Abstract
The availability of generic drugs is essential for giving patients access to cheap medications and corresponding reference listed drugs (RLDs) have a pivotal role in the authorization of these medicines, which acts as a standard for comparison. This article outlines the importance of RLDs in the authorization of generic drugs and meet requirements like bioequivalence studies, stability studies and proper labelling. It also looks at the challenges they face, such as limited access to RLD samples or strategies like pay for delay agreements, authorized generics, and product hopping. It also discusses laws like the Creates Act and Affordable Care Act, which aim to encourage fair competition. Finally, this article shows how generic drug launches can reduce prices and affect the sales of brand name drugs, using real world examples to highlight these effects.
Get full access to this article
View all access options for this article.
References
1.
Food and Drug Administration
. Generic drugs: questions & answers . Current as of 16 March 2021 . https://www.fda.gov/drugs/frequently-asked-questions-popular-topics/generic-drugs-questions-answers (Accessed 28 January 2025 ).
2.
Mittal
B
. How to integrate quality by efficient design (QbED) in product development . Academic Press , 2019 .
3.
Eaglstein
WH
. The FDA drug approval . In: Comprehensive dermatologic drug therapy . SP RSC Publishing , 2019 , p. 49 .
4.
Boehm
G
Yao
L
Han
L
, et al. Development of the generic drug industry in the US after the Hatch-Waxman Act of 1984 . Acta Pharm Sin B 2013 ; 3 (5 ): 297 –311 .
5.
Food and Drug Administration
. Referencing approved drug products in ANDA submissions [draft guidance] . Issued 27 October 2020 . https://www.fda.gov/media/102360/download (Accessed 31 January 2025).
6.
Liddicoat
J
Liddell
K
Darrow
J
, et al. Repositioning generic drugs: empirical findings and policy implications . IIC-Int Rev Intel Prop Comp Law 2022 ; 53 (9 ): 1287 –1322 .
7.
Food and Drug Administration
. Abbreviated new drug application . Current as of 16 September 2025 . https://www.fda.gov/drugs/types-applications/abbreviated-new-drug-application-anda (Accessed 18 September 2025).
8.
Food and Drug Administration
. Abbreviated approval pathways for drug products: 505 (b) (2) or ANDA . Current as of 19 September 2019 . https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/abbreviated-approval-pathways-drug-product-505b2-or-anda (Accessed 20 February 2025).
9.
Food and Drug Administration
. Abbreviated new drug application (ANDA) forms and submission requirements . Current as of 9 September 2025 . https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/abbreviated-new-drug-application-anda-forms-and-submission-requirements (Accessed 18 September 2025).
10.
Food and Drug Administration
. Manual of policies and procedures . Current as of 3 October 2023 . https://www.fda.gov/media/144976/download?attachment (Accessed 27 April 2025).
11.
Food and Drug Administration
. New and updated FDA forms . Current as of 7 September 2023 . https://www.fda.gov/about-fda/forms/new-and-updated-fda-forms (Accessed 27 April 2025).
12.
Food and Drug Administration
. Instructions for completing form FDA 3794 . https://www.fda.gov/media/132787/download?attachment (Accessed 30 April 2025).
13.
Food and Drug Administration
. Certification of compliance . https://www.fda.gov/media/74213/download (Accessed 26 April 2025).
14.
Food and Drug Administration
. Drug master files (DMFs) . Current as of 7 January 2025 . https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs (Accessed 26 April 2025).
15.
Food and Drug Administration
. Abbreviated new drug application (ANDA) forms and submission requirements . Current as of 26 April 2023 . https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-pre-assigned-application-number (Accessed 25 May 2023).
16.
Food and Drug Administration
. Approved drug products with therapeutic equivalence evaluations orange book . Current as of 12 September 2025 . https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book (Accessed 16 September 2024).
17.
Food and Drug Administration
. Listing of patent information in the orange book . Current as of 1 June 2020 . https://www.regulations.gov/document/FDA-2020-N-1127-0001 (Accessed 27 January 2025).
18.
Nagadurga
DH
. Bioavailability and bioequivalence . In: Pharmaceutical formulation design: recent practices . IntechOpen , 2020 , p. 65 .
19.
International Council for Harmonisation
. ICH quality guidelines . https://www.ich.org/page/quality-guidelines (Accessed 15 June 2025).
20.
