FDA acts as public health protector by ensuring that all drugs on the market are safe and effective. Authority to do this comes from the 1938 Federal Food, Drug, and Cosmetic Act, a law that has undergone many changes over the years, just as it changed earlier drug regulation. Some major milestones in the evolution of U.S. drