexibility is helpful. However, this lack of specificity may also place a burden on FDA reviewers who will be responsible for making a determination on cases where it is not clear if the 1,000 patient “threshold” has been crossed. Fortunately, the RDPPC’s involvement should help ensure consistency across the Agency.

Speaking of the RDPPC, we are happy to see its established role in this process. Part of the challenge of rare disease drug development is that the different parts of FDA have applied flexibility differently. These differences are apparent between divisions and, particularly, between centers. Although the RDPPC will certainly benefit from the specific expertise of the relevant review divisions, the involvement of a single coordinating rare disease council with broad rare disease expertise will hopefully smooth out these differences. Hopefully, this role for the RDPPC signals greater consistency moving forward for rare diseases Agency-wide.

We are looking forward to getting additional clarity on the mechanics of RDEP. Hopefully, we will hear more about this, and other new initiatives, soon – perhaps at the next RISE meeting? Onward!