Use of Expedited Regulatory Programs and Clinical Development Times for FDA-Approved Novel Therapeutics

Alissa K Wong; Maryam Mooghali; Reshma Ramachandran; Joseph S Ross; Joshua D Wallach

doi:10.1001/jamanetworkopen.2023.31753

. 2023 Aug 31;6(8):e2331753. doi: 10.1001/jamanetworkopen.2023.31753

Use of Expedited Regulatory Programs and Clinical Development Times for FDA-Approved Novel Therapeutics

Alissa K Wong ¹, Maryam Mooghali ^1,², Reshma Ramachandran ^1,², Joseph S Ross ^1,^2,^3,⁴, Joshua D Wallach ^5,^✉

¹Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut

²Yale Collaboration for Regulatory Rigor, Integrity and Transparency, Yale School of Medicine, New Haven, Connecticut

³Department of Health Policy and Management, Yale School of Public Health, New Haven, Connecticut

⁴Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, Connecticut

⁵Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia

Accepted for Publication: July 25, 2023.

Published: August 31, 2023. doi:10.1001/jamanetworkopen.2023.31753

^✉

Corresponding Author: Joshua D. Wallach, PhD, MS, Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Room 3033, Atlanta, GA 30322 (joshua.wallach@emory.edu).

Author Contributions: Ms Wong and Dr Wallach had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ross, Wallach.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wong, Wallach.

Critical review of the manuscript for important intellectual content: Mooghali, Ramachandran, Ross, Wallach.

Statistical analysis: Wong, Mooghali, Wallach.

Administrative, technical, or material support: Ramachandran.

Supervision: Ross, Wallach.

Conflict of Interest Disclosures: Dr Mooghali reported receiving grants from Arnold Ventures during the conduct of the study. Dr Ramachandran reported receiving grants from Arnold Ventures for the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT) during the conduct of the study; personal fees from ReAct–Action on Antibiotic Resistance Strategic Policy Program; grants from Stavros Niarchos Foundation; and grants from the US Food and Drug Administration (FDA) outside the submitted work as well as serving unpaid as Chair of the FDA Task Force for Doctors for America and as Board President for Universities Allied for Essential Medicines North America. Dr Ross reported receiving grants from Arnold Ventures during the conduct of the study and grants from the FDA, Johnson & Johnson, Medical Devices Innovation Consortium, Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) outside the submitted work as well as serving as an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. Dr Wallach reported receiving grants from Arnold Ventures during the conduct of the study; grants from the National Institute on Alcohol Abuse and Alcoholism of the NIH, Johnson & Johnson, and the FDA outside the submitted work; and personal fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants from Arnold Ventures to the Yale CRRIT.

Role of the Funder/Sponsor: The funder 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.

Data Sharing Statement: See the Supplement.

^✉

Corresponding author.

PMCID: PMC10472182 PMID: 37651145

Abstract

This cross-sectional study evaluates the duration between application to US Food and Drug Administration (FDA) and approval for new drugs and biologics in the US from 2015 to 2022.

Introduction

The US Food and Drug Administration (FDA) has 3 regulatory programs intended to expedite both clinical development and FDA’s review of novel therapeutics targeting serious conditions: fast track, accelerated approval, and breakthrough.¹ Fast track and breakthrough provide opportunities for increased interaction between manufacturers and the FDA as well as rolling review of marketing applications.¹ Breakthrough and accelerated approval allow for approval based on preliminary clinical evidence, including trials using surrogate markers as primary end points to shorten the duration and size of clinical trials, reducing clinical development times.¹ A fourth regulatory program, priority review, was designed to expedite the review process from 10 to 6 months. Previous studies have evaluated the implications of the FDA’s expedited regulatory programs for the combined clinical development and review times for novel therapeutics, but their findings have been inconsistent and have not focused on clinical development times, the target of these 3 programs.^2,3 Given their growing use,⁴ we assessed whether expedited regulatory programs were associated with faster clinical development times for FDA-approved novel therapeutics.

Methods

In accordance with the Common Rule, this cross-sectional study was exempt from ethics review and informed consent because it used public, nonidentifiable data and was not human participant research. We followed the STROBE reporting guideline.

We used the FDA Novel Drug Summary to identify all new drugs and biologics that were approved between January 2015 and December 2022 and their corresponding expedited regulatory programs. Drugs@FDA was used to identify Investigational New Drug (IND) application dates, corresponding with the start of human testing, and New Drug Application (NDA) or Biologics License Application (BLA) submission and approval dates. For therapeutics without IND application dates on Drugs@FDA, we searched patent extension notices using the Federal Register, ClinicalTrials.gov, or Google for these dates or phase-1 study start dates. For therapeutics with multiple formulations, we selected the earliest IND application dates. Clinical development times and combined clinical development and review times were calculated as the time from IND application to NDA or BLA submission and approval, respectively, and were compared across expedited regulatory program used (primary analysis: ≥1 vs none; secondary analyses: fast track, accelerated approval, or breakthrough vs none) along with therapeutic type and area.

Analysis was performed using Mann-Whitney tests in RStudio (Posit). Two-tailed P < .05 were considered statistically significant.

Results

The FDA approved 367 therapeutics between 2015 and 2022, of which 7 had multiple formulations, 6 were developed outside of the US, and 14 had no publicly available IND dates. Of the remaining 340 approvals, 196 (57%) used at least 1 expedited regulatory program: 118 (35%) fast track, 64 (19%) accelerated approval, and 109 (32%) breakthrough.

Median (IQR) clinical development times for approvals using 1 or more vs no expedited regulatory programs were 6.0 (4.0-8.2) vs 7.2 (5.3-9.5; P = .001) years, respectively (Table 1). Median (IQR) combined clinical development and review times were 7.0 (4.8-9.0) and 8.3 (6.5-11.4; P < .001) years, respectively, for 1 or more vs no expedited regulatory programs (Table 2). Differences were consistently statistically significant only for cancer and hematology and other category therapeutics. Compared with approvals using no expedited program (7.2 [5.3-9.5] years), approvals using accelerated approval (4.9 [4.0-7.4] years; P < .001) and breakthrough (5.2 [3.8-7.6] years; P < .001) had significantly shorter median (IQR) clinical development times, but not fast track (6.6 [4.2-9.3] years; P = .10).

Table 1. Duration Between Investigational New Drug Application and New Drug Application (NDA) or Biologics License Application (BLA) Submission Date for Novel Therapeutics Approved by the Food and Drug Administration From 2015 to 2022 .

	Total No. (%)	Approvals using no expedited programs		Approvals using ≥1 expedited programs		P value
	Total No. (%)	No. (%)	Median (IQR), y	No. (%)	Median (IQR), y	P value
Overall	340 (100)	144 (42.4)	7.2 (5.3-9.5)	196 (67.6)	6.0 (4.0-8.2)	.001
Therapeutic type
BLA	96 (28.2)	33 (34.4)	7.5 (5.7-10.1)	63 (65.6)	6.5 (4.0-8.3)	.02
NDA	244 (71.8)	111 (45.5)	7.0 (5.2-9.0)	133 (54.5)	5.9 (4.1-8.2)	.008
Therapeutic area
Cancer and hematology	120 (35.3)	28 (23.3)	6.9 (5.7-11.4)	92 (76.7)	5.7 (4.0-7.9)	.007
Infectious disease	44 (12.9)	9 (20.5)	7.7 (2.3-9.1)	35 (79.5)	8.0 (3.6-10.4)	.49
CVD, diabetes, and hyperlipidemia	22 (6.5)	14 (63.6)	5.4 (4.4-8.1)	8 (26.3)	7.5 (6.7-10.9)	.19
Autoimmune, musculoskeletal, and dermatology	41 (12.1)	25 (61.0)	6.5 (5.5-7.7)	16 (39.0)	5.9 (4.6-7.2)	.14
Neurology and psychiatry	46 (13.5)	30 (65.2)	7.5 (6.0-8.7)	16 (34.8)	5.2 (4.4-7.5)	.07
Other^a	67 (19.7)	38 (56.7)	7.3 (5.0-10.7)	29 (43.3)	6.0 (4.0-7.5)	.03

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Abbreviation: CVD, cardiovascular disease.

^{^a}

Other included endocrinology (excluding diabetes) and metabolic disorders; gastroenterology; gynecology; nephrology; opthalmology; pulmonology; and therapeutics for the treatment of amyloidosis, prevention of nausea and vomiting (after surgery or delayed phase chemotherapy–induced), induction and maintenance of procedural sedation, reversing effects of neuromuscular blocking drugs during surgery, treatment of submental fat, and management of acute pain.

Table 2. Duration Between Investigational New Drug Application and New Drug Application (NDA) or Biologics License Application (BLA) Approval Date for Novel Therapeutics Approved by the US Food and Drug Administration From 2015 to 2022 .

	Total No. (%)	Approvals using no expedited programs		Approvals using ≥1 expedited programs		P value
	Total No. (%)	No. (%)	Median (IQR), y	No. (%)	Median (IQR), y	P value
Overall	340 (100)	144 (42.4)	8.3 (6.5-11.4)	196 (57.6)	7.0 (4.8-9.0)	<.001
Therapeutic type
BLA	96 (28.2)	33 (34.4)	8.4 (7.1-11.4)	63 (65.6)	7.2 (4.8-9.1)	.007
NDA	244 (71.8)	111 (45.5)	8.1 (6.4-11.1)	133 (54.5)	6.9 (4.7-9.0)	<.001
Therapeutic area
Cancer and hematology	120 (35.5)	28 (23.3)	7.7 (6.5-12.0)	92 (76.7)	6.3 (4.7-8.6)	.004
Infectious disease	44 (12.9)	9 (20.5)	9.5 (2.8-11.9)	35 (79.5)	8.7 (4.5-11.2)	.75
CVD, diabetes, and hyperlipidemia	22 (6.5)	14 (63.6)	7.0 (6.0-9.0)	8 (36.4)	8.2 (7.6-12.-0)	.33
Autoimmune, musculoskeletal, and dermatology	41 (12.1)	25 (61.0)	7.8 (6.9-8.7)	16 (39.0)	6.7 (5.0-8.1)	.07
Neurology and psychiatry	46 (13.5)	30 (65.2)	8.7 (6.9-11.2)	16 (34.8)	6.0 (4.6-8.3)	.02
Other^a	67 (19.7)	38 (56.7)	8.5 (6.8-11.9)	29 (43.3)	7.2 (4.7-8.6)	.007

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Abbreviation: CVD, cardiovascular disease.

^{^a}

Discussion

We found that FDA approvals using expedited regulatory programs had shorter clinical development times and combined clinical development and review times by approximately 1 to 2 years, demonstrating the association of these programs with faster therapeutic clinical testing and approval. Study limitations included the reliance on publicly available IND submission dates, which were not uniformly reported. Given that expedited regulatory programs often facilitate faster approval through postmarketing studies required to address residual clinical uncertainties, ongoing efforts are needed to ensure that these studies are completed and reported in a timely manner.^5,6

Supplement.

Data Sharing Statement

Click here for additional data file.^{(16KB, pdf)}

References

1.US Food and Drug Administration . Expedited programs for serious conditions: drugs and biologics. Accessed May 10, 2023. https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf
2.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 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Brown DG, Wobst HJ, Kapoor A, Kenna LA, Southall N. Clinical development times for innovative drugs. Nat Rev Drug Discov. 2022;21(11):793-794. doi: 10.1038/d41573-021-00190-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Zhang AD, Puthumana J, Downing NS, Shah ND, Krumholz HM, Ross JS. Assessment of clinical trials supporting US Food and Drug Administration approval of novel therapeutic agents, 1995-2017. JAMA Netw Open. 2020;3(4):e203284. doi: 10.1001/jamanetworkopen.2020.3284 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.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]
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]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

Data Sharing Statement

Click here for additional data file.^{(16KB, pdf)}

[zld230162r1] 1.US Food and Drug Administration . Expedited programs for serious conditions: drugs and biologics. Accessed May 10, 2023. https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf

[zld230162r2] 2.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 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zld230162r3] 3.Brown DG, Wobst HJ, Kapoor A, Kenna LA, Southall N. Clinical development times for innovative drugs. Nat Rev Drug Discov. 2022;21(11):793-794. doi: 10.1038/d41573-021-00190-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zld230162r4] 4.Zhang AD, Puthumana J, Downing NS, Shah ND, Krumholz HM, Ross JS. Assessment of clinical trials supporting US Food and Drug Administration approval of novel therapeutic agents, 1995-2017. JAMA Netw Open. 2020;3(4):e203284. doi: 10.1001/jamanetworkopen.2020.3284 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zld230162r5] 5.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]

[zld230162r6] 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]

PERMALINK

Use of Expedited Regulatory Programs and Clinical Development Times for FDA-Approved Novel Therapeutics

Alissa K Wong, BS

Maryam Mooghali, MD, MSc

Reshma Ramachandran, MD, MPP, MHS

Joseph S Ross, MD, MHS

Joshua D Wallach, PhD, MS

Abstract

Introduction

Methods

Results

Table 1. Duration Between Investigational New Drug Application and New Drug Application (NDA) or Biologics License Application (BLA) Submission Date for Novel Therapeutics Approved by the Food and Drug Administration From 2015 to 2022 .

Table 2. Duration Between Investigational New Drug Application and New Drug Application (NDA) or Biologics License Application (BLA) Approval Date for Novel Therapeutics Approved by the US Food and Drug Administration From 2015 to 2022 .

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Use of Expedited Regulatory Programs and Clinical Development Times for FDA-Approved Novel Therapeutics

Alissa K Wong, BS

Maryam Mooghali, MD, MSc

Reshma Ramachandran, MD, MPP, MHS

Joseph S Ross, MD, MHS

Joshua D Wallach, PhD, MS

Abstract

Introduction

Methods

Results

Table 1. Duration Between Investigational New Drug Application and New Drug Application (NDA) or Biologics License Application (BLA) Submission Date for Novel Therapeutics Approved by the Food and Drug Administration From 2015 to 2022 .

Table 2. Duration Between Investigational New Drug Application and New Drug Application (NDA) or Biologics License Application (BLA) Approval Date for Novel Therapeutics Approved by the US Food and Drug Administration From 2015 to 2022 .

Discussion

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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