by Don Fink, Ph.D.
originally published 7/14/2025
download this article in PDF
{update on 9/10/2025 to add coda below:}
Since this CUA piece was originally shared online, FDA CBER Center Director, Dr. Vinay Prasad made remarks at a recent (September 3, 2023) public workshop co-convened by the Duke-Margolis Institute for Health Policy and the U.S. Food and Drug Administration Rare Disease Innovation Hub regarding the imminent implementation of a new pathway for rare disease treatments. The pathway could include supporting data from N-of-1 clinical trials, would be centered on individualized "bespoke" therapies customized for a single patient with the possibility for approval based on a scientific rationale for plausible mechanism even in the absence of extensive clinical data. Such an approval pathway appears to be more limited in scope with respect to eligible disease indications than what is outlined in the CUA thought piece.ENDPOINTSNEWS: New FDA approval pathway for n-of-1 therapies coming soon, Prasad says. https://endpoints.news/new-fda-approval-pathway-for-n-of-1-therapies-coming-soon-pra[…]ay%20for%20n-of-1%20therapies%20coming%20soon%20Prasad%20says
1. INTRODUCTION
Stakeholders continually challenge the US Food and Drug Administration (FDA) to develop and deploy regulatory tools that hasten access to new products intended for treatment of serious or life-threatening diseases and conditions. Recently, the call for FDA to adopt a more flexible approach to the evaluation and approval of this category of products has intensified. This is particularly the case for cell and gene therapy (CGT) products which have the potential to provide curative treatments. Collaterally, Congress has been prompted to propose legislation that would codify a conditional approval pathway for products developed to treat serious or life-threatening diseases. Most recently, the FDA Commissioner has put forward a new Commissioner’s National Priority Voucher pilot program for products being developed that address U.S. national priorities, which is designed to align speed of product review with gold-standard science.1,2
At present, the primary regulatory tools facilitating expedited patient access to products intended to treat serious or life-threatening diseases are “accelerated approval” and “priority review.” Priority review provides limited time savings as it is performed at the time a marketing application is reviewed, i.e., not until the final stage of product development. Accelerated approval is a pathway intended to realize earlier approval and access to drugs and biologics that treat serious or life-threatening diseases as well as fill an unmet medical need. Accelerated approval decisions are based on the sensitivity of a surrogate endpoint marker(s) believed to predict clinical benefit but which are not themselves an actual measure of clinical benefit. Conceptually developed during the AIDS crisis, accelerated approval has proven to be valuable in the oncology disease space. With expanded application to a broader portfolio of clinical indications, difficulties have been encountered that portend to limit the overall utility of accelerated approval, including standards of evidence necessary to support approval based on the surrogate endpoint(s), failure of sponsors to conduct required confirmatory trials post-approval that verify product efficacy, and growing concern about steep reimbursement costs for products lacking confirmed efficacy demonstration. Notably, it has been suggested by former senior FDA officials that accelerated approval may be ill-suited as an approach for getting new CGT products to patients in an expedited manner, especially in the context of rare diseases, and that development of alternative pathways underlying patient accessibility to new products is to be encouraged.
A regulatory tool that is at FDA’s disposal is granting authorized use for unapproved products. During the COVID-19 pandemic, FDA effectively used its emergency use authorization authority to get unapproved products into the hands of physicians, patients, and caregivers. Product use authorization does not constitute approval and is rescinded when the conditions for granting the authorization cease to exist.
Against this backdrop, I propose that a conditional use authorization (CUA) pathway can be adopted by the agency as a mechanism for expediting patient access to promising innovative products, including CGTs, intended for treating serious and rare diseases. Eligibility for the proposed CUA pathway is to be limited to products intended to treat diseases outlined in the congressional conditional approval legislation. In its particulars, as described in this article, CUA for an investigational product is based on clinical demonstration of patient safety and evidence of substantial improvement on clinically significant endpoint(s) over what is observed for available therapies, is time-constrained in terms of its duration, and allows for cost-contained reimbursement which will enable sustained development towards product approval.
