NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
Phillip Zhang ; Preeti Patel ; Nicole R. Winston .
Last Update: February 12, 2024 .
This activity examines the regulatory landscape governing the development of medications in the United States. Overseen by the Food and Drug Administration (FDA), the process mandates a collaborative effort among drug sponsors, clinical researchers, and regulatory authorities. Navigating the drug development pipeline, from initial discovery through rigorous investigation, extensive clinical trials, and ultimate FDA approval, is crucial for ensuring the safety and efficacy of pharmaceuticals before their introduction to the consumer market. By scrutinizing federal medication development regulations, this discussion sheds light on the dynamic interactions between the FDA, drug manufacturers, and clinical researchers, offering comprehensive insights into the complexities of bringing new medications to fruition.
Participants in this activity will gain a greater understanding of the multifaceted framework that guides the development of medications in the United States. The program delves into the intricacies of coordination among drug sponsors, clinical researchers, and regulatory authorities within the context of federal regulations. Examining the entire drug development process, from initial discovery to FDA approval, this activity illuminates the interplay between the key stakeholders involved. By explaining the regulatory requirements and expectations, this initiative equips healthcare professionals with the knowledge necessary to navigate the landscape of medication development, fostering a deeper appreciation for the regulatory safeguards that underpin the introduction of new pharmaceuticals to the healthcare market.
Identify specific laws about FDA regulations for drug development. Evaluate the new drug application process, including expedited review programs. Interpret the intellectual property laws regulating drug development. Evaluate the process of regulating the production of generic small-molecule drugs and biologics.Before 1906, there were few controls on drug distribution, and products were often inconsistent in strength or poorly labeled.[1] The Federal Drug Administration (FDA) was formed as part of the Pure Food and Drug Act of 1906, which prohibited misleading drug labeling and created consumer protections for drug safety. The Federal Food, Drug, and Cosmetic Act (FDCA) of 1938 would replace the former act and strengthen the FDA's ability to regulate the medication development process. It required manufacturers to provide proof of safety and adequate information on labels.[2]
Numerous amendments were added to the FDCA to modify the regulations and oversight of the FDA. The Durham-Humphrey Amendment was enacted to regulate unsafe medications to be taken without medical supervision, distinguishing between over-the-counter and prescription drugs.[3]
In 1961, thalidomide was shown to cause severe congenital disabilities after being marketed in Europe, prompting increased regulations on medication development.[4] There were also cases of thalidomide-induced congenital disabilities in the US. However, the FDA did not approve the medicine. The passage of the Kefauver-Harris Amendment in 1962 would allow the FDA to require proof that drugs were both safe and effective before approval. This amendment contained provisions for obtaining informed consent for clinical trials and initiated Good Manufacturing Practices (GMP).
The FDA approval process requires comprehensive pre-clinical testing followed by multi-phase clinical trials to ensure safety and efficacy. Discovery is the beginning of medication development involving disease study, molecular models, and high-throughput screening to determine potential new drug molecules. Pre-clinical testing involves in vitro and in vivo experiments using cellular and animal models.
The submission of an Investigational New Drug (IND) application is required before the drug is administered to human participants.[5] Once submitted, the FDA has 30 days to decide if the drug is suitable for human testing. When the FDA approves an IND, human testing can proceed with multi-phase clinical trials, which may last 6 to 7 years and average $48 million per drug.[6] Fewer than 14% of drug candidates will reach FDA approval during this rigorous process.[7] Additionally, severe and fatal adverse events must be reported to the FDA Adverse Event Reporting System (FAERS) within 15 days. The FDA can halt clinical trials at any time if an investigational drug causes significant harm to patients. The phases of clinical trials (I to IV) are summarized in Table I.[8]
Initial testing of fewer than 100 healthy patients to determine the pharmacokinetics, toxicology, and drug safety in humans. Roughly two-thirds of drugs complete phase I testing and proceed to phase II clinical trials. Phase IV (more. )
If drug sponsors can demonstrate adequate safety and efficacy during clinical trials phases I to III, they may subsequently submit a New Drug Application (NDA) or Biologics License Application (BLA).[9] If the FDA accepts the quality of clinical trial data, then the NDA or BLA will be approved, and drug manufacturers can begin marketing. One of many FDA-expedited review programs may shorten the developmental process. These expedited processes are granted for investigational drugs that fill an unmet medical need or represent a substantial increase in efficacy for severe medical conditions.[10]
Priority review can be used for an NDA or BLA to decrease the FDA review period and may be combined with other expedited review programs.[11] Fast-track review can be requested for IND applications for drugs that fulfill an unmet medical need. Fast-track review allows drug sponsors to meet with the FDA to advance drug development. Breakthrough therapy review can be requested for drugs with clinical data demonstrating significant improvement over existing drugs. Breakthrough drugs also allow drug sponsors to meet with the FDA and sometimes enable sponsors to avoid components of the standard review process. Accelerated approval is intended for developing drugs with long-term clinical endpoints that may be difficult to measure during clinical trials. Other expedited review programs may also be used alongside accelerated approval.
The FDA continues to monitor newly approved drugs and biologics for long-term safety. Phase IV clinical trials are used for post-market surveillance involving thousands of participants.[8] During phase IV, drug sponsors must send periodic reports on safety and tolerability to the FAERS. Additionally, the FDA regulates the use of potentially harmful drugs by requiring manufacturers to use Risk Evaluation and Mitigation Strategy (REMS) programs. Such programs were formalized by the Food and Drug Administration Amendments Act of 2007 and helped to ensure safe drug use by consumers.[12] For example, isotretinoin is commonly used for acne treatment but has teratogenic effects if taken while pregnant. Isotretinoin is dispensed by a REMS program called iPLEDGE. The iPLEDGE program mandates that female patients using isotretinoin must use 2 birth control methods, take doctor-administered pregnancy tests, and complete online educational modules to mitigate the risk of bearing children with severe congenital disabilities.[13] There are currently 61 REMS programs with varying degrees of implementation and effectiveness.[14]
US governing authorities heavily regulate intellectual property. The US Patent and Trademark Office grants drug patents, whereas the FDA sets data exclusivity for new medicines. Exclusivity involves inhibiting the approval of competing drugs for a set period to balance novel drug creation and consumer medication accessibility. The FDA allows 5 years of exclusivity for novel small-molecule drugs and 12 years for biologics.[15] New clinical uses of existing drugs may be granted 3 years of exclusivity. Under the Best Pharmaceuticals for Children Act, 6 months of exclusivity may be added to existing pediatric drugs. Under the Orphan Drug Act, 7 years of market exclusivity is granted for treating rare diseases.[16]
Following the expiration of patents for name-brand drugs, the FDA regulates the production of generic drugs by requiring the submission of an Abbreviated New Drug Application (ANDA). The FDA approval of an ANDA requires evidence from a manufacturer that their production of a generic small-molecule drug is bioequivalent to the existing name-brand drug.[17] Generic drug applications are considered abbreviated because the FDA does not require pre-clinical and clinical trials to be performed. Exclusivity for ANDAs may be granted for 180 days during a patent challenge by a generic drug manufacturer and 180 days for competitive generic therapy.
However, biologics are regulated under different rules and require submission of an abbreviated Biologics License Application (aBLA). Generic biologics, or biosimilars, may differ considerably in molecular structure from the original biologic, unlike generic small-molecule drugs.[18] Manufacturers must prove that a biosimilar exhibits equivalent safety and efficacy as the name-brand biologic despite having molecular heterogeneity. All manufacturers must adhere to GMP regulations set in place by the FDA to ensure quality and safety during medication production. Likewise, Good Clinical Practice (GCP) is the norm for designing, performing, conducting, monitoring, auditing, recording, analyzing, and reporting clinical trials. The goal of GCP is to protect the integrity, confidentiality, and rights of trial participants and to assure the precision of data and documented results.[19]
Due to the stringent requirements set by the FDA, some studies have revealed the issue of “drug lag” in the US markets. Particularly in the 1970s, new drugs were often approved and marketed far earlier in European markets than in US markets.[20] This resulted from increased regulatory standards in the US, which increased the time required to verify drug safety. Therefore, while European consumers were already using novel medications, US consumers often could not access these drugs. The duration of clinical trials continues to increase across all phases as the scope of federal regulations continues to expand, which may continue to hinder the ability of the FDA to approve medications promptly. However, some evidence suggests that the burden of drug lag has decreased in recent years as federal regulations on the pharmaceutical industry have evolved.[21]
The increasing cost of performing clinical trials creates another significant barrier to approving new drugs. The average price of conducting a clinical trial is nearly $48 million per drug.[6] One reason for the rising costs of clinical trials includes increasing clinical procedures and administrative staff needed throughout each trial.[22] Greater disease complexity, increasing comparator drugs, and higher failure risk contribute to the growing costs of clinical trials. The rising costs may adversely affect drug manufacturers, leading to fewer new drugs for consumers and decreased pharmaceutical innovation.
