AA indicates accelerated approval; BT, breakthrough therapy; FDA, US Food and Drug Administration; FT, fast-track; PR, priority review. Clinical development times were calculated from the date of the Investigational New Drug (IND) application to the date of FDA approval. Any expedited program means any of PR, AA, FT, or BT. Development times were not available for 2 drugs in the study cohort. Error bars indicate interquartile ranges.
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Hwang TJ, Darrow JJ, Kesselheim AS. The FDA’s Expedited Programs and Clinical Development Times for Novel Therapeutics, 2012-2016. JAMA. 2017;318(21):2137–2138. doi:10.1001/jama.2017.14896
The US Food and Drug Administration (FDA) has 4 expedited programs to speed the development and review of drugs treating serious diseases: (1) priority review leads to FDA review in 6 months (vs 10 months for standard review); (2) accelerated approval permits approval based on surrogate measures; and (3) fast-track and (4) breakthrough therapy programs are intended to reduce the duration of clinical trials (Table).1 Clinical development times for drugs in these expedited programs, particularly the newly created breakthrough program (enacted in 2012), have not been comprehensively assessed. We analyzed clinical development times within each of the 4 expedited programs separately and between drugs qualifying for any vs no expedited program. Because fast-track and breakthrough programs are intended to abbreviate the overall drug development process, we also examined development times for drugs receiving either or both of these 2 programs (regardless of other programs).
We identified all new FDA-approved drugs and biologics from January 2012 through December 2016 using the Drugs@FDA database and extracted the date of approval and expedited program(s) (priority review, accelerated approval, fast-track, or breakthrough).
Clinical development times were calculated as the time elapsed from the Investigational New Drug (IND) application (when human testing begins) to first FDA approval. IND application dates were obtained from FDA documents, administrative correspondence, and patent extension notices. Dates could not be located for 2 products. The Mann-Whitney test compared median development times between drugs not in any expedited program vs those in at least 1 (a drug can qualify for all 4). We compared development times for priority review or accelerated approval (but not fast-track or breakthrough) drugs vs no expedited program. We also compared, regardless of other programs, (1) drugs with vs without fast-track status; (2) drugs with vs without breakthrough status; (3) fast-track, nonbreakthrough drugs vs breakthrough, non–fast-track drugs; and (4) breakthrough, fast-track drugs vs breakthrough, non–fast-track drugs. Statistical analyses were performed using Stata (StataCorp), version 12. Two-tailed P values less than .05 were considered statistically significant.
Of 174 new drug approvals, 105 (60%) were in 1 or more expedited programs. The expedited programs for 90 drugs included priority review (52%); accelerated approval for 26 drugs (15%); fast-track for 63 drugs (36%); and breakthrough for 29 drugs (17%).
The median development time for drugs in at least 1 expedited program was 7.1 years (interquartile range [IQR], 5.1-10.1) compared with 8.0 years for nonexpedited drugs (IQR, 6.5-10.0; P = .04) (Figure). For nonbreakthrough, non–fast-track drugs, development times were not significantly different between drugs with priority review or accelerated approval vs no expedited program (8.2 years [IQR, 6.4-10.6] vs 8.0 years [IQR, 6.5-10.0]; P = .35).
Development times were shorter for fast-track vs non–fast-track drugs (7.0 years [IQR, 5.2-9.5] vs 8.0 years [IQR, 6.2-10.3]; P = .03) and for breakthrough vs nonbreakthrough drugs (4.8 years [IQR, 3.6-7.7] vs 8.0 years [IQR, 6.2-10.3]; P < .001), regardless of other programs. Breakthrough, non–fast-track drugs had shorter development times than fast-track, nonbreakthrough drugs (4.8 years [IQR, 3.6-8.3] vs 7.1 years [IQR, 5.5-9.6]; P = .001). Development times were similar for breakthrough, fast-track drugs vs breakthrough, non–fast-track drugs (5.0 years [IQR, 2.9-7.7] vs 4.8 years [IQR, 3.6-8.3]; P = .93).
The median time from IND application to FDA approval was 0.9 years shorter for drugs with vs without any expedited program. Although priority review provides 4-month shorter FDA review, drugs with priority review (or accelerated approval) were not associated with faster overall development times. The shortest median development time of 4.8 years (32% shorter than fast-track drugs) was observed for drugs with breakthrough status, which provides qualifying manufacturers with all of the benefits of the fast-track designation plus even more intensive guidance on efficient drug development.2 Study limitations are that only approved agents were analyzed, and potential bias may exist in which drugs are selected for expedited programs.
Through December 2016, 165 investigational drugs received breakthrough status, and the frequency of breakthrough therapy approvals has increased.2 Despite the association of breakthrough status with heightened expectations of benefit by physicians and patients,4,5 expedited drug approvals have also been associated with greater postmarket safety risks.3 Although this program provides greater speed, regulators should ensure clear communication about the limitations of the collected evidence and the additional risks that these drugs may impose on patients.
Accepted for Publication: September 7, 2017.
Corresponding Author: Aaron S. Kesselheim, MD, JD, MPH, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 1620 Tremont St, Ste 3030, Boston, MA 02120 (firstname.lastname@example.org).
Author Contributions: Mr Hwang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Hwang, Kesselheim.
Drafting of the manuscript: Hwang, Darrow.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Hwang.
Obtained funding: Kesselheim.
Supervision: Darrow, Kesselheim.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr Hwang reported prior employment by Blackstone and Bain Capital, which have invested in healthcare companies. Dr Kesselheim reported receiving grant funding from the US Food and Drug Administration Office of Generic Drugs and Division of Health Communication (2013-2016). No other disclosures were reported.
Funding/Support: This work was supported by grants from the Laura and John Arnold Foundation (Dr Kesselheim) and Harvard Program in Therapeutic Science (Dr Kesselheim) and the Engelberg Foundation (Dr Kesselheim).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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