The United States Food and Durg Administration (FDA) charter exists in the US statues and has as its main priority the safety of the public. Prior to 1906, literally thousands of so-called remedies for diseases were sold all over the United States, everywhere to everyone. These medicines usually had large amounts of alcohol of narcotics as their main ingredient. In 1906 Theodore Roosevelt signed into law the Food, Drug and Cosmetics Act. In this bill, the Bureau of Chemistry was given the mandate to prohibit the adulteration and misbranding of food and drugs. The bill stated that food and drug labeling could not be false or misleading, and furthermore, dangerous ingredients such as alcohol, heroin and cocaine had to be listed on the label. Unfortunately, this bill did not provide enough oversight. The misbranding and adulteration of drugs increased greatly during the 1920s and 1930s. During this period, a tonic was found to contain radium that led to slow, painful deaths. An eyelash dye blinded many women. In 1937, a drug company sold a new sulfa drug elixir for pediatric patients and others who had difficulty swallowing pills or capsules. Called “Elixir Sulfanilamide” it contained a solvent that was a chemical analogue of antifreeze. The drug killed over 100 individuals. Consumer protection organizations aided by journalists at the time compelled congress to pass a new bill that would allow for legally mandated quality and identity standards for food, prohibit false drug claims, and include cosmetics and medical devices within their oversight. The new law also mandated premarket approval of new drugs. Before a drug could be marketed, pharmaceutical companies would have to give evidence to the government that a drug was safe. The FDA came into being when Franklin D. Roosevelt singed the Food and Drug Act on June 30, 1938. This law was tightened by the passage of the Kefauver-Harris Amendments in 1962. These amendments stated that the FDA must assess the efficacy of all drugs and the FDA, not the Federal Trade Commission, should regulate prescription drug advertising. In 1984 the FDA passed regulations that allowed the agency to approve generic, low-cost versions of brand name drugs without repeating research that had already been conducted to prove the safety of a particular drug. In this case, bioequivalence was to be proven. In the 1990s laws were passed that forced clear information on ingredients and safety on food labels. During this time the FDA as well as the NIH mandated that clinical studies enroll sufficient groups of women, children and minority groups as evidence revealed that these groups responded to drugs differently that white males. The clinical design of studies was to include all groups of individuals to truly represent the US population. Vaccine approval study designed to show safety and efficacy were also strengthened. It was recognized that pregnancy was not an exclusion criterion in clinical premarketing studies. Throughout its existence the FDA has the mandate to protect the safety of the public.The FDA utilizes Advisory Committees composed of outside experts in science, medicine, statistics, chemistry, and biology as well as public members, industry representatives and patient advocates to assist in decisions by providing advice on complex scientific, technical and policy issues. These meetings are open to the public and meeting materials are available at least two days prior to meetings.These meetings are convened when data presented to the FDA is unclear in support of approval or disproval of a particular drug or device or if the risk/benefit is unclear.The Obstetrics, Reproduction and Urology Committee and the Obstetrics and Gynecology Devices Panel are two committees of interest to reproductive scientists.The members of Advisory Committees give non -binding advice to FDA who makes the final decision The FDA has outlined clear stages in drug development which have been refined overtime as science has become more complex. These stages are based on scientific evidence. As science is a process and new facts as discovered continually, these outlines will change as needed.The first sage is Discovery which occrus in the laboratory. New sights into disease processes, tests of many molecular compounds, new technologies and a new use of existing drugs all factor into this stage of development. Many new developments are generated in studies conducted in research universities.The next stage is Development. During this stage the absorption, distribution, metabolism and excretion of the drug in animals is examined. The potential benefits, and mechanisms of action are determined, the best dosage and the best administration (oral, injection, intravenous) is determined. Side effects and drug interactions are determined. The question as to how the drug effects racial, ethnical groups and men and women is answered. Finally, the new drug’s equivalency with current drugs is studied. At this point in time the drug is evaluated in Preclinical Research. In this stage toxicity is studied, both in vitro and in vivo. The FDA reviews the study conduct, personnel, facilities, equipment, written protocol, operative procedures, insists on good lab practice (which is a professional consensus document) Throughout this stage the study reports are reviewed and quality assurance and safety are factored into the evaluation. At this stage many potential drugs are eliminated. Then the potential drug is ready for clinical trials in humans. Phase 1 clinical trials are designed to