Background of the Food and Drug Administration
Creation of the Food and Drug Administration
CDER World: pediatric drug development. 2020.
- Francis M.
- (1)The 1938 Federal Food, Drug, and Cosmetic (FD&C) Act required drug sponsors to establish safety before the marketing of new drugs and required submission of a new drug application to the FDA before marketing. The FD&C Act was spurred by the sulfanilamide tragedy, an antimicrobial agent that was dissolved in a sweet-tasting liquid targeted to pediatric patients. The drug sponsor did not conduct toxicity testing on the sweet solvent, which contained ethylene glycol (antifreeze), and it caused over 100 deaths, including that of many children.4US Food and Drug Administration
Part II: 1938, Food, Drug, Cosmetic Act. 2018.https://www.fda.gov/about-fda/fdas-evolving-regulatory-powers/part-ii-1938-food-drug-cosmetic-actDate accessed: January 6, 2021
- (2)The 1962-Kefauver-Harris Amendments required drug sponsors to establish the efficacy of new drugs, in addition to safety, and required that the FDA give positive approval before new drugs could be marketed. Thanks to Dr Frances O. Kelsey’s careful review of the safety of thalidomide, a sedative for pregnant women that was highly teratogenic, this drug was never marketed in the United States, averting the clusters of rare, severe birth defects in thousands of babies seen in other countries.5The avoidance of a near disaster propelled passage of these amendments and fundamentally changed drug regulation.Changing the Face of Medicine
Dr. Frances Kathleen Oldham Kelsey. 2015.
Current Food and Drug Administration organization
Fact sheet: FDA at a glance. 2020.
Drug development and the Food and Drug Administration drug review process
Guidance on Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. 2009.
Preclinical safety evaluation of Biotechnology-Derived Pharmaceuticals. 2011.
Guidance for industry: reproductive and developmental toxicities—integrating study results to assess concerns. 2011.
Detection of reproductive and developmental toxicity for human pharmaceuticals. 2020.
- (1)Male and female fertility: damage to reproductive organs, alterations in endocrine regulation or function, effects on sperm count, motility, or morphology, mating behavior or the ability to mate, reduction in fertility, and effects on estrous cycling;
- (2)Parturition: abnormal or difficult delivery (dystocia) or changes in the onset and duration of parturition;
- (3)Lactation: concentration of the drug in breast milk through sampling; effects on the quantity and quality of milk would manifest as abnormal growth and development of the offspring.
- (1)Mortality: pre-or postimplantation loss, early or late resorption, abortion, stillbirth, neonatal death, or postweaning loss;
- (2)Dysmorphogenesis (structural abnormalities): skeletal or soft tissue malformations or variations in the offspring;
- (3)Alterations in growth: growth retardation, excessive growth, early maturation (via measurement of body weight, crown-rump length, and anogenital distance);
- (4)Functional impairment: developmental neurobehavioral effects and reproductive function of offspring as measured through assessments on locomotor activity, learning and memory, reflex development, time to sexual maturation, mating behavior, and fertility.
Guidance for industry: nonclinical safety evaluation of pediatric drug products. 2006.
Nonclinical safety testing in support of development of pediatric pharmaceuticals. 2020.
Benefit and risk assessment in the Food and Drug Administration’s decision making
Analysis of the target condition and available treatment
Assessment of benefits and risks
Approved labeling for indomethacin.
|Dimension||Evidence and uncertainties||Conclusions and reasons|
|Analysis of condition|
Questions to consider:
|Preeclampsia affects 2%–8% of pregnant women worldwide.|
Potentially life-threatening: can cause vascular, hematologic, hepatic and renal injury; preeclampsia and eclampsia account for 10%–15% of direct maternal deaths.
Preeclampsia: clinical features and diagnosis. 2019.
Date accessed: January 6, 2021
A previous history of preeclampsia is a major risk factor for recurrent preeclampsia, although not all women will experience a recurrence.
Fetal consequences can include growth restriction, oligohydramnios, placental abruption, nonreassuring fetal status, increased risk for spontaneous or indicated preterm delivery.
|Preeclampsia is a major public health concern and is a potentially life-threatening condition to both pregnant women and their fetuses.|
Questions to consider:
Unmet medical need? Treatment options available?
|No approved treatment.|
Professional guidelines recommend off-label use of low-dose aspirin initiated between 12 and 28 wk of gestation and continuing until delivery.
|This is an area of unmet medical need with no approved treatment.|
Questions to consider:
Benefit to woman, fetus or both?
|Patients with a history of preeclampsia treated with Normotensive had a lower relative risk of developing recurrent preeclampsia than those treated with the placebo (RR, 0.7; 95% CI, 0.5–0.9).|
Patients with a history of preeclampsia treated with Normotensive had a lower relative risk of developing recurrent preeclampsia with severe features than those treated with placebo (RR, 0.8; 95% CI, 0.7–0.9).
