The foundation of FDA’s regulatory authorities was laid in the 1906 Pure Food and Drug Act, which focused on misbranding and adulteration. In keeping with other consumer product laws, it focused on postmarketing remedies only. That is, if a drug already on the market was proven to be a hazard, it could be seized and further sales halted.

In the wake of deaths due to elixir of sulfanilamide in 1937, the 1906 law was replaced with a stronger form of regulation in the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938. The new law changed the emphasis to the period of time before a drug enters the market, and required manufacturers to notify FDA before beginning testing on human subjects and to submit proof of the drug’s safety (though not of its efficacy) (Hutt, 1992). The requirement was a major advance in drug regulation, but it was nonetheless still somewhat weak, as marketing could begin 60 days after submission of the information to the FDA unless the FDA affirmatively found the drug to be unsafe.

The statutory scheme for drug regulation went through yet another revision in 1962, after thousands of European children with limb defects were born to mothers who had been administered thalidomide (Kaplan, 1995; FDA, 2006). The Drug Amendments of 1962 shifted the burden of proof from FDA (which previously had to prove harm to keep a drug from being marketed) to manufacturers, who now were required to demonstrate both safety and efficacy prior to receipt of marketing approval (Hutt, 1991). The early 1960s also marked the crystallization of clinical trials into the sequence of phase 1, 2, 3 trials still in use today and described in greater detail in Chapter 2 (DHEW, 1963).

The FDA’s ability to form judgments about the safety and efficacy of drugs depends upon the submission of data, usually from drug company sponsors, rather than on the use of data developed independently or on its own initiative. As a result, the statutory scheme governing drug approval in the United States has also included a series of measures to provide an incentive for third parties to develop safety and efficacy data for use by FDA. These incentives include patent extensions (the Drug Price Competition and Patent Term Extension Act of 1984), and periods of market exclusivity in exchange for developing information about new drugs, new indications for old drugs, and new information about the action of old drugs in special populations, such as children (The Orphan Drug Act of 1982; The FDA Modernization Act of 1997 [FDAMA]; the Best Pharmaceuticals for Children Act of 2002). Thus, the statutory scheme is characterized by carrots rather than sticks, in that the development of new information on drug safety and efficacy is achieved more by creating incentives than by issuing mandates.

The 1938 FD&C Act, as amended several times, defines FDA’s regula-

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