30 Years of Accelerated Approvals: Fast-Tracking Innovation in Drug Development
Mar 2, 2025PAO-25-30-07
In the early 1980s, the established U.S. drug approval process required extensive data collection through preclinical studies and clinical trials that typically took 10 or more years to complete. The emergence of the AIDS epidemic, which resulted in the deaths of tens of thousands of people in a few short years, led activist groups to push the U.S. Food and Drug Administration (FDA) to develop a faster pathway for desperately needed treatments, even if the treatments were not “perfect.”1
At this time, the use of surrogate endpoints — clinical endpoints that are not direct measures of efficacy but known to be good predictors of long-term clinical benefits — was being explored.2 AZT, a drug that improves T cell counts, which was shown to predict fewer infections in AIDS patients, was provisionally approved for certain AIDS patients in March 1987 and for all AIDs patients in 1990. The success of this use of a surrogate endpoint put even more pressure on FDA to create an accelerated approval process, at least for patients with life-threatening diseases for which there are no existing treatments.1
Passage of the Prescription Drug User Fee Act (PDUFA) by the U.S. Congress in 1992 provided a source of funding for new product approvals (via pharmaceutical company user fees).3 The same year, the FDA issued a final rule establishing the Accelerated Approval Program, which would allow faster approval of drugs that addressed unmet medical needs for severe diseases through the use of surrogate endpoints.2
As first established, the accelerated approval pathway applied to drug candidates that met a significant unmet medical need, particularly those that targeted severe and life-threatening diseases lacking available and effective treatments.
Approval timelines are reduced by allowing the use of surrogate endpoints that can be met in a much shorter timeframe than that required for traditional clinical endpoints, such as overall survival or progression-free survival.4 They may include, for example, lab values, imaging results, physical signs, and other accepted measures.5 The sponsor must provide data clearly indicating that the surrogate endpoint is reasonably likely to predict the desired clinical benefit.2
A single clinical trial with a smaller number of patients generating acceptable evidence of effectiveness can be sufficient for receiving marketing approval.2 The safety of the investigational drug product must also be demonstrated, and post-marketing, confirmatory studies must be conducted to verify that the surrogate endpoint is indeed predictive of clinical outcomes.
If verification of predictability is not demonstrated or clinical benefits are found not to justify any risks posed by the drug, the FDA may withdraw its approval, leading to revision of the label indication or removal from the market.2
Despite the strong outcry for faster drug approvals, use of the accelerated approval pathways was limited for the first several years. In each of 1992, 1993, and 1994, just one drug was approved through the program, all of which targeted HIV patients.3 In 1995 and 1996, those numbers climbed to five and eight, respectively, and included not only treatments for HIV but also one for low blood pressure and two for cancer. Low approval numbers continued, but by 1999 cancer predominated the five approvals.
From 1992 to 2001, a total of 52 drugs were approved through the accelerated approval pathway. From 2002 to 2001, only a slightly higher number (59) were granted accelerated approval.6 That works out to an average of just 5-6 approvals per year. In both decades, 44 of the accelerated approvals were converted to full approvals, with the average time to confirm clinical benefit 4.5–5 years. Six and 12 products were withdrawn in the first and second decades with average times to withdrawal of approximately nine and 10 years, respectively.
Over the first decade, not surprisingly, most of the candidates receiving accelerated approval treated infectious diseases. The number of drugs targeting cancer and other rare diseases rose in the second decade. As a result, from 1992 through 2010, just under 40% of drugs receiving accelerated approval treated HIV, nearly 36% targeted cancer, and slightly less than 25% address other rare conditions.2 Notably, a 2011 study found that the time for oncology drugs receiving accelerated approval to reach the market was nearly five years shorter than cancer treatments approved via the traditionally pathway.
Through the end of 2022, a total of 290 drugs were approved using the accelerated approval pathway.7 That number increased to nearly 330 by the end of 2024.8 The majority of these drugs were approved following passage of the FDA Safety and Innovation Act (FDASIA) of 2012, which amended the fast-track designation and accelerated approval pathway, removing the requirement for evidence of added therapeutic benefit over existing treatments.9 Three other special designations were also created under this law.
Before 1992, the median time for FDA approval of a novel drug was 26.6 months.9 With funding from the PDUFA and the introduction of the accelerated approval pathway and other expedited programs, the median approval time fell to 12.9 months. After passage of the FDASIA, it dropped further, to 9.9 months.
In 2021, 28% of FDA-approved products followed the accelerated approval pathway, with oncology drugs most commonly using the program.9 From 2010 to 2020, 85% of all accelerated approvals were for oncology indications.2 For instance, between 2016 and 2022, 67–83% of accelerated approvals were for cancer treatments and just 7–28% for non-oncology drugs.7 It has been suggested that advances in technology for the development of targeted cancer therapies with more predictive and understood surrogate endpoints has supported greater use of the accelerated approval program.6
A study of accelerated approvals from 1992 through the end of 2022 concluded that the accelerated approval program was successful in reducing approval times for drugs targeting serious and life-threatening diseases.6 It also found that the median time for conversion of accelerated approvals to traditional approvals following completion of confirmatory trials was 3.2 years for half of the approvals granted during that period.
While over 300 drugs have received accelerated approvals in reduced timeframes, concerns have been raised in recent years about the overall value and effectiveness of the program. One focuses on the lack of strict standards for the completion of confirmatory trials, which has led to some studies remaining pending for many years.2
Another concern regards the impact that product withdrawals may have on patients.10 Delays in withdrawal of drugs lacking confirmation of clinical benefit mean that patients continue to use therapies that may not be effective.10 Furthermore, product labels are often not updated, which also leads to incorrect continued use. Indeed, lack of communication and education of physicians and patients is often highlighted as an issue with accelerated approvals,11 which the FDA has recognized potentially carry more risk due to their approval with limited clinical data.12
What many think are questionable FDA approvals of drug products submitted for accelerated approval have also raised questions about the program. The two most notable cases are Avastin for breast cancer and Adhuhelm for Alzheimer’s disease.3 In the first case, the FDA review committee did not recommend conversion to traditional approval based on results of two post-marketing clinical studies. In the second, not a single member of the review committee voted for initial accelerated approval. Despite the negative committee decisions, the agency elected to approve both products.
Several product withdrawals in recent years have led to even higher scrutiny of the accelerated approval process.13 Notable examples include Pfizer’s Oxbryta (2024), Biogen and Eisai’s Aduhelm (2024), Takeda’s Exkivity (2023), TG Therapeutics’ Ukoniq (2022), and Gilead Sciences’ Zydelig (2022). Separately, Sarepta’s gene therapy Elevidys for Duchenne muscular dystrophy failed its confirmatory trial, but still won full FDA approval in June 2024.14
In fact, other drugs have been converted to full approvals without demonstrating a clinical benefit in confirmatory trials. One study found that of 46 oncology drugs that received accelerated approval from 2013 to 2023, 63% were converted to regular approvals (22% withdrawn) despite 43% of the products lacking supporting data from confirmatory trials after more than five years.15
In some cases, companies resist withdrawing products that fail confirmatory trials. Examples include AMAG Pharmaceuticals (Makena for prevention of preterm birth) and Genentech (Avastin for breast cancer).10 In fact, several withdrawals of checkpoint inhibitor accelerated approvals for various indications have occurred.
With increased focus in the biopharmaceutical industry on development of treatments for rare diseases and growing interest in novel modalities such as cell and gene therapies, it is anticipated that use of the accelerated approval pathway for a large percentage of drug candidates will continue.2 The rising criticisms of the accelerated approval program may, in addition, lead to revisions of the pathway that could also ultimately lead to its increased use.
Meet the other FDA Expedited Approval Pathways
In addition to accelerated approval, the FDA has introduced a total of eight other expedited pathways. The three other major designations — Fast Track, Priority Review, and Breakthrough Therapy — were outlined along with the Accelerated Approval Program in the FDA’s Final Guidance Expedited Programs for Serious Conditions: Drugs and Biologics issued in March 2014.16
The Fast Track designation applies to candidates that address an unmet medical need. Sponsors benefit from “rolling” FDA review, which means they can submit data as they become available, rather than all at once at the time of New Drug Application (NDA) or Biologics License Application (BLA) submittal.
The Priority Review designation applies to candidates with significantly improved safety or efficacy over available products. Request for this designation is made when filing an NDA and affords a six-month versus regular 10-month review period.
Breakthrough Therapy designation applies to candidates with the potential to be transformative compared with existing products and allows for approvals based on phase I or II study results. Sponsors receive more rapid FDA input and increased communications, as well as rolling application review.