2. CURRENT EXPEDITED PATHWAY DESIGNATIONS
Regulatory authorities across the globe have engineered their drug approval frameworks to incorporate approaches for making drug products available in an expedited manner to patients suffering from serious or life-threatening diseases for which no suitable treatment option is available. Examples of expedited, non-standard approvals include Conditional Marketing Authorization (European Union, European Medicines Authority), Notice of Compliance with Conditions (Canada, Health Canada), Conditional Approval (Korea, Ministry for Food and Drug Safety; Japan, Pharmaceuticals and Medical Devices Agency), Provisional Approval Pathway (Australia, Therapeutic Goods Administration), and Accelerated Approval (United States, Food and Drug Administration).
The US Food and Drug Administration (FDA) provides guidance to sponsors engaged in development of candidate products intended to treat serious or life-threatening conditions that outlines recommendations pertaining to the expedited development and review of these potential therapies.3,4 Investigational drug and biologic products that are being developed to treat, modify, reverse, or cure serious or life-threatening conditions may be eligible for one or more of the FDA expedited programs, including fast track designation, breakthrough therapy designation, Regenerative Medicine Advanced Therapy (RMAT) designation (restricted to cell and gene-based products), accelerated approval, and priority review designation, presuming they meet eligibility criteria for the various programs.
Of the expedited programs referenced, accelerated approval and priority review designation are the two options likely to result in a shortened timeline for drug approval. Fast track, breakthrough, and RMAT designations are intended to provide advantages that may facilitate development during the investigational phase of clinical development and could result in an earlier time to submission of a license application for product approval. Enhancements provided by the expedited pathway designations include additional opportunities for FDA engagement and rolling review of a biologics license application that allows sponsors to submit sections of a license application to FDA as they are completed rather than compiling in a single submission.3 These designations in and of themselves do not constitute an approval when granted and do not guarantee abbreviation of the timeline leading to eventual product approval. Under these expedited pathway designations, development timeline shortening is a hypothetical construct that may be attributed to avoidance of missteps during manufacturing optimization and clinical testing as a consequence of more frequent opportunities to engage the agency during the investigational product life-cycle.
In contrast, the priority review designation results in an actualized time savings realized during review of a biologics license application (BLA). Priority review designation is a decision reached by FDA for every product license application submitted. The designation is targeted for review of applications of drugs/biologics that if approved would lead to significant improvements in the safety or effectiveness of available treatment, diagnosis, or prevention of serious or life-threatening conditions. It is FDA’s goal to act on a BLA that has received a priority review designation within 6-months as compared to 10 months for a standard review, resulting in a 4-month time savings occurring at the end of product development.
Unlike the expedited pathway designations referenced above, accelerated approval is a marketing authorization intended to expedite accessibility of products confronted by prohibitive logistical and feasibility challenges with respect to demonstrating safety and efficacy. Accelerated approval is used primarily in circumstances in which the disease course of the targeted indication is long and an extended period of time would be required to measure the intended clinical benefit of an investigational drug/biologic. Under Section 506(c) of the Food, Drug, and Cosmetic (FD&C) Act, FDA is authorized permission to grant accelerated approval for drugs and biologics, including CGTs, that are intended for serious or life-threatening diseases or conditions based on a determination that the product has an effect on an agreed-upon surrogate endpoint considered reasonably likely to predict clinical benefit taking into account the severity, rarity, or prevalence of the disease or condition and the availability, or lack thereof, of alternative treatments. FDA defines approval of a drug/biologic to mean that upon review of safety and effectiveness data collected during clinical investigation, the product’s known and potential benefits outweigh known and potential risks. When FDA grants either a regular approval or an accelerated approval, this indicates the agency has determined that the evidentiary standard of safety and effectiveness have been satisfactorily met for a product’s intended use. In the context of accelerated approval, FDA acknowledges there is an element of uncertainty associated with the established surrogate endpoint and whether ultimately there will be demonstrable correlation between the treatment’s effect on a surrogate endpoint and ultimate clinical benefit for the targeted indication. Accordingly, accepting a greater degree of uncertainty with respect to demonstrated effectiveness represents a concession for achieving more rapid patient access to critical therapies being developed for serious or life-threatening diseases and conditions. Since July of 2020, FDA’s Center for Biologics Evaluation and Research (CBER) has granted seven accelerated approvals for CGTs (one product, ELEVIDYS, has received two accelerated approvals, each for a different patient population) as shown in Table 1 below. To date, only one of these products, ELEVIDYS (manufactured by Sarepta) for the treatment of Duchenne muscular dystrophy has transitioned from accelerated to regular approval for a defined patient population.
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Accelerated approval was adopted in 1992 as a more flexible alternative to existing review practices when deaths due to the HIV/AIDS epidemic quickly eclipsed development and approval of effective treatments. Since then, it has been used effectively to make available on an expedited basis new effective therapies for oncology indications. Successful adoption of accelerated approval in the oncology space has been tempered by its application to other indications where demonstration of likely clinical benefit has been questionable and post-approval clinical studies as required under accelerated approval have either not be conducted or have failed to confirm clinical findings premised on results for surrogate endpoints. As a consequence of these latter circumstances when the reliability of an approval decision has not been borne out, use of the accelerated approval pathway has come under increased scrutiny, with criticism levied that lower regulatory standards are tolerated than those expected for regular drug approval. It has been further intimated that required post-approval confirmatory trials are not being pursued with due diligence and that there are undue delays in initiating withdrawal of accelerated approvals for drugs for which required post-approval studies have failed to confirm clinical benefit.5,6
Two examples of recent accelerated approvals deemed ‘controversial’ include ADUHELM, a monoclonal antibody biologic for treatment of Alzheimer’s disease (accelerated approval date: June 7, 2021) and ELEVIDYS, a gene therapy for the treatment of Duchenne muscular dystrophy (accelerated approval date: June 22, 2023). In both cases, accelerated approvals were authorized by senior leadership in FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), respectively, overruling the recommendations of, and despite objections from, the respective product review teams. Discontinued development and commercialization of ADUHELM was announced by the manufacturer in January of 2024, due to an internal re-prioritization of assets to advance development of other treatment modalities. The initial accelerated approval for ELEVIDYS was converted to a regular approval in June of 2024, despite failure of the product to achieve specified primary clinical endpoints in a required follow-on confirmatory clinical trial.
3. CALL FOR CONDITIONAL USE AUTHORIZATION AS AN ALTERNATIVE PATHWAY FOR EXPEDITED PRODUCT ACCESS
Given concerns expressed regarding questionable circumstances when relying on accelerated approval, a clarion call is issuing from an expanding coalition of interested parties for establishment of a new pathway in lieu of accelerated approval to expedite patient access to new products under investigation for serious or life-threatening diseases.
In recognition that the canonical approach to product development and standard product approval is ill-suited for the rare disease space, former CBER director, Peter Marks, energetically promoted more aggressive use of accelerated approval which was rolled out as a pilot program referred to as Support for Clinical Trials Advancing Rare disease Therapeutics (START).7 Under the START pilot, FDA reviewers are to work more closely with the companies selected to participate in the program allowing for more frequent and impromptu communication. It is projected that an increased level of collaboration could allow biotech innovators to avoid potholes encountered that have previously slowed development of cellular and gene therapy products targeted for serious and rare diseases with an unmet medical need.
This messaging has been echoed by former FDA commissioner, Robert Califf.8 In public remarks, Dr. Califf indicated that it is unlikely that current approval pathways, including accelerated approval, can be considered optimal for rare and ultra rare diseases which are often are highly debilitating and affect small patient populations. Commissioner Califf has highlighted the need for getting creative in terms of regulatory approaches used in these contexts.
