PHS 2101 - Chapter 24

• History of the FDA

  • Bureau of Chemistry in Dept. of Agriculture

  • 1906 Pure Food and Drug Act

  • Prohibited transport and trade of “adulterated and misbranded food and drugs”
• Early 1900s


  • Patent or proprietary medicines

  – Unproven claims

  – Dangerous substances

  – Sugar water

  • Emergence of pharmacology, toxicology, clinical research > modern medicine

  • 1906: Pure Food and Drug Act

  – only required accurate and complete list of

  ingredients
• Pure Food and Drug Act, 1906


  • Accurate listing of ingredients

  • Physician’s prescription NOT required

  • No mandate for testing before marketing for safety and efficacy
• 1937

  • Elixir Sulfanilamide mixed with diethylene glycol

  • 107 people died

  • Congress passed Food, Drug and Cosmetic Act

  • Drugs must be proved to be safe for use as labelled

  • Manufacturer responsible for presenting data to FDA re: safety

  • Pre-market review
• Food, Drug and Cosmetic Act, 1938


  • Evidence that drug was not toxic

  • Did NOT mandate evidence for efficacy

  • FDA had only 60 days to take action before drug could be marketed
• 1950s

  • Thallidomide: antiemetic agent and sedative

  • Pregnant women

  • Highly teratogenic > severe defect of limb development

  • Frances Kelsey, reviewer at FDA, denied approval for distribution in U.S.

  – Sponsor did not present pharmacologic and toxicologic data about drug
• DES

  • Diethylstilbesterol promoted to prevent miscarriage

  • 1953 randomized controlled study showed it was ineffective; marketed anyway

  • Serious adverse effects of exposure in utero

  – Risk of rare vaginal adenocarcinomas in young girls

  • Needless exposure of 5-10 million women and children
• 1962 Kefauver-Harris Amendments


  • Drug manufacturers must provide substantial evidence of efficacy based on “adequate and well-controlled studies”

  • Established standards of evidence

  • Increased likelihood that drug worked

  • 70% of drug claims could not be substantiated

  • 1/3 of marketed drugs lacked even a single effect
• FDA Standards

  • Establish rigorous testing methods and analysis: regulatory science

  • Randomized controlled clinical trials carried out by drug sponsor

  • Rigorous review by experts at FDA

  • Promote innovation and progress in drug development
• Safety and Efficacy

  • Safety:

  – benefit is greater than risk

  – Adverse events, how severe, how prevalent

  • Benefit: produces the effect intended

  – Measured by some outcome(s)

  – Must be retested if used for different application, e.g. hydroxychloroquine for treating COVID
• How much testing is enough?

  • Balance between rigorous testing and timely release of innovative therapies

  • Kefauver Harris Amendments 1962 delineate the process for required testing and submission of applications to FDA
• Testing of New Drugs

  • Preclinical

  – Submit results of testing in animals in an Investigational New Drug Application to proceed to Clinical Trials in humans

  • Clinical

  – Phase 1

  – Phase 2

  – Phase 3

  – Submit results in New Drug Application for approval to market
• Phase 1


  • 20-60 healthy volunteers

  • Pharmacokinetics, pharmacodynamics of drugs in human body

  • Assess safety at varying doses

  • Preliminary evidence of efficacy
• Phase 2


  • Few hundred participants with condition to be treated

  • Evaluation of adverse effects

  • Efficacy for intended purpose

  • Surrogate measures

  • No control group

  • Not blinded

  • Not randomized
• Phase 3

  • Several hundred to several thousand participants

  • Evidence that Benefit>Risk

  • Multiple sites and researchers

  • Placebo-controlled group vs. experimental group

  • Randomization

  • Blinding

  • Outcome measures

  – Extension life expectancy

  – Physiological indicator of improved health
• Laws aimed to Increase Patient Access to Treatments

  • Patients with diseases for which there is no effective therapy or where existing therapies have failed

  • Expanded access: “compassionate care;” “right to try”

  • Expedited approval:

  – Fast Track Program 1988

  – Accelerated Approval 1992 (surrogate markers)

  – 21st Century Cures Act 2016 (expand surrogate/predictive markers for approval)
• FDA Review Process

  • Requires expert personnel – costly

  • Number of new drugs to be reviewed increases, review time increases

  • Prescription Drug User Fee Act 1992

  – Expedited review for fee paid by sponsor

  – Concern about conflict of interest

  • Breakthrough Therapies 2012

  – Greater FDA attention to expedite development/approval of innovative drugs
• Hatch Waxman Act 1984: Generic Drugs


  • Patented medications and exclusivity

  • Generic drugs: companies do not have research and development costs

  • Full clinical trials not required if they are identical in their active ingredients, dosage, route of administration and exhibit similar response (Bioequivalence)

  • Abbreviated New Drug Applications

  – Must present data that it produces same effects as patented drug
• 2007 FDA Amendments Act


  • Even large clinical trials contain narrow subset of patients

  • In populations who will use drugs, heterogeneity, e.g. age

  – Adverse events occurring at low frequency would not be observed (e.g. 1 event in 1,000,000 cases)

  – New adverse effects can occur in diverse pop.

  • Active Postmarketing Surveillance

  – More difficult than clinical trials

  • Continue to track adverse events

  • Aggregate data from millions of patients from data collected by insurers, government agencies
• FDA Responsibilities 


  • Public Health

  • FDA: drug approval for marketing is ONE of its responsibilities

  • Post-marketing surveillance

  • Oversight of advertising and promotion of drugs

  • Develop expertise in emerging areas of science

  • Control of surging drug costs
• Globalization and the FDA

  • FDA oversees products from 150 countries, 130,000 importers and 300,000 foreign facilities

  • 20 million shipments of food, drugs, devices, cosmetics per year

  • 10-15% U.S. food supply

  • 50% fresh fruits, 20% vegetables, 80% seafood

  • 40 % finished drugs

  • 80 % active pharmaceutical ingredients

  • 35% medical devices
• Questions/Controversies

  • Intensification of relationship between industry and regulatory agency

  – Conflicts of interest

  – User fees

  • Increasing reliance on external experts

  • FDA as counterpart to pharmaceutical industry as “protector and promoter of public health”