Food and Drug Administration
. Guidance for industry ANDAs: Stability testing of drug substances and products [draft guidance] . Issued June 2013 . https://www.fda.gov/media/84437/download (Accessed 26 April 2025).
21.
International Council for Harmonisation
. Bracketing and matrixing designs for stability testing of new drug substances and products Q1D . Last updated 7 February 2002 . https://database.ich.org/sites/default/files/Q1D_Guideline.pdf (Accessed 27 April 2025).
22.
International Council for Harmonisation
. Impurities in new drug substances Q3A(R2) . Last updated 25 October 2006 . https://database.ich.org/sites/default/files/Q1D_Guideline.pdf (Accessed 10 May 2025).
23.
International Council for Harmonisation
. Impurities in new drug substances Q3B(R2) . Last updated 2 June 2006 . https://database.ich.org/sites/default/files/Q3B%28R2%29_Guideline.pdf (Accessed 10 May 2025).
24.
Food and Drug Administration
. Anda submissions content and format guidance for industry [draft guidance] . Issued 20 June 2019 . https://www.fda.gov/media/128127/download (Accessed 25 January 2025).
25.
Food and Drug Administration
. Small business assistance: 180-day generic drug exclusivity . Current as of 26 October 2023 . https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-assistance-180-day-generic-drug-exclusivity (Accessed 12 June 2025).
26.
Olson
LM
Wendling
BW
. Estimating the causal effect of entry on generic drug prices using Hatch–Waxman exclusivity . Rev Ind Organ 2018 ; 53 (1 ): 139 –172 .
27.
Food and Drug Administration
. Development of a shared system rems guidance for industry [draft guidance] . Issued 6 January 2018 . https://www.fda.gov/files/drugs/published/Development-of-a-Shared-System-REMS-Guidance-for-Industry.pdf (Accessed 27 January 2025).
28.
Food and Drug Administration
. FDA drug competition action plan . Current as of 15 January 2025 . https://www.fda.gov/drugs/guidance-compliance-regulatory-information/fda-drug-competition-action-plan (Accessed 28 June 2025).
29.
Assistant Secretary for Planning and Evaluation
. Price increase for the prescription drugs, 2016–2022 . Last updated 30 September 2022 . https://aspe.hhs.gov/sites/default/files/documents/e9d5bb190056eb94483b774b53d512b4/price-tracking-brief.pdf (Accessed 20 July 2025).
30.
Assistant Secretary for Planning and Evaluation
. Comprehensive plan for addressing high drug prices . Last updated 9 September 2021 . https://aspe.hhs.gov/sites/default/files/2021-09/Competition_EO_45-Day_Drug_Pricing_Report_9-8-2021.pdf (Accessed 1 July 2025).
31.
Food and Drug Administration
. FDA working to lift barriers to generic drug competition . Current as of 21 June 2017 . https://www.prnewswire.com/news-releases/fda-voice-blog-fda-working-to-lift-barriers-to-generic-drug-competition-300477549.html (Accessed 3 February 2025).
32.
Onoe
Y
. Pay-for-delay settlements in pharmaceutical litigation: drawing a fine line between patent zone and antitrust zone . J Marshall Rev Intell Prop L 2009 ; 9 : 527 .
33.
Jones
GH
Carrier
MA
Silver
RT
, et al. Strategies that delay or prevent the timely availability of affordable generic drugs in the United States . Blood 2016 ; 127 (11 ): 1398 –1402 .
34.
United States Patent and Trademark Office
. Patent basics . https://www.uspto.gov/patents/basics/general-information-patents (Accessed 16 July 2025).
35.
Miller
E
. Big pharma’s block on competition - a bad prescription for U.S. drug price . Drugwatch Published on 14 September 2017 . https://www.drugwatch.com/featured/big-pharmas-competition-block/ (Accessed 4 August 2025).
36.
Food and Drug Administration
. Frequently asked questions on patents and exclusivity . Current as of 2 May 2020 . https://www.fda.gov/drugs/development-approval-process-drugs/frequently-asked-questions-patents-and-exclusivity (Accessed 4 August 2025).
37.
Velásquez
G
. The international debate on generic medicines of biological origin. No. 82. Research paper, 2017 . https://www.southcentre.int/wp-content/uploads/2017/11/RP82_The-International-Debate-on-Generic-Medecines-of-Biological-Origin_EN.pdf (Accessed 12 August 2025).