Current FDA commissioner, Dr. Martin (Marty) Makary, has taken up the cause for championing a new approval pathway to expedite patient access to new therapies.9 Commissioner Makary has publicly stated that plans are being developed for a “new, customized conditional drug approval pathway” that could be applied to therapies for rare diseases. The approvals would be authorized “on a conditional basis” and not require execution of a randomized, controlled clinical trial but instead be based on “plausible mechanism,” a criterion which has yet to be defined.
Congress has demonstrated its interest in refining FDA’s approach to product approval and the Senate has introduced a bill titled To amend the Federal Food, Drug, and Cosmetic Act to establish a time-limited conditional approval pathway, subject to specific obligations, for certain drugs and biological products, and for other purposes, or “Promising Pathway Act 2.0” for short.10 The Promising Pathway Act 2.0 is intended to amend the FD&C Act by introducing a conditional approval pathway for new human drugs for individuals with rare, progressive, and serious diseases. Under the proposed act, a drug or biologic (including CGTs), may be eligible for conditional approval consideration if intended to treat a disease or condition that (i) is rapidly progressive, terminal, and has substantial unmet medical need, or (ii) is a rare disease or condition that results in a substantially shortened lifespan, reduction in quality of life, or other substantial adverse health effect. With respect to requirements, a conditional approval will be granted if 1) evidence of safety has been established by completion of a phase 1 clinical study or other appropriate demonstration of safety and 2) (a) evidence of effectiveness in treating a given indication as specified in the act is established by an ongoing or completed phase 2 clinical investigation or, (b) in the case of a drug intended to treat a terminal pediatric rare disease or condition that does not primarily affect adults, the drug shows preliminary evidence of clinical effectiveness based upon studies in animal models.
Under the provisions of the Promising Pathway Act 2.0, if it is determined that a drug meets the standard for conditional approval, it is eligible for rolling submission. Conditional approval under the Promising Pathway Act 2.0 is effective for a 2-year period. A sponsor may request renewal of such conditional approval for up to 3 subsequent 2-year periods. The conditional approval status of a drug shall not exceed a total of 8 years from the initial date the drug was granted conditional approval. If a drug receiving conditional approval is granted regular approval during the period in which a conditional approval is in effect, such conditional approval shall be automatically withdrawn. Conditions for reimbursement are also provided in the Promising Pathways Act 2.0. While core elements of the Promising Pathway Act 2.0 are consistent with expedited approval pathways employed globally in other regulatory jurisdictions, an overarching concern is that adding the prefix “conditional” to approval will further erode confidence in the evidentiary standards used to justify granting an approval.
4. CONDITIONAL USE AUTHORIZATION (CUA) AS AN ALTERNATIVE PATHWAY FOR EXPEDITING PATIENT ACCESS TO INNOVATIVE THERAPIES
Current state regular and accelerated product approval pathways rely on the same evidentiary standard with respect to demonstration of safety and effectiveness. Despite this expectation, criticism has been levied against the widening use of accelerated approval, based on concern that lower regulatory standards are tolerated beyond what is expected for a regular drug approval. It isn’t unreasonable to conclude that this concern regarding a perceived lowering of regulatory standards would be further exacerbated by adopting an approval pathway preceded by the prefix “conditional” because such a term could intimate a further erosion of the standard for effectiveness demonstration. Rather than additionally degrading the integrity of FDA product approval in order to expedite patient access to promising new therapies during their clinical development, consideration should be given to developing viable alternatives to product approval that achieve the objective of earlier patient access without compromising the rigor with which evidence for product safety and effectiveness is judged.
