Abstract
This cross-sectional study compares the duration of postapproval trials with that of the pivotal trials used as the basis for the US Food and Drug Administration’s (FDA’s) approval for all indications receiving accelerated approval from 2009-2018.
Introduction
Under the US Food and Drug Administration’s (FDA’s) accelerated approval program, therapeutic agents that address serious or life-threatening disease can receive conditional approval on the basis of trials that use surrogate markers that are reasonably likely to predict clinical benefit.1 Although drug sponsors are required to conduct postapproval trials to confirm clinical benefit, the amount of time sponsors are granted by the FDA to complete these studies has come under increased scrutiny after the recent accelerated approval of aducanumab for Alzheimer disease,2 which included a 9-year deadline for the completion of the confirmatory trial. Better understanding whether postapproval trial durations, which are generally expected to measure clinical outcomes and be longer than pivotal trials focused on surrogate markers, justify the study timelines set by the FDA is critical because these drugs can remain on the market for an extended period without confirmatory evidence. Therefore, we compared the duration of postapproval trials with that of the pivotal trials used as the basis for the FDA’s approval, as well as FDA-established postapproval trial results reporting deadlines, for all indications receiving accelerated approval from January 1, 2009, through December 31, 2018.
Methods
In this cross-sectional study, we used the Drugs@FDA database to identify all new drugs and biologics granted accelerated approval by the FDA from January 1, 2009, through December 31, 2018. This study did not require institutional review board approval because it was based on publicly available information, in accordance with 45 CFR §46. Informed consent was not needed because no patient data were used. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. For each therapeutic agent, we used previously described approaches to identify pivotal and postapproval trials designed to confirm efficacy,3,4,5 classify postapproval trials as either new or ongoing at the time of approval,4 identify FDA-established postapproval trial results reporting deadlines,4,6 and locate ClinicalTrials.gov registrations and publications.4 We used FDA labels/letters and medical reviews, ClinicalTrials.gov registrations, and publications to identify pivotal and postapproval trial primary outcomes and the timing of their ascertainment (ie, median duration of follow-up or response for event-driven trials). For indications with more than 1 pivotal study and/or postapproval trial, we calculated the median of the trial durations. For each indication, we then calculated the difference between the durations of the postapproval and pivotal trials. As suggested during the peer review of this manuscript, we also estimated trial durations by taking the difference between the actual or estimated study start and primary completion dates available for all trials registered on ClinicalTrials.gov. These data analyses were conducted from July 1 to September 1, 2021, using Excel (Microsoft, Inc).
Results
From Jauary 1, 2009, through December 31, 2018, the FDA approved 41 new therapeutic agents for 45 indications via the accelerated approval program. Of these, information on trial duration could be ascertained for 31 therapeutic agents (76%) approved for 32 indications (76%). Of 32 indications approved, 21 (66%) were for drugs, 11 (34%) were for biologics, and 27 (84%) were for therapeutic agents related to cancer and hematology (Table 1).
Table 1. Characteristics of 32 Indications Receiving US Food and Drug Administration Accelerated Approval, 2009-2018a.
| Indication characteristic | No. (%) |
|---|---|
| Class | |
| Drug | 21 (66) |
| Biologic | 11 (34) |
| Therapeutic area | |
| Cancer and hematology | 27 (84) |
| Other | 5 (16) |
| Priority review | |
| Yes | 28 (88) |
| No | 4 (12) |
| Fast track | |
| Yes | 17 (53) |
| No | 15 (47) |
| Breakthrough therapy | |
| Yes | 17 (53) |
| No | 15 (47) |
| Orphan drug designation | |
| Yes | 29 (91) |
| No | 3 (9) |
| Converted from accelerated to regular approval | |
| Yes | 19 (59) |
| No | 13 (41) |
| Total sample size per indication, median (IQR) | |
| Pivotal trial | 164 (105-235) |
| Postapproval confirmatory trial | 520 (386-709) |
For 1 therapeutic agent (Iclusig [ponatinib hydrochloride]; Takeda Pharmaceutical Company Limited), 1 pivotal and 1 postapproval confirmatory trial evaluated 2 indications (chronic myeloid leukemia and acute lymphoblastic leukemia). Therefore, we counted this as 1 indication approval.
Overall, the median pivotal trial duration was 10 months (range, 0-42 months) and the postapproval trial duration was 17 months (0-72 months) (median difference, 5 months [range, −6 to 36 months]) (Table 2). The median time from approval to FDA-established postapproval trial results reporting deadlines for sponsors was 50 months (3-116 months), a median of 30 months (range, −19 to 106 months) more than the postapproval trial durations.
Table 2. Pivotal and Postapproval Trial Durations.
| Trial type | Trial duration, median (range), mo | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary analysesa | Sensitivity analysesb | ||||||||||
| Postapproval trial status at approval | Postapproval end point type | Overall | Postapproval trial status at approval | Postapproval end point type | Overall | ||||||
| New (n = 17) | Ongoing (n = 15) | Surrogate (n = 19) | Clinical (n = 13) | New (n = 20) | Ongoing (n = 16) | Surrogate (n = 22) | Clinical (n = 14) | ||||
| Pivotal | 9 (0 to 42) |
10 (2 to 29) |
10 (2 to 26) |
8 (0 to 42) |
10 (0 to 42) |
32 (12 to 92) |
55 (10 to 117) |
39 (10 to 117) |
29 (12 to 92) |
37 (10 to 117) |
|
| Postapproval | 19 (4 to 72) |
15 (0 to 41) |
17 (0 to 36) |
17 (4 to 72) |
17 (0 to 72) |
43 (4 to 111) |
45 (19 to 120) |
50 (14 to 11) |
37 (4 to 120) |
44 (4 to 120) |
|
| Differencec | 7 (−2 to 30) |
4 (−6 to 36) |
5 (−3 to 24) |
6 (−6 to 36) |
5 (−6 to 36) |
2 (−57 to 77) |
1 (−85 to 97) |
1.5 (−85 to 77) |
−5.5 (−57 to 97) |
1 (−85 to 97) |
|
Duration based on timing of primary end point ascertainment among 32 indications. This included 5 indications with ongoing trials for which estimated trial durations were used.
Duration based on ClinicalTrials.gov study start and primary completion dates among 37 indications. This included 7 indications with ongoing trials for which only estimated primary completion dates were available.
Difference was calculated by subtracting the pivotal trial duration from the postapproval trial duration.
Median pivotal and postapproval trial durations were consistent across indications for which the FDA required new postapproval trials vs results reporting or extended follow-up of ongoing postapproval trials and for indications for which postapproval trials used surrogate markers vs clinical outcomes as primary end points (Table 2). Among 37 indications with information on study start and completion dates on ClinicalTrials.gov, the median difference between pivotal and postapproval trial durations based on these data was 1 month (range, −85 to 97 months).
Discussion
The findings of this cross-sectional study suggest that, for therapeutic agents receiving accelerated approval by the FDA from January 1, 2009, through December 31, 2018, median postapproval trial durations were not much longer than pivotal trial durations. These findings raise questions about the use of the accelerated approval program for certain therapeutic agents, especially if postapproval confirmatory trials neither consistently evaluate clinical outcomes nor are much longer than pivotal trials using surrogate end points.
Limitations of this study include the reliance on publicly available data, the inability to account for postapproval trial recruitment challenges or other reporting deadline changes, and that these results may not be generalizable across all therapeutic areas. Nevertheless, this study’s findings suggest that prolonged results reporting deadlines may not be justified given the marginal differences in pivotal and postapproval trial durations of therapeutic indications recently receiving accelerated approval by the FDA.
References
- 1.Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849-856. doi: 10.1001/jamaoncol.2017.5618 [DOI] [PubMed] [Google Scholar]
- 2.Gyawali B, Ross JS, Kesselheim AS. Fulfilling the mandate of the US Food and Drug Administration’s accelerated approval pathway: the need for reforms. JAMA Intern Med. 2021. doi: 10.1001/jamainternmed.2021.4604 [DOI] [PubMed] [Google Scholar]
- 3.Downing NS, Aminawung JA, Shah ND, Krumholz HM, Ross JS. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA. 2014;311(4):368-377. doi: 10.1001/jama.2013.282034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wallach JD, Egilman AC, Dhruva SS, et al. Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis. BMJ. 2018;361:k2031. doi: 10.1136/bmj.k2031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Skydel JJ, Zhang AD, Dhruva SS, Ross JS, Wallach JD. US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018. Clin Trials. 2021;18(4):488-499. doi: 10.1177/17407745211005044 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wallach JD, Egilman AC, Ross JS, Woloshin S, Schwartz LM. Timeliness of postmarket studies for new pharmaceuticals approved between 2009 and 2012: a cross-sectional analysis. J Gen Intern Med. 2019;34(4):492-495. doi: 10.1007/s11606-018-4779-x [DOI] [PMC free article] [PubMed] [Google Scholar]