The regulations provided by the FDA have assured the production of safe and efficacious medications for consumers. For instance, the Kefauver-Harris Amendment, also known as the "Drug Efficacy Amendment," required pharmaceutical companies to show evidence of drug efficacy before approval. The legislation also worked to prevent the rebranding of generic drugs as breakthrough drugs at a higher price. As a result of modern drug regulations, physicians and pharmacists can inform patients about adverse effects, safe dosages, and the proven effectiveness of medicines in treating disease. In addition, drug sponsors must monitor adverse drug reactions through the FAERS to safeguard clinical trial participants and consumers.[23] Historically, the FDA has stopped drug trials prematurely due to high rates of adverse events in concordance with such reporting systems. Thus, patient safety is the foundation of many laws governing drug development.
Government oversight of intellectual property laws also has clinical implications. Drug manufacturers are allowed drug data exclusivity for several years, during which the manufacturer can recoup the enormous costs associated with research and clinical trials. Data exclusivity promotes pharmaceutical innovation so that novel drugs are created for consumers. Privatized drug innovation is balanced by producing cheaper generic drugs after data exclusivity ends. Clinicians are, therefore, able to prescribe more affordable generic medicines to their patients without compromising drug efficacy. The regulations for generic drugs provide significantly better health care to consumers from lower socioeconomic backgrounds.
Federal regulations have evolved to improve consumer safety. As mentioned, the FDA attempts to balance pharmaceutical drug innovation with public access to affordable medicines. The processes involved have implications for physicians and pharmacists prescribing medications. Physicians and pharmacists need to consider the bioequivalence of generic drugs when prescribing and educating patients. Furthermore, health professionals researching novel drugs should know drug development processes and federal regulations. A better understanding of these regulations by physicians and pharmacists alike will enhance the complex drug development process.
Barkan ID. Industry invites regulation: the passage of the Pure Food and Drug Act of 1906. Am J Public Health. 1985 Jan; 75 (1):18-26. [PMC free article : PMC1646146 ] [PubMed : 3881052 ]
Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995 Mar 15; 122 (6):456-61. [PubMed : 7856995 ]
Swann JP. FDA and the practice of pharmacy: prescription drug regulation before the Durham-Humphrey Amendment of 1951. Pharm Hist. 1994; 36 (2):55-70. [PubMed : 11613485 ]
Greene JA, Podolsky SH. Reform, regulation, and pharmaceuticals--the Kefauver-Harris Amendments at 50. N Engl J Med. 2012 Oct 18; 367 (16):1481-3. [PMC free article : PMC4101807 ] [PubMed : 23075174 ]
Holbein ME. Understanding FDA regulatory requirements for investigational new drug applications for sponsor-investigators. J Investig Med. 2009 Aug; 57 (6):688-94. [PMC free article : PMC4435682 ] [PubMed : 19602987 ]
Moore TJ, Heyward J, Anderson G, Alexander GC. Variation in the estimated costs of pivotal clinical benefit trials supporting the US approval of new therapeutic agents, 2015-2017: a cross-sectional study. BMJ Open. 2020 Jun 11; 10 (6):e038863. [PMC free article : PMC7295430 ] [PubMed : 32532786 ]
Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019 Apr 01; 20 (2):273-286. [PMC free article : PMC6409418 ] [PubMed : 29394327 ]
Umscheid CA, Margolis DJ, Grossman CE. Key concepts of clinical trials: a narrative review. Postgrad Med. 2011 Sep; 123 (5):194-204. [PMC free article : PMC3272827 ] [PubMed : 21904102 ]
Hearns-Stewart RM, Farley J, Lee KJ, Connelly S, Lowy N, Stein P, Bugin K. The Integrated Review: FDA Modernizes the Review of New Drug Marketing Applications. Ther Innov Regul Sci. 2021 May; 55 (3):467-472. [PubMed : 33236259 ]
Hwang TJ, Darrow JJ, Kesselheim AS. The FDA's Expedited Programs and Clinical Development Times for Novel Therapeutics, 2012-2016. JAMA. 2017 Dec 05; 318 (21):2137-2138. [PMC free article : PMC5820715 ] [PubMed : 29209711 ]
Kantor A, Haga SB. The Potential Benefit of Expedited Development and Approval Programs in Precision Medicine. J Pers Med. 2021 Jan 14; 11 (1) [PMC free article : PMC7828670 ] [PubMed : 33466644 ]
Toyserkani GA, Huynh L, Morrato EH. Adaptation for Regulatory Application: A Content Analysis of FDA Risk Evaluation and Mitigation Strategies Assessment Plans (2014-2018) Using RE-AIM. Front Public Health. 2020; 8 :43. [PMC free article : PMC7052173 ] [PubMed : 32158741 ]
Prevost N, English JC. Isotretinoin: update on controversial issues. J Pediatr Adolesc Gynecol. 2013 Oct; 26 (5):290-3. [PubMed : 24147278 ]
Huynh L, Toyserkani GA, Morrato EH. Pragmatic applications of implementation science frameworks to regulatory science: an assessment of FDA Risk Evaluation and Mitigation Strategies (REMS) (2014-2018). BMC Health Serv Res. 2021 Aug 06; 21 (1):779. [PMC free article : PMC8348874 ] [PubMed : 34362367 ]
Goldman DP, Lakdawalla DN, Malkin JD, Romley J, Philipson T. The benefits from giving makers of conventional 'small molecule' drugs longer exclusivity over clinical trial data. Health Aff (Millwood). 2011 Jan; 30 (1):84-90. [PMC free article : PMC3804334 ] [PubMed : 21209443 ]
Herder M. What Is the Purpose of the Orphan Drug Act? PLoS Med. 2017 Jan; 14 (1):e1002191. [PMC free article : PMC5207521 ] [PubMed : 28045908 ]
Wittayanukorn S, Rosenberg M, Schick A, Hu M, Wang Z, Babiskin A, Lionberger R, Zhao L. Factors that have an Impact on Abbreviated New Drug Application (ANDA) Submissions. Ther Innov Regul Sci. 2020 Nov; 54 (6):1372-1381. [PubMed : 32495310 ]
Rumore MM, Randy Vogenberg F. Biosimilars: Still Not Quite Ready for Prime Time. P T. 2016 Jun; 41 (6):366-75. [PMC free article : PMC4894513 ] [PubMed : 27313434 ]
Arango J, Chuck T, Ellenberg SS, Foltz B, Gorman C, Hinrichs H, McHale S, Merchant K, Seltzer J, Shapley S, Wild G. Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency. Ther Innov Regul Sci. 2016 Jul; 50 (4):480-486. [PMC free article : PMC4923807 ] [PubMed : 27390628 ]
Wardell WM. Introduction of new therapeutic drugs in the United States and Great Britain: an international comparison. Clin Pharmacol Ther. 1973 Sep-Oct; 14 (5):773-90. [PubMed : 4147119 ]
Wileman H, Mishra A. Drug lag and key regulatory barriers in the emerging markets. Perspect Clin Res. 2010 Apr; 1 (2):51-6. [PMC free article : PMC3148610 ] [PubMed : 21829782 ]
Sertkaya A, Wong HH, Jessup A, Beleche T. Key cost drivers of pharmaceutical clinical trials in the United States. Clin Trials. 2016 Apr; 13 (2):117-26. [PubMed : 26908540 ]
Sakaeda T, Tamon A, Kadoyama K, Okuno Y. Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci. 2013; 10 (7):796-803. [PMC free article : PMC3689877 ] [PubMed : 23794943 ]
Disclosure: Phillip Zhang declares no relevant financial relationships with ineligible companies.
Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.
Disclosure: Nicole Winston declares no relevant financial relationships with ineligible companies.