prove that the drug is safe and the best dosage. The number of subjects in these trials is small. They are designed to show that the drug is deemed safe for humans. Following this a phase 2 study is conducted. During this phase several hundred subjects are enrolled and efficacy and side effects are evaluated. If this study shows that the drug treatment goals of a positive outcome and has minimal side-effects, a phase 3 clinical study enrolling hundreds to thousands of subjects and lasting several years designed to fully test efficacy is conducted. During this phase clinical adverse events are monitored carefully. The FDA approves the beginning of all clinical trials and monitors the progression of the study. It may delay or stop the investigation following interval evaluations. These interval evaluations consider a statistical review of outcomes and adverse events during a review by a Data Monitoring and Safety Committee by scientific experts who are not involved in the study. Examples of situations where a study is stopped are: a serious life-threatening adverse event such as death or serious injury; review of the study outcomes show such positive outcomes that it is not necessary to continue the study to determine statistical significance. Alternatively, a study would be stopped if the statistical evaluation showed that the drug is harmful and that continuation of the study would not change the outcome. A company applying for approval of a new drug must provide adequate data form two large controlled clinical studies. Controlled studies carefully determine prior to the study what the comparison group will be. For instance. if the study drug is for a product that would treat a disease for which an effective drug is already approved, the proper control is to compare the new drug to the existing one. In this case a placebo trial would be unethical as it would not provide individuals with a known treatment. There can be exceptions to this general ethical consensus for various reasons such as a short trial. In any case subjects must be aware of all the risks as well as benefits of the study and its design and provide consent to be enrolled in the study. The FDA reviews all study reports, safety update reports, proposed labeling, drug abuse information, patient information inserts, IRB, (Internal Review Board) compliance from the institution or institutions conducting the studies and data from studies conducted outside the USA. A new drug review takes usually six to ten months. However, when a situation is deemed urgent an expedited review is able to be granted. A generic drug which is chemically equivalent to a trade-marked drug must show that the same dosage, is effective at the equivalent dosage, same side effect profile, and demonstrate good quality manufacturing practices. When a drug is approved by the FDA a post marketing evaluation is started. During this review the FDA conducts continued safety monitoring, inspects manufacturing facilities and looks at drug advertising to make sure it is true to the evidence. Reporting tools such as MedWatch and others that use electronic medical records also inform the FDA about safety and efficacy. If the FDA discovers that a drug no longer is safe or efficacious, it is able to withdraw the drug. A recent example of such action was when the FDA after a complete review including input from the appropriate Advisory Committee withdraw a progesterone drug marketed as a treatment for the prevention of preterm labor. Large international clinical studies demonstrated that the drug did not do what it was thought to do. It did now show that the drug prevented preterm birth. The FDA released its final decision for approval withdrawal following an Advisory Committee that made this recommendation. Throughout its existence the FDA has the mandate to protect the safety of the public. As science has progressed and become more complex the federal agency has continued to refine the process of assuring the health and welfare of the population.
Additional Reading:
Abbas-Hanif A, Rezai H, Ahmed SF, Ahmed A. The impact of COVID-19 on pregnancy and therapeutic drug development. Br J Pharmacol. 2022 May;179(10):2108-2120. doi: 10.1111/bph.15582. Epub 2021 Jul 6. PMID: 34085281; PMCID: PMC8239854.
Gholap AD, Uddin MJ, Faiyazuddin M, Omri A, Gowri S, Khalid M. Advances in artificial intelligence for drug delivery and development: A comprehensive review. Comput Biol Med. 2024 Aug;178:108702. doi: 10.1016/j.compbiomed.2024.108702. Epub 2024 Jun 7. PMID: 38878397.
Ma C, Peng Y, Li H, Chen W. Organ-on-a-Chip: A New Paradigm for Drug Development. Trends Pharmacol Sci. 2021 Feb;42(2):119-133. doi: 10.1016/j.tips.2020.11.009. Epub 2020 Dec 16. PMID: 33341248; PMCID: PMC7990030.
Michaeli DT, Michaeli T, Albers S, Boch T, Michaeli JC. Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. Eur J Health Econ. 2024 Aug;25(6):979-997. doi: 10.1007/s10198-023-01639-x. Epub 2023 Nov 14. PMID: 37962724; PMCID: PMC11283430.
Yellepeddi V, Rower J, Liu X, Kumar S, Rashid J, Sherwin CMT. State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development. Clin Pharmacokinet. 2019 Jan;58(1):1-13. doi: 10.1007/s40262-018-0677-y. PMID: 29777528.
Zhang Y, Mastouri M, Zhang Y. Accelerating drug discovery, development, and clinical trials by artificial intelligence. Med. 2024 Sep 13;5(9):1050-1070. doi: 10.1016/j.medj.2024.07.026. Epub 2024 Aug 21. PMID: 39173629.
Websites:https://www.drugs.com/fda-approval-process.html
https://www.fda.gov/patients/learn-about-fda-advisory-committees