For all these designations, if post-marketing studies are required, they must be underway at the time of candidate approval, and any unfinished phase III trials must be completed.
The remaining expedited programs include the Regenerative Medicine Advanced Therapy (RMAT), Orphan Drug, Priority Review Voucher, Qualified Infectious Disease Product (QIDP,) and Real-Time Oncology Review (RTOR) designations. 4,5
RMAT is similar to the Breakthrough Therapy designation but applies specifically to advanced biologic therapies, such as cell and gene and tissue-replacement therapies, that offer advantages in safety of efficacy over existing treatments. Orphan drugs target rare diseases affecting fewer than 200,000 individuals in the United States and benefit from tax credits, extended market exclusivity, and in some cases faster reviews. Priority Review vouchers are awarded to sponsors who earn FDA approval for drugs that treat certain rare pediatric and tropical diseases or serve as material threat medical countermeasures and provide a six-month review for another candidate. They can be sold (typically for ~$100 million).
The QDIP designation was introduced to encourage development of new antibiotic and antifungal products targeting a list of qualifying pathogens. Candidate also benefit from fast-track status and, if approved, sponsors receive an additional five years of market exclusivity. The RTOR program applies to oncology products with clear endpoints and usually known mechanisms of action and facilitates approval before the assigned PDUFA date. From 2008 through 2021, use of expedited programs increased significantly, particularly for orphan drugs and biologics.
Our parent company, That’s Nice, is committed to supporting the companies and innovators driving the next wave of pharma and biotech innovation. To celebrate That’s Nice’s 30th anniversary, Pharma’s Almanac is diving into 30 groundbreaking advancements, trends, and breakthroughs that have shaped the life sciences, highlighting the industry-defining milestones our agency has had the pleasure of growing alongside. Here’s to 30 years of innovation and the future ahead!
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2. Stengel, Kylie, Megan West (Olsen), Kolton Gustafson, Zachary Zalewski, and Amelia Nell. “Understanding the History and Use of the Accelerated Approval Pathway.” Avalere Insights. 4 Jan. 2022.
3. “Accelerated Approval and the FDA.” Cancer History Project. 20 Jan. 2023.
4. Ridley, Tyler. “The Road to Regulatory Approval: Understanding FDA Special Review Designations.” Weaver. 16 May 2024.
5. Chandanais, Ryan. “An Overview Of The 9 FDA Special Designations for Pipeline Drugs.” Outsourced Pharma. 8 Sep. 2023.
6. Beakes-Read, Ginny, Madison Neisser, Patrick Frey, and Mara Guarducci. “Analysis of FDA's Accelerated Approval Program Performance December 1992–December 2021.” Ther. Innov. Regul. Sci. 56:698–703 (2022).
7. Anderson, Maia. “A brief history of the FDA’s accelerated approvals program.” Healthcare Brew. 6 Feb. 2023.
8. “CDER Drug and Biologic Accelerated Approvals Based on a Surrogate Endpoint As of December 31, 2024.” U.S. Food and Drug Administration. 31 Dec. 2024.
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10. Young, Kerry Dooley. “The FDA’s accelerated approval process: When drugs are cleared for sale based on limited evidence.” Journalist Resource. 18 Oct. 2021.
11. The Food and Drug Administration's Accelerated Approval Process for New Pharmaceuticals: Proceedings of a Workshop—in Brief. National Academies of Sciences, Engineering, and Medicine. Washington, DC: The National Academies Press. 2023.
12. Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products. Drug Guidance for Industry. U.S. Food and Drug Administration. 2021.
13. McKenzie, Heather. “5 Accelerated Approvals Gone Wrong.” Biospace. 14 Oct. 2024.
14. McKenzie, Heather. “Deep Dive: FDA’s Accelerated Approval Pathway Under Fire.” Biospace. 18 Nov. 2024.
15. “Fewer Than Half of Accelerated Approval Drugs Showed Clinical Benefit in Confirmatory Trials After Five Years.” American Association for Cancer Research. 7 Apr. 2024.
16. Gaffney, Alexander. “FDA Finalizes Expedited Product Guidance With Hundreds of Major, Minor Changes.” Regulatory Focus. 29 May 2014.
17. Monge Andrea N et al. “Use of US Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021.” JAMA Netw. Open. 5:e2239336 (2022).
