Key Takeaways
FDA expedited programs, including Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review, and RMAT, are designed to speed development or review for therapies addressing serious conditions and unmet medical need.
Accelerated Approval can enable earlier patient access based on surrogate or intermediate endpoints, but confirmatory trials remain essential to verifying clinical benefit.
Recent FDA guidance and oversight reports have increased pressure on sponsors to plan confirmatory trials earlier and execute them more reliably.
EMA’s PRIME scheme and FDA’s RMAT designation show how expedited pathways are evolving toward earlier, more interactive regulatory support for complex and advanced therapies.
For drug developers and CDMOs, expedited pathways can compress development timelines and increase the importance of early CMC, analytical, clinical supply, and comparability planning.
The Promise and Burden of Regulatory Speed
For patients with serious or life-threatening diseases, time is not an abstract variable. A therapy that reaches the market years earlier may arrive while a patient can still benefit from it, while the same therapy delivered later may be clinically irrelevant for those with aggressive cancers, progressive neurologic disorders, rare genetic diseases, or other conditions with few effective options. That urgency is the ethical foundation for expedited drug development and review programs. The U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), pharmaceutical companies, clinicians, and patient communities all recognize that conventional evidence-generation timelines may not always be appropriate when unmet medical need is high and early clinical signals are compelling.
However, speed was never the only promise. Expedited pathways were built on a broader bargain: earlier regulatory engagement, faster review, or earlier access may be justified when the disease is serious, the unmet need is substantial, and uncertainty can be managed through rigorous follow-up. The question is not whether expedited programs can move products faster. In many cases, they can. The critical question is whether they reliably convert early promise into confirmed clinical benefit and whether the development ecosystem surrounding these programs has matured enough to support that responsibility.
That question is increasingly urgent. The FDA’s expedited programs for serious conditions include Fast Track designation, Breakthrough Therapy designation, Accelerated Approval, and Priority Review designation, while regenerative medicine products may also qualify for Regenerative Medicine Advanced Therapy (RMAT) designation. In Europe, EMA’s Priority Medicines (PRIME) scheme provides enhanced regulatory support for medicines that may offer a major therapeutic advantage or address unmet need. Each program has a distinct purpose, but all reflect the same regulatory challenge: how to act earlier without lowering the ultimate expectation that medicines should provide meaningful benefit to patients.1–3
What the Major Pathways Are Designed to Do
Much of the debate around accelerated pathways suffers from blurred terminology. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review, RMAT, and PRIME are often discussed as if they are variations of the same mechanism, but they operate differently. Some are development designations that increase interaction with regulators, some affect review timelines, some allow approval on earlier forms of evidence, and some combine elements of development support with potential downstream review acceleration.
Fast Track is intended to facilitate development and expedite review of drugs that treat serious conditions and fill an unmet medical need. Its practical value lies in earlier and more frequent FDA interaction, and in some cases rolling review, which allows a sponsor to submit sections of a marketing application before the full application is complete. Breakthrough Therapy designation is also intended to expedite development and review for serious conditions, but it requires preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. Both designations are development-shaping tools, but Breakthrough Therapy carries a higher evidentiary threshold at the designation stage.4
Accelerated Approval is different. It is an approval pathway that can allow earlier approval for drugs for serious conditions that address unmet medical need based on a surrogate endpoint or an intermediate clinical endpoint considered reasonably likely to predict clinical benefit. That structure deliberately moves part of the evidence-generation burden into the postapproval period. Sponsors are expected to conduct confirmatory studies to verify and describe the anticipated clinical benefit, and the product’s long-term regulatory status depends on that follow-through.5
Priority Review, by contrast, does not necessarily alter the development program or evidentiary basis for approval. It is a review-timeline mechanism for applications that, if approved, would represent significant improvements in safety or effectiveness for the treatment, diagnosis, or prevention of serious conditions. Its role is narrower than that of Accelerated Approval or Breakthrough Therapy designation, but it can still be consequential because the final review period itself is compressed.1
RMAT designation extends expedited-development logic into regenerative medicine. Enacted under the 21st Century Cures Act, RMAT applies to qualifying regenerative medicine therapies intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition when preliminary clinical evidence indicates the potential to address unmet medical needs. The designation reflects the specific scientific and operational complexities of cell therapies, gene therapies, tissue-engineered products, and related modalities, where small patient populations, specialized manufacturing, and evolving clinical endpoints can complicate traditional development models.2
PRIME occupies a related but distinct position in Europe. EMA describes PRIME as a scheme that supports medicines that may offer a major therapeutic advantage over existing treatments or benefit patients with no treatment options. It builds on existing regulatory tools, including scientific advice and accelerated assessment, with the goal of helping developers generate robust evidence earlier and prepare more effectively for marketing authorization review.3,6
The Access Argument
The strongest case for expedited pathways begins with patients who cannot wait. In serious diseases with limited or no treatment options, the risks of delay are not theoretical. A conventional development timeline may protect against uncertainty, but it can also defer access to therapies that may offer meaningful benefit. Expedited programs were created to navigate that tension by allowing regulators to engage earlier, review faster, or accept earlier forms of evidence under defined conditions.
There is evidence that at least some expedited designations have shortened development timelines. A Health Affairs analysis found that Breakthrough Therapy designation was associated with a reduction in late-stage clinical development time, supporting the view that intensive regulatory interaction can accelerate progress when early clinical evidence is compelling.7 The FDA’s own framework also emphasizes that these programs are intended to facilitate and expedite development and review for therapies addressing serious conditions and unmet medical need.1
Accelerated Approval offers a particularly clear example of the access rationale. The pathway allows earlier approval based on endpoints that can be measured sooner than direct clinical outcomes. In oncology, for example, objective response rate or other tumor-based measures may provide an early indication of activity in settings where waiting for overall survival data could delay access for years. In rare diseases, where patient populations may be small and disease progression may be heterogeneous, accelerated or otherwise flexible approaches may help make development feasible when conventional large trials are difficult to conduct.
Recent regulatory and policy discussions show that this access argument remains powerful. Reuters has reported on FDA interest in approaches to accelerate development for ultra-rare diseases and personalized gene therapies, including situations in which traditional large trials may be impractical.8,9 These examples do not resolve the evidentiary questions, but they underscore why the pressure for more flexible pathways is not diminishing. Scientific advances are generating therapies for smaller, more molecularly defined populations, and the regulatory system is being asked to adapt.
Recent approvals also show how the pathway operates in practice. Reuters reported that FDA granted accelerated approval to Jazz Pharmaceuticals’ Ziihera for metastatic HER2+ biliary tract cancer based on objective response data from a mid-stage study, with conversion to standard approval dependent on confirmatory evidence of clinical benefit.10 That kind of case illustrates the central premise of Accelerated Approval: earlier access may be appropriate when the disease is serious and the early signal is meaningful, but the approval remains linked to the need for further evidence.
The Evidence Trade-Off
The access argument is compelling, but it does not eliminate uncertainty. It changes where uncertainty is managed. Accelerated Approval rests on the idea that a surrogate or intermediate clinical endpoint can be reasonably likely to predict clinical benefit, but the endpoint is not itself the final proof. The FDA maintains a table of surrogate endpoints that have supported approval or licensure, reflecting both the importance and the complexity of endpoint selection in modern development.5
The evidence trade-off is most visible in oncology. A JAMA study of cancer drugs receiving Accelerated Approval from 2013 to 2023 found that many indications did not demonstrate benefit in overall survival or quality of life within five years. Among 46 indications with more than five years of follow-up, 29 were converted to regular approval, 10 were withdrawn, and seven remained ongoing after a median follow-up of 6.3 years. The study’s findings do not mean that Accelerated Approval lacks value, but they show that early evidence does not always translate cleanly into confirmed patient benefit.11
The same tension appears in Breakthrough Therapy–designated approvals. A JAMA Network Open study of original FDA approvals with Breakthrough Therapy designation from 2013 to 2023 found that 157 original indications were approved during the study period, including 52 through Accelerated Approval and 105 through traditional approval. All 52 accelerated approvals were based on pivotal trials using surrogate markers as primary endpoints and had FDA-required postmarketing studies to confirm efficacy. Among the 105 traditional approvals, 61 used surrogate markers as primary endpoints, and only four of those 61 had FDA-required postmarketing studies to confirm efficacy.12
That finding is important because it broadens the discussion beyond Accelerated Approval alone. Reliance on surrogate markers is not confined to the accelerated pathway. Expedited development programs can shape evidence standards more broadly, especially when therapies target serious conditions, early activity is strong, and regulators determine that earlier approval is justified. The result is a development environment in which the distinction between speed and certainty is often negotiated across multiple regulatory tools, rather than within a single pathway.