Neonates born to patients treated with Normotensive had a lower risk of fetal growth restriction than those treated with placebo (RR, 0.8; 95% CI, 0.7–0.9).
No differences were seen between the treatment groups in the gestational age at delivery.
|Benefits of Normotensive outweighs its risks.|
The drug label will recommend that neonates be observed in a monitored unit for at least 24 h after birth for respiratory complications.
Required postmarketing study: evaluate safety outcomes of neonates to 2 y of age.
|Risk and risk management|
Questions to consider:
Risk to mother? Risk to fetus?
Ways to mitigate risks?
|Patients treated with Normotensive gave birth to neonates with a higher incidence of neonatal respiratory distress syndrome, requiring intubation (5%), than placebo (1%).|
Otherwise, there are no substantial differences in other serious risks in fetuses or neonates or pregnant women.
Food and Drug Administration Advisory Committee meetings
CFR - Code of Federal Regulations Title 21: CFR 14.80(b)(1). 2020.
About advisory committees. 2018.
Food and Drug Administration approval
Demonstrating substantial evidence of effectiveness for human drug and biological products guidance for industry. 2019.
CFR - Code of Federal Regulations 21: CFR 314.126(b). 2020.
Types of drug approval
- (1)Traditional: this is the most common pathway for drug approval. A marketing application receives traditional (regular) approval when substantial evidence of the effectiveness of a drug on a clinical endpoint is demonstrated, such as 1 that directly measures how patients feel, function, or survive (ie, clinical benefit). An example of a clinical endpoint is the death rate linked to cardiovascular causes for a drug intended to treat congestive heart failure. Traditional approval can also be granted when a drug demonstrates effectiveness on a validated surrogate endpoint. Unlike clinical endpoints, surrogate endpoints do not directly measure how patients feel, function, or survive. A surrogate endpoint that is validated, however, is known to predict clinical benefit. For instance, a reduction in blood pressure, which does not directly measure patient survival, is known to reduce the risk for cardiovascular death.
- (2)Accelerated: the accelerated approval pathway, instituted in 1992 in response to the HIV and AIDS epidemic, is intended to speed up the availability of promising therapies that treat serious or life-threatening conditions and that seem to provide an advantage over other available therapies. This approval pathway is especially useful when the drug treats a disease with a long disease course and an extended period is needed to measure its effect. This approval pathway must meet the same statutory evidentiary standards for safety and effectiveness–substantial evidence of the effectiveness of the drug and benefits of the drug that outweigh its risks–as those for traditional approval.
Makena (hydroxyprogesterone caproate injection) information. 2020.
Food and Drug Administration-approved drug label
Pregnancy and lactation labeling rule
Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling; 2014.
Pregnancy, lactation and reproductive potential: labeling for human prescription drug and biological products—content and format guidance for industry. 2020.
- (1)Pregnancy subsection 8.1: in lieu of a pregnancy letter category, the pregnancy subsection 8.1 now contains summaries of the pertinent available evidence informing the safety of the drug in pregnancy. This subsection includes information on pregnancy exposure registries, if available, including how to enroll in the registry or obtain information about the registry. The risk summary informs decision making about drug use during pregnancy and sums up the risks for adverse developmental outcomes based on the available and relevant human data, animal data, and/or the drug’s pharmacology. The risk summary also includes a statement referring to the background risk for major birth defects and miscarriages in the United States. This statement is to convey that there is a baseline risk for these adverse outcomes without drug exposure. The clinical considerations section discusses disease-associated maternal and embryofetal risks, dose adjustments during pregnancy and the postpartum period, maternal adverse reactions, fetal or neonatal adverse reactions, and effects on labor and delivery. Finally, human and animal data supporting the risk summary are presented. Harking back to similar outcomes evaluated in nonclinical studies, adverse developmental outcomes here include structural abnormalities, embryofetal or infant mortality, functional impairments, and alterations to growth.
