Some milestones in the history of US drug regulation

The idea of this post is to provide a snapshot of some milestones in the history of US drug regulation. Medicines regulation is by no means ever perfect but the legislation is constantly evolving. With each evolution, the intent is always to improve the lives of patients in some measurable way. Whether the intent is always achieved substantially or wholly is a matter for debate and deliberation.

1820 (U.S. Pharmacopoeia established)
  • Concerned about the dangers of poor-quality medicines in America, a small group of physicians came together to protect patients by forming the U.S. Pharmacopeia (USP), an independent, scientific, non-profit organisation dedicated to improving public health.
  • The U.S. Pharmacopeia, the first compendium of standard drugs for the United States was established.
  • USP published the first edition of a national, uniform set of guidelines for the best understood medicinal substances and preparations of the day.
1848 (Drug Importation Act)

Congress passed the Drug Importation Act requiring U.S. Customs Service inspection to stop the entry of adulterated drugs from overseas. This legislation recognised USP standards for strength and purity, arming inspectors at ports of entry with tools to identify drugs that were substandard or deliberately adulterated.

1862 (Bureau of Chemistry)

President Abraham Lincoln appointed Charles M. Wetherill, a chemist, to serve in the new Department of Agriculture.  This was the beginning of the Bureau of Chemistry, the predecessor to the Food and Drug Administration.

1902 (Biologics Control Act also known as the Virus-Toxin Law)

The Biologics Control Act was passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans.

1906 (The Pure Food and Drugs Act also known as the Wiley Act)
  • Congress passed the The Pure Food and Drugs Act of 1906 on 30 June 1906, signed by President Theodore Roosevelt.
  • It is also known as the Wiley Act after the consumer advocate Harvey Wiley, who largely wrote the act and became known as the “Father of the Pure Food and Drugs Act”
  • It is often considered the first (if vaccines aren’t included) of many US laws enacted to protect the health of the public from ineffective or dangerous drugs.
  • The FDA didn’t exist at this point, and the provisions of this Act were enforced by the Bureau of Chemistry of the Department of Agriculture.
  • The 1906 Act prohibited the interstate transport of unlawful food and drugs under penalty of seizure of the questionable products and/or prosecution of the responsible parties.
  • The basis of the law rested on the regulation of product labeling rather than pre-market approval.
  • Drugs, defined in accordance with the standards of strength, quality, and purity in the United States Pharmacopoeia and the National Formulary, could not be sold in any other condition unless the specific variations from the applicable standards were plainly stated on the label.
  • Also, the drug label could not be false or misleading in any particular and the presence and amount of eleven dangerous ingredients, including alcohol, heroin, and cocaine, had to be listed.
1927

The Bureau of Chemistry was reorganised into two separate entities:
i)  Food, Drug, and Insecticide Administration in which the regulatory functions were located.
ii) Bureau of Chemistry and Soils in which non-regulatory research was located.

1930 (Food and Drug Administration)

The name of the Food, Drug, and Insecticide Administration was shortened to Food and Drug Administration (FDA) under an agricultural appropriations act.

1933

FDA recommended a complete revision of the obsolete 1906 Pure Food Food and Drugs Act. The first bill was introduced into the Senate, launching a five-year legislative battle.

1937 (The sulfanilamide disaster)
  • More than 100 people in the U.S., many of them children, died after taking a fruit-flavored, antibiotic liquid, Elixir Sulfanilamide which included the poisonous solvent, diethylene glycol.
  • The company control lab had only tested the mixture for flavor, appearance, and fragrance and found it satisfactory.
  • The new formulation had not been tested for toxicity. At the time,  the food and drugs law did not require that safety studies be done on new drugs.
  • Selling toxic drugs was undoubtedly bad for business and could damage a firm’s reputation but it was not illegal.
1938 (The Federal Food, Drug, and Cosmetic (FD&C) Act) 
  • In response to the Sulfanilamide Elixir tragedy, The Federal Food, Drug, and Cosmetic (FD&C) Act of 25 June 1938 was passed by Congress.
  • The enactment of the 1938 Food, Drug, and Cosmetic Act tightened controls over drugs and food, included new consumer protection against unlawful cosmetics and medical devices, and enhanced the government’s ability to enforce the law
  • It required companies to test all new drugs to verify that they met USP standards for identity, strength, quality, and purity, and submit the data to the FDA before marketing.
  • The FD&C act allowed the FDA to inspect facilities.
  • At the time, the act had serious shortcomings e.g. manufacturers could sell a drug if the FDA didn’t act within 60 days to prevent its marketing,  and FDA had no authority to enforce good manufacturing processes.
1962 (The Thalidomide tragedy)

Thalidomide, a new sleeping pill, was found to have caused birth defects in thousands of babies born in western Europe. News reports on the role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U.S. market aroused public support for stronger drug regulation.