This does not make surrogate endpoints inherently problematic. In many settings, they are scientifically meaningful, clinically useful, and necessary for feasible development. The problem arises when the surrogate endpoint is treated as the end of the evidentiary story rather than the beginning of the next phase of evidence generation. If the pathway works as designed, early access is followed by timely confirmation. If confirmatory studies are delayed, inconclusive, or misaligned with the original uncertainty, the pathway’s credibility weakens.
Confirmatory Trials Are Becoming the Central Test
Confirmatory trials are now the fulcrum of the accelerated approval debate. They determine whether the initial regulatory judgment was borne out in a clinically meaningful way, and they are increasingly central to the FDA’s expectations before approval is granted. Under the Consolidated Appropriations Act of 2023, the FDA received additional authority related to confirmatory trials, including authority to require that studies be underway before approval or within a specified period after approval.5
The FDA’s January 2025 draft guidance focuses on how the agency intends to interpret whether a confirmatory trial is “underway.” The guidance signals that accelerated approval planning cannot be separated from confirmatory trial planning. Sponsors may need to demonstrate not only that a postapproval trial is conceptually appropriate, but that its operational execution is sufficiently advanced to support the regulatory decision. Legal analysis of the guidance has emphasized that this shift may affect how sponsors plan development timelines, trial initiation, enrollment, and application strategy.5,13,14
Oversight bodies have been pressing on this issue for several years. The Health and Human Services (HHS) Office of Inspector General (OIG) reported in 2022 that delays in confirmatory trials for drugs granted Accelerated Approval raised concerns, including concerns around whether sponsors completed required trials on schedule and whether the FDA’s oversight was sufficiently effective. In 2025, the OIG reported that its review identified concerns in 3 of 24 reviewed drugs that had received Accelerated Approval.15,16
These findings suggest that the promise of Accelerated Approval cannot be evaluated at the point of market entry alone. Approval based on a surrogate endpoint may be appropriate, but the pathway succeeds only if the confirmatory evidence arrives in a reasonable time and answers the right question. For patients and clinicians, unresolved uncertainty can affect treatment decisions. For payers, it can complicate coverage and reimbursement. For sponsors, it can create regulatory, commercial, and reputational risk if the confirmatory program lags behind the access granted through approval.
The recent policy direction is therefore not a retreat from accelerated pathways, but a tightening of their evidentiary discipline. The FDA is not abandoning the logic of earlier access. Instead, it is moving toward a model in which the confirmatory evidence plan must be more mature at the time of approval. That change matters because it shifts accelerated approval from a sequential model, in which confirmatory planning could follow approval, toward a more integrated development model.
RMAT, PRIME, and the Evolution of Expedited Support
RMAT and PRIME show how expedited programs are evolving beyond faster review into more active development support. RMAT reflects the needs of regenerative medicine, where therapies may be highly complex, manufacturing processes may be product-defining, and clinical development may involve small patient populations or diseases with limited precedent. The FDA’s RMAT designation framework provides an expedited-development mechanism for qualifying regenerative medicine therapies with preliminary clinical evidence indicating potential to address unmet need.2
The FDA’s public RMAT tables also provide a window into the program’s uptake. The agency reports cumulative CBER RMAT designation requests by fiscal year, including requests granted, denied, and withdrawn through FY2025.17 Those figures show that RMAT is not a marginal pathway, even though the number of approved RMAT-designated products remains much smaller than the number of requests. That gap is not surprising. A designation can support development, but it does not guarantee approval, and regenerative medicine products often face substantial challenges in manufacturing, comparability, clinical design, and long-term follow-up.
The sponsor-facing relevance of RMAT lies partly in that distinction. A designation may help align a sponsor with the FDA earlier, but it does not remove the need to build a credible development and manufacturing package. For cell and gene therapies, the operational dimensions of evidence generation are tightly linked to the product itself. Changes in process, scale, vector, cell source, formulation, or release testing can affect comparability and complicate interpretation of clinical data. In that sense, RMAT may increase the value of early regulatory engagement while also raising the importance of disciplined chemistry, manufacturing, and controls planning.
PRIME provides a useful European comparison. The EMA describes PRIME as a scheme for medicines that may offer a major therapeutic advantage or address unmet need, and its five-year analysis describes how the program supports developers through earlier interaction, scientific advice, and preparation for marketing authorization assessment.3,6 PRIME is not identical to any single FDA pathway. It is better understood as a structured support mechanism that can improve development readiness and help eligible products prepare for accelerated assessment.
The EMA’s framing is notable because it places evidence generation at the center of expedited support. The goal is not simply to compress review, but to help developers generate robust data for medicines that may address high unmet need. That emphasis aligns with the direction of FDA policy as well. Across RMAT, PRIME, Breakthrough Therapy, and Accelerated Approval, the regulatory trend is toward earlier interaction combined with greater expectations for evidence planning.
Implications for Sponsors and Development Partners
For drug developers, accelerated pathways are not only regulatory opportunities. They are operating models. A company pursuing Fast Track, Breakthrough Therapy, Accelerated Approval, RMAT, or PRIME must be prepared for a development program in which clinical, regulatory, manufacturing, and commercial planning converge earlier than they might in a conventional timeline. Early access can shorten the distance to market, but it can also reduce the margin for delayed decisions, fragmented documentation, weak endpoint strategy, or late manufacturing changes.
The FDA’s expedited-program guidance encourages early communication with the agency around eligibility, endpoints, clinical trial design, and confirmatory trial planning.1 That guidance has practical implications. If a sponsor is pursuing Accelerated Approval, the confirmatory trial strategy cannot be treated as a late-stage obligation. It must be integrated into the development plan early enough to support the application, satisfy regulatory expectations, and provide a credible path to verification of benefit.
This has direct relevance for contract development and manufacturing organizations (CDMOs), contract research organizations (CROs), analytical partners, and other development collaborators. Expedited pathways can compress timelines for clinical supply, process development, analytical method qualification, comparability planning, stability strategy, and technology transfer. They can also increase the importance of continuity between early-phase and later-phase development. A sponsor that obtains an expedited designation but lacks a scalable manufacturing process, robust analytical control strategy, or timely clinical supply plan may find that the pathway accelerates pressure as much as progress.
For advanced therapies, the operational implications are even more pronounced. RMAT-eligible products may involve living cells, viral vectors, gene-editing components, autologous or allogeneic workflows, specialized logistics, and long-term follow-up. In those settings, manufacturing is not a back-office function. It is inseparable from product identity, clinical consistency, and regulatory confidence. Advanced therapies developers and their partners must be able to iterate quickly while preserving documentation, traceability, and comparability.
The same logic applies to confirmatory trials. If the FDA expects a confirmatory trial to be underway before Accelerated Approval or within a defined period after approval, sponsors need reliable execution across clinical operations, drug supply, data management, and regulatory reporting. Development partners that can anticipate these needs may help sponsors avoid preventable delays, but the claim should remain operational rather than financial. The validated evidence supports the conclusion that expedited pathways create planning and execution implications for sponsors and partners; it does not prove that CDMOs directly benefit financially from those pathways.
Are They Delivering?
Expedited pathways are delivering on part of their promise. They have created mechanisms for earlier regulatory engagement, faster review, and earlier access in serious diseases with unmet need. Breakthrough Therapy designation has been associated with shorter late-stage development time, Accelerated Approval has provided a route to market based on earlier endpoints, RMAT has created a framework for qualifying regenerative medicine therapies, and PRIME has given the EMA a structured way to support medicines that may offer major therapeutic advantage.2,3,5,7
They are delivering less consistently on the promise of confirmed clinical benefit. Retrospective evidence in oncology shows that many accelerated approvals did not demonstrate overall survival or quality-of-life benefit within five years, and evidence from Breakthrough Therapy–designated approvals shows broad reliance on surrogate endpoints, including in some traditional approvals that did not carry FDA-required postmarketing studies to confirm efficacy.11,12 These findings do not invalidate expedited programs, but they make clear that speed alone is an insufficient metric.
The most constructive answer is that accelerated pathways are neither failing nor fully vindicated. They are entering a more demanding phase. Regulators appear to be preserving the access rationale while strengthening expectations around confirmatory evidence, earlier trial initiation, and accountability. Pharma companies must approach expedited pathways not as shortcuts, but as compressed development strategies that require more integration, not less.
The next measure of success will be whether these programs can maintain justified speed while reducing unresolved uncertainty. That will depend on better surrogate endpoint selection, more disciplined confirmatory trial planning, earlier regulatory engagement, and operational readiness across clinical development, manufacturing, analytics, and supply. For patients, the value of expedited pathways lies in access to therapies that may alter the course of serious disease. For regulators and sponsors, the obligation is to ensure that early access is followed by evidence strong enough to confirm that the promise was real.
References
1. “Expedited Programs for Serious Conditions — Drugs and Biologics.” U.S. Food and Drug Administration. 28 Nov. 2023.
2. “Regenerative Medicine Advanced Therapy Designation.” U.S. Food and Drug Administration. 4 Nov. 2025.
3. “PRIME: Priority Medicines.” European Medicines Agency. Accessed 5 Jun. 2026.
4. “Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review.” U.S. Food and Drug Administration. 12 Jun. 2023.
5. “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial Is Underway.” U.S. Food and Drug Administration. 6 Jan. 2025.
6. “PRIME: Analysis of the First 5 Years’ Experience.” European Medicines Agency. 16 Dec. 2021.
7. Miller, Kathleen L, et al. “FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time.” Health Affairs. 43:1003–1010 (2024).
8. “US FDA Proposes Framework to Speed Rare Disease Gene Therapy Approvals.” Reuters. 23 Feb. 2026.
9. “US Health Secretary Kennedy Looks to Fast-Tracking Approvals for Rare Disease Drugs.” Reuters. 5 Jun. 2025.
10. “Jazz Pharmaceuticals Receives FDA Approval for Biliary Tract Cancer Treatment.” Reuters. 21 Nov. 2024.
11. Liu, Ian TT, Aaron S Kesselheim, and Edward R Scheffer Cliff. “Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval.” JAMA. 331:1471–1479 (2024).
12. Mooghali, Maryam, et al. “Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies.” JAMA Network Open. 7: e2430486 (2024).
13. U.S. Food and Drug Administration. “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial Is Underway.” Federal Register. 7 Jan. 2025.
14. “FDA Issues New Draft Guidance on Getting Confirmatory Trials Underway for Accelerated Approval.” Arnold & Porter. 13 Jan. 2025. https://www.arnoldporter.com/en/perspectives/advisories/2025/01/fda-guidance-confirmatory-trials-for-accelerated-approval
15. “Delays in Confirmatory Trials for Drug Applications Granted FDA’s Accelerated Approval Raise Concerns.” U.S. Department of Health and Human Services Office of Inspector General. 29 Sept. 2022.
16. “How FDA Used Its Accelerated Approval Pathway Raised Concerns in 3 of 24 Drugs Reviewed.” U.S. Department of Health and Human Services Office of Inspector General. 14 Jan. 2025.
17. “Cumulative CBER Regenerative Medicine Advanced Therapy Designation Requests Received by Fiscal Year.” U.S. Food and Drug Administration.