- (2)Lactation subsection 8.2: this subsection includes the risk summary of information about the presence of a drug and its active metabolite(s) in human breast milk, the effects of a drug and its active metabolite(s) on a breastfed child, and the effects of a drug and its active metabolite(s) on milk production. This includes a risk and benefit statement providing a framework for healthcare providers and lactating women to use when considering the benefits of breastfeeding to the mother and infant and the mother’s need for treatment and benefits vs potential risks to the infant. Clinical considerations include minimizing exposure of the breastfed infant to the drug and monitoring for adverse reactions. Again, human and/or animal data are presented.
- (3)Females and males of reproductive potential subsection 8.3: this section discusses information about the need for pregnancy testing, contraception recommendations, and information about infertility as it relates to the drug.
Pregnancy registries. 2018.
Prescription drugs in pregnancy
Drugs approved for obstetrical indications
- (1)Methergine (methylergonovine maleate)–approved in 1946 based on the safety data for use following delivery of the placenta, for routine management of uterine atony, hemorrhage and subinvolution of the uterus, and for control of uterine hemorrhage during the second stage of labor following delivery of the anterior shoulder. The effectiveness of the drug was reviewed under the FDA’s Drug Efficacy Study Implementation (DESI); Methergine was determined to be effective for its intended uses in 1968.
- (2)Syntocinon (oxytocin nasal spray)–approved based on safety data in 1960 and found to be effective for “initial milk letdown” in 1968, also through a DESI proceeding.
- (3)Pitocin (oxytocin for intramuscular or intravenous administration)–approved in 1980 for the “initiation or improvement of uterine contractions and to control postpartum bleeding.”
- (4)Yutopar (ritodrine)–approved in 1980 as a tocolytic, but it is no longer marketed.
- (5)Prepidil (dinoprostone)–approved in 1992 “for ripening an unfavorable cervix in pregnant women at or near term with a medical or obstetrical need for labor induction.”
- (6)Cervidil (dinoprostone)–approved in 1995 “for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor.”
- (7)Magnesium sulfate–approved in 1995 for the “prevention and control of seizures in preeclampsia and eclampsia, respectively.”
- (8)Makena (hydroxyprogestserone caproate)–gained accelerated approval in 2011 “to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.”
- (9)Diclegis (doxylamine succinate and pyridoxine hydrochloride) –approved in 2014 (a product with the same combination of doxylamine and pyridoxine that had been marketed as Bendectin (1976) until 1983) “for the treatment of nausea and vomiting of pregnancy in women who do not respond to conservative management.”
Drugs prescribed for approved indications during pregnancy
Approved drugs prescribed for unapproved uses in pregnancy
- (1)Reviewer Guidance–Evaluating the Risks of Drug Exposure in Human Pregnancies.31This guidance is intended to help the FDA staff evaluate human fetal outcome data generated after medical product exposures during pregnancy. The goal of such evaluations is to assist in the development of product labeling that is useful to healthcare providers when they care for patients who are pregnant or planning to become pregnant. The review of human pregnancy drug exposure data and assessment of fetal risk (or lack of risk) requires consideration of human embryology and teratology, pharmacology, obstetrics, and epidemiology.US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
Reviewer guidance: evaluating the risks of drug exposure in human pregnancies. 2005.
- (2)Guidance for Industry–Pharmacokinetics in pregnancy–Study Design, Data Analysis, and Impact on Dosing and Labeling.32This guidance describes a basic framework for designing and conducting pharmacokinetic and pharmacodynamic studies in pregnant women. It provides recommendations to drug companies about how to assess the influence of pregnancy on the pharmacokinetics, and, where appropriate, the pharmacodynamics of drugs or biological products and vaccines. In addition, this guidance provides recommendations to clinical researchers and clinical pharmacologists about the issues to consider when designing and conducting pharmacokinetic studies in pregnant women.US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
Guidance for industry: pharmacokinetics in pregnancy—study design, data, analysis, and impact on dosing and labeling. 2004.
- (3)The draft guidance “Pregnant Women: Scientific and Ethical considerations for Inclusion in Clinical Trials: guidance for Industry.”33The FDA endorses an informed and balanced approach to gathering data informing the safe and effective use of drugs and biological products during pregnancy through judicious inclusion of pregnant women in clinical trials and careful attention to potential fetal risk. The guidance addresses scientific and ethical issues as they apply both to clinical trials that enroll pregnant subjects and to clinical trials that allow enrolled subjects who become pregnant to remain in the trial.US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)
Pregnant women: scientific and ethical considerations for inclusion in clinical trials guidance for industry. 2018.
- https://www.ajog.org/cms/asset/ebaad64f-05f1-457b-a617-997e93bdf7fc/mmc1.mp4Loading ...
- Task force on research specific to pregnant women and lactating women. 2018.(Available at:)Accessed December 11, 2020)
- CDER World: pediatric drug development. 2020.(Available at:)https://www.accessdata.fda.gov/scripts/cderworld/index.cfm?action=newdrugs:main&unit=4&lesson=1&topic=3Date accessed: January 6, 2021
- How Upton Sinclair’s ‘the Jungle’ unintentionally spurred food safety laws. 2020.(Available at:)https://interactive.wttw.com/playlist/2020/01/23/the-jungle-food-safetyDate accessed: January 6, 2021
- Part II: 1938, Food, Drug, Cosmetic Act. 2018.(Available at:)https://www.fda.gov/about-fda/fdas-evolving-regulatory-powers/part-ii-1938-food-drug-cosmetic-actDate accessed: January 6, 2021
- Dr. Frances Kathleen Oldham Kelsey. 2015.(Available at:)
- Fact sheet: FDA at a glance. 2020.(Available at:)
- FDA organization chart. 2020.(Available at:)
- Guidance on Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. 2009.(Available at:)
- Preclinical safety evaluation of Biotechnology-Derived Pharmaceuticals. 2011.(Available at:)
- Guidance for industry: reproductive and developmental toxicities—integrating study results to assess concerns. 2011.(Available at:)
- Detection of reproductive and developmental toxicity for human pharmaceuticals. 2020.(Available at:)https://database.ich.org/sites/default/files/S5-R3_Step4_Guideline_2020_0218_1.pdfDate accessed: December 2, 2020
- Guidance for industry: nonclinical safety evaluation of pediatric drug products. 2006.(Available at:)
- Nonclinical safety testing in support of development of pediatric pharmaceuticals. 2020.(Available at:)https://database.ich.org/sites/default/files/S11_Step4_FinalGuideline_2020_0310.pdfDate accessed: December 11, 2020
- Benefit-risk assessment in drug regulatory decision-making. Draft PDUFA Vi Implement Plan. 2018.(Available at:)Accessed January 5, 2021:(FY 2018–2022))
- Approved labeling for indomethacin.(Available at:)https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/016059s100lbl.pdfDate accessed: January 6, 2021
- Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.Obstet Gynecol. 2020; 135: e237-e260
- The global impact of pre-eclampsia and eclampsia.Semin Perinatol. 2009; 33: 130-137
- Preeclampsia: clinical features and diagnosis. 2019.(Available at:)https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosisDate accessed: January 6, 2021
- 743: low-dose aspirin use during pregnancy.Obstet Gynecol. 2018; 132: e44-e52
- CFR - Code of Federal Regulations Title 21: CFR 14.80(b)(1). 2020.(Available at:)https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=14.80Date accessed: January 6, 2021
- Association between Food and Drug Administration Advisory Committee recommendations and Agency actions, 2008-2015.Milbank Q. 2019; 97: 796-819
- About advisory committees. 2018.(Available at:)
- Demonstrating substantial evidence of effectiveness for human drug and biological products guidance for industry. 2019.(Available at:)
- CFR - Code of Federal Regulations 21: CFR 314.126(b). 2020.(Available at:)https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.126Date accessed: January 6, 2021
- Makena (hydroxyprogesterone caproate injection) information. 2020.(Available at:)https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/makena-hydroxyprogesterone-caproate-injection-informationDate accessed: January 6, 2021
- Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling; 2014.(Available at:)https://www.federalregister.gov/documents/2014/12/04/2014-28241/content-and-format-of-labeling-for-human-prescription-drug-and-biological-products-requirements-forDate accessed: January 5, 2021
- Pregnancy, lactation and reproductive potential: labeling for human prescription drug and biological products—content and format guidance for industry. 2020.(Available at:)
- Pregnancy registries. 2018.(Available at:)https://www.fda.gov/science-research/womens-health-research/pregnancy-registriesDate accessed: January 6, 2021
- Federal register: 33 Fed. Reg. 8325 (June 5, 1968). 1968.(Available at:)
- Federal register: 33 Fed. Reg. 9001 (June 19, 1968). 1968.(Available at:)
- Reviewer guidance: evaluating the risks of drug exposure in human pregnancies. 2005.(Available at:)
- Guidance for industry: pharmacokinetics in pregnancy—study design, data, analysis, and impact on dosing and labeling. 2004.(Available at:)
- Pregnant women: scientific and ethical considerations for inclusion in clinical trials guidance for industry. 2018.(Available at:)
The authors report no conflict of interest.
All authors are employees of the US Federal Government.