The Kefauver-Harris Amendments (proof of efficacy requirement added to new drug approval) 

  • Prior to 1962, drugs were approved for safety only.
  • The Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act  (sponsored in Congress by Sen. Estes Kefauver and Rep. Oren Harris) were signed into law by President John F. Kennedy.
  • They added a proof-of-efficacy requirement to new drug approval so that new drugs are required be proven to be safe and effective prior to the Food and Drug Administration’s (FDA’s) approval.
  • This landmark legislation established the scientific safeguards used today by the Food and Drug Administration (FDA) to ensure that consumers will not be the victims of unsafe and ineffective medicines.
1983 (Orphan Drug Act(ODA)) 
  • The Orphan Drug Act (ODA) was passed, enabling FDA to promote research and marketing of drugs needed for treating rare diseases.
  • In 1984 the ODA was amended, redefining rare diseases as those affecting “less than 200,000 persons in the United States” (the prevalence-based definition) or more than 200,000 persons, but for whom “there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from the sale in the United States” (a commercial viability definition)
1984 (Drug Price Competition and Patent Term Restoration act,  commonly known as the Hatch-Waxman Act)
  • The Hatch-Waxman Act established the legal and economic foundation for today’s generic pharmaceutical industry.
  • It is a comprehensive legal framework enacted by Congress in 1984 to streamline the process for generic pharmaceutical approvals and preserve incentives for innovation, including the creation of a procedure for patent litigation involving generic pharmaceuticals.
  • It is supposed to expedite the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without repeating the research done to prove them safe and effective.

Prescription Drug User Fee Act (PDUFA)
In the years preceding PDUFA, there was an increasing backlog of drugs to be reviewed, delaying drugs from entering the market.

  • The Prescription Drug User Fee Act (PDUFA) was created by Congress in 1992 and authorises FDA to collect fees from companies that produce certain human drug and biological products.
  • The act also requires FDA to use these funds to hire more reviewers to assess applications. User fees added resources for more review staff to eliminate the backlog of overdue applications and improve review timeliness.
  • FDA agreed to meet specific performance goals.
  • Since the passage of PDUFA, user fees have played an important role in expediting the drug approval process.
  • PDUFA must be reauthorised every five years, and was renewed in 1997 (PDUFA II), 2002 (PDUFA III), 2007 (PDUFA IV), and 2012 (PDUFA V) and 2017 (PDUFA VI).

Priority review

  • In 1992, under PDUFA, FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times i.e.  Standard Review and Priority Review.
  • A Priority Review designation means FDA’s goal is to take action on an application within 6 months (compared to 10 months under standard review).
  • A Priority Review designation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

Accelerated approval

  • A positive therapeutic effect that is clinically meaningful in the context of a given disease is known as “clinical benefit”.
  • Mindful of the fact that it may take an extended period of time to measure a drug’s intended clinical benefit, in 1992 FDA instituted the Accelerated Approval regulations.
  • These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
  • Using a surrogate endpoint enabled the FDA to approve these drugs faster.
1997

Food and Drug Administration Modernisation Act (FDAMA)

  • The Food and Drug Administration Modernisation Act (FDAMA), enacted on Nov. 21, 1997 amended the Federal Food, Drug, and Cosmetic Act relating to the regulation of food, drugs, devices, and biological products.
  • With the passage of FDAMA, Congress enhanced FDA’s mission in ways that recognised the Agency would be operating in a 21st century characterised by increasing technological, trade and public health complexities

Some of the most important provisions of the act are:

  • Prescription Drug User Fees
  • FDA Initiatives and Programs
  • Information on Off-label Use and Drug Economics
  • Risk-based Regulation of Medical Devices

Fast Track

  • Fast Track was introduced by the the FDAMA act.
  • Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
  • Its purpose is to get important new drugs to the patient earlier.
  • It addresses a broad range of serious conditions.
  • Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially better than available therapy.
  • Any drug being developed to treat or prevent a condition with no current therapy obviously is directed at an unmet need.
  • If there are available therapies, a fast track drug must show some advantage over available therapy.
2002 (Best Pharmaceuticals for Children Act (BPCA))

In January of 2002, Congress passed the Best Pharmaceuticals for Children Act (BPCA).

  • The 1997 FDA Modernisation Act (FDAMA) provided a 6-month extension to existing marketing exclusivity for pharmaceutical companies to study medications in pediatric populations as requested by the FDA in a Written Request (WR).
  • This left a gap for studies needed to improve peadiatric labeling for off-patent products, or for products where the manufacturer declined to perform the requested studies.
  • In 2002, the Best Pharmaceuticals for Children Act (BPCA) was signed into law, which expanded the program to include a role for the National Institutes of Health (NIH) to cover this gap.
2003 (Paediatric Research Equity Act (PREA)
  • PREA gives FDA the authority to require pediatric studies in certain drugs and biological products.
  • Studies must use appropriate formulations for each age group.
  • The goal of the studies is to obtain pediatric labeling for a product.
2012 (Food and Drug Administration Safety Innovations Act (FDASIA)

In July 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). This Act expands the FDA’s authorities and strengthens the agency’s ability to safeguard and advance public health by:

  • Giving FDA the authority  to collect user fees from industry to fund reviews of innovator drugs, medical devices, generic drugs and biosimilar biological products
  • Promoting innovation to speed patient access to safe and effective products e.g via breakthrough therapy designation (see below)
  • Increasing stakeholder involvement ensuring that interested parties have a variety of opportunities to provide input to FDA decision-making
  • Enhancing the safety of the drug supply chain.

Breakthrough therapy 

  • FDASIA gave FDA a new and powerful expedited drug development tool, known as the ‘breakthrough therapy‘ designation.
  • Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

Generic Drugs User Fee Amendments (GDUFA)

  • Congress first enacted GDUFA in 2012, following negotiations between the FDA and industry and with input from public stakeholders.
  • It as enacted to ensure patients have access to safe, high-quality and affordable generic drugs.
  • GDUFA enables FDA to assess industry user fees to bring greater predictability and timeliness to the review of generic drug applications.
2017 (Food and Drug Administration Reauthorisation Act (FDARA))

Further information is available on the FDA website here.

This post was inspired by an excellent course from Stanford University that I undertook on the edX online learning platform. I can confirm that I have no affiliation to the university or the online learning platform.