A model that can be reliably drawn upon for learnings in crafting an alternative pathway is FDA’s reliance on Emergency Use Authorization (EUA) as exercised during the declared COVID-19 public health emergency (January 27, 2020, to May 11, 2023).11 The EUA authority allows FDA to strengthen US public health protections against chemical, biological, radiological, and nuclear (CBRN) threats including infectious diseases by facilitating availability and use of medical countermeasures as necessary during public health emergencies. When declared by the Secretary of Health and Human Services that authorized emergency use of medical products is appropriate, FDA may authorize unapproved medical products or unapproved uses of approved medical products to be used in the context of a declared emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN threat agents including infectious diseases.12 During the COVID-19 pandemic, EUAs were granted for numerous unapproved medical products or unapproved uses of approved medical products including vaccines, convalescent plasma, drugs and non-vaccine biological products as well as medical devices (blood purification devices, continuous renal replacement therapy, hemodialysis devices, in vitro diagnostics, personal protective equipment, respiratory assist devices, ventilators and ventilator accessories). Of note, an emergency use authorization does not constitute approval of an unapproved product. In general, upon termination of an HHS EUA declaration, all EUAs issued under the EUA declaration cease to be in effect on the date of the termination with the exception of certain instances when, at the discretion of the HHS Secretary, there may be continued use of an EUA product even after an EUA declaration has been terminated.
Drawing on the COVID-19 pandemic EUA experience as an instructive precedent, a framework can be envisioned that is premised on the concept of a Conditional Use Authorization (CUA) intended to support development of investigational drug/biologic products, including CGTs for treatment of serious or life-threatening diseases and conditions for which no alternative effective treatments are available. In contrast to regular and accelerated approval which allows for commercial distribution of the approved product, a CUA is intended to provide patients with broader access to investigational products during their clinical development under an Investigational New Drug Application (IND).
Essential to implementation of CUA is the opportunity for reimbursement through government programs (Medicare or Medicaid) and private insurance companies in order to further clinical development of investigational products under an IND application. Costs would be contained through an enhanced cost-recovery program that incorporates an established cap. This feature will enable revenue generation necessary to support uninterrupted product development which could lead to eventual accelerated or regular approval. In public comments, former FDA Commissioner Robert Califf defines creative approaches for product approval to include regulatory pathways that permit essential sustained generation of funds necessary to permit collection of high quality clinical evidence of safety and efficacy even in the context of trials performed in small patient populations.8 In its conception, signal features associated with introduction of a CUA pathway option will include delineating investigational product eligibility criteria, the extent of clinical evidence sufficient to support a CUA, duration of the CUA, and the opportunity for a non-commercial product level of reimbursement intended to support continued product development.
5. PROPOSED FRAMEWORK FOR CONDITIONAL USE AUTHORIZATION (CUA)
The framework for the proposed novel CUA approach is built on appreciation for the benefits afforded by existing FDA expedited programs to facilitate development of products for serious conditions and the success of Emergency Use Authorization (EUA) implemented during the COVID-19 pandemic as a tool for making unapproved products available for general distribution. As an outcome of this precedent regulatory awareness and real-life experience, I maintain that the proposed framework for a CUA expedited pathway should include the elements summarized below in Table 2:
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6. IMPLEMENTING THE FRAMEWORK FOR CONDITIONAL USE AUTHORIZATION
To offer use of CUA as a means to expedite patient access while providing continued support for clinical development of products intended to treat serious or life-threatening diseases for which no suitable treatment option is available, statutory codification will be necessary. There are various avenues that can be taken to achieve this objective, each having been used successfully to enact FDA priorities. Essential will be a commitment to adopting CUA on the part of the agency, the legislative branch of government, the executive branch, or all three working in concert.
One approach to codification of the CUA pathway is via amendment of the Food, Drug & Cosmetic Act, 21 USC 356: Expedited approval of drugs for serious or life-threatening diseases or conditions. Legislatively this can be achieved by approval of an act of Congress. For example, modernization of the accelerated approval pathway was introduced in the Food and Drug Omnibus Reform Act (FDORA) of 2022 as part of the Consolidated Appropriations Act, 2023.15
もう一つの現実的なアプローチとして、「Promising Pathway Act 2.0」のような法案を上下両院に提出することが挙げられます。10 この法案は、条件付き承認プロセスの確立を提案するものです。同様の取り組みとして、重篤で生命を脅かす希少疾患の治療を目的とした治験薬・生物学的製剤に対し、条件付き使用許可（Conditional Use Authorization）の確立を提案する新たな法案を議会に提出することも考えられます。
さらに、2025年9月または10月に開始予定の、2028年度から2032年度に向けた「処方薬ユーザーフィー法（PDUFA VIII）」の再承認に関する交渉において、FDAが条件付き使用許可（CUA）の確立に向けた姿勢を示すことも可能です。FDA長官による最近の国家優先バウチャー発行に関する発表と同様に、1パイロットプログラムを立ち上げ、革新的な新薬への患者アクセスを迅速化する手段としてCUAの運用を開始することができます。このパイロットプログラムの発表と併せて、FDAは製品の臨床開発プログラムの一環としてCUAを導入する際の基本的な考え方を示すガイダンスを発行するでしょう。
7. 主なポイント
1992年にエイズ公衆衛生危機における新薬へのアクセス迅速化を目的として導入されて以来、重篤な疾患や症状に対する新薬や生物学的製剤の承認経路として「迅速承認（accelerated approval）」の利用が拡大してきましたが、その信頼性に対する懸念も高まっています。特に、迅速承認経路による承認は、安全性と有効性の立証に関するFDAの規制審査基準が緩和された結果であるとの指摘がなされています。FDAの元幹部らは、迅速承認は特に希少疾患の文脈において、CGT（細胞・遺伝子治療）製品を患者に届けるための最適なアプローチではない可能性があり、より早期の患者アクセスを促進する代替経路の開発が推奨されると示唆しています。
医療ニーズが満たされていない重篤な疾患や症状の治療を目的とした有望な治療薬への患者アクセスを、製品開発ライフサイクルのより早い段階で実現する一つの機会として、COVID-19パンデミック時に活用された「緊急使用許可（EUA）」の成功例を活かすことが挙げられます。EUAをモデルとして、重篤で生命を脅かす希少疾患の治療を目的とし、既存の治療法と比較して有効性や安全性の実質的な改善を示す予備的な臨床データが得られている医薬品・生物学的製剤に対し、期間限定の「条件付き使用許可（CUA）」という選択肢を設けることができます。重要な点として、CUAは法定の安全性および有効性の要件を満たした「承認」と同等のものではありません。しかし、CUAは治験薬申請に基づき臨床評価中の製品へのアクセスをより広く迅速化し、同時に継続的な製品開発を奨励・支援する役割を果たします。
本稿で概説するCUAの主な特徴は以下の通りです。
まとめ
FDAが規制慣行や手続きの近代化に取り組む中、同庁は重篤で生命を脅かす疾患や症状に対する革新的な新薬への早期アクセスを求める患者や医療従事者からの要求に直面し続けています。当初はこの目的のために開発された迅速承認制度が、製品アクセスの迅速化を目指すFDAの規制慣行の最前線にありました。しかし、迅速承認の有用性には限界があることが明らかになり、この迅速開発経路の改善を求める声が高まっています。これまでの修正は、大部分が表面的なものにとどまっています。この現状は、既存の製品承認経路を修正するだけで、責任ある形で迅速な製品アクセスを実現できるのかという疑問を投げかけています。FDAの規制ツールボックスには、ユニークな方法で採用されれば、製品承認の法定要件では得られない柔軟性を提供できる別の選択肢が存在します。それは、未承認製品、あるいは未承認の方法で使用される製品に対して使用許可を与えることです。現在は公衆衛生上の緊急事態に限定されていますが、この許可された使用範囲を重篤で生命を脅かす疾患の治療薬・生物学的製剤の開発にまで拡大することは、製品アクセスを迅速化するための実行可能なメカニズムとなります。適切な予備的な安全性および有効性データに基づき、ライセンス取得前の臨床開発段階で条件付き使用許可（CUA）を付与することは、より早期の製品アクセスを提供するという難題に対処するための現実的な代替案です。この時間制限付きのアプローチは、治験薬開発プログラムの不可欠な機能となり、最終的な承認につながる可能性のある有望な製品の臨床試験を維持するために必要な資金を生み出すための、費用回収の拡大を可能にするでしょう。
参考文献：
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