38.
Downing
NS
Ross
JS
Jackevicius
CA
, et al. Avoidance of generic competition by Abbott laboratories’ fenofibrate franchise . Arch Intern Med 2012 ; 172 (9 ): 724 –730 .
39.
Food and Drug Administration
. Determining whether to submit an ANDA or a 505(b)(2) application guidance for industry [draft guidance] . Issued 10 May 2019 . https://www.fda.gov/media/124848/download (Accessed 10 August 2025).
40.
Food and Drug Administration
. Patent certifications and suitability petitions . Current as of 9 April 2025 . https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/patent-certifications-and-suitability-petitions (Accessed 10 August 2025).
41.
Food and Drug Administration
. Statement from FDA commissioner Scott Gottlieb, M.D. on the Trump Administration’s plan to lower drug prices . Current as of 11 May 2018 . https://www.prnewswire.com/news-releases/statement-from-fda-commissioner-scott-gottlieb-md-on-the-trump-administrations-plan-to-lower-drug-prices-300647197.html (Accessed 8 August 2025).
42.
U.S. Congress
. Further consolidated appropriations act, 2020 . Published online 20 December 2019 . https://www.congress.gov/116/plaws/publ94/PLAW-116publ94.pdf (Accessed 27 April 2025).
43.
Food and Drug Administration
. Access to product samples: the creates act . Current as of 28 December 2022 . https://www.fda.gov/drugs/guidance-compliance-regulatory-information/access-product-samples-creates-act (Accessed 11 July 2025).
44.
Joanne
SE
. FDA’s revised MAPP outlines procedures for generic drug labeling changes . Published online 27 July 2021 . https://www.raps.org/news-and-articles/news-articles/2021/7/fda-outlines-new-procedures-for-handling-generic-d (Accessed 12 August 2025).
45.
Bristol-Myers Squibb
. 2021 annual report . Published 2022 . https://annual-report.bms.com/assets/bms-ar/documents/2021-annual-report.pdf (Accessed 28 April 2025).
46.
Bristol-Myers Squibb
. 2023 annual report . Published 2024 . https://www.bms.com/assets/bms-ar/documents/2023/2023-bms-annual-report.pdf (Accessed 30 April 2025).
47.
Amgen, Inc
. 2015 annual report . Published online 31 March 2016 . https://investors.amgen.com/static-files/09df49df-2225-4ec5-8cdd-058629d59a3b (Accessed 27 April 2025).
48.
Amgen, Inc
. 2024 annual report . Published online 2 April 2025 . https://investors.amgen.com/static-files/95644920-150e-471b-99ee-4facd7c4e1ac (Accessed 27 April 2025).
49.
Johnson & Johnson
. 2015 annual report . Published online 8 March 2016 . https://www.annualreports.com/HostedData/AnnualReportArchive/j/NYSE_JNJ_2015.pdf (Accessed 28 April 2025).
50.
Johnson & Johnson
. 2024 annual report . Published online March 2025 . https://www.jnj.com/download/johnson-johnson-2024-annual-report (Accessed 28 April 2025).
51.
Prism Biopharma
. The rise of generic drugs in global markets , 2023 . Published online . https://www.prismbiopharma.com/the-rise-of-generic-drugs-in-global-markets (Accessed 24 August 2025).
52.
IQVIA Institute for Human Data Science
. The global use of medicines 2023: outlook to 2027 . Published online 18 January 2023 . https://www.iqvia.com/insights/the-iqvia-institute/reports/the-global-use-of-medicines-2023 (Accessed 25 August 2025).
53.
Evaluate Ltd
. Evaluate pharma world review 2023, outlook to 2028 . Published online 2023 . https://www.evaluate.com/wp-content/uploads/2024/02/World-Preview-Webinar_FINAL_0.pdf (Accessed 27 August 2025).
54.
OECD
. Health at a glance 2023: OECD indicators . Published 7 November 2023 . https://www.oecd.org/en/publications/health-at-a-glance-2023_7a7afb35-en/full-report/generics-and-biosimilars_2bcec977.html (Accessed 26 April 2025).
55.
Grand View Research
. Generic pharmaceuticals market size, share & trends analysis report, 2023–2030 . Published online February 2023 . https://www.grandviewresearch.com/industry-analysis/generic-pharmaceuticals-market-report (Accessed 27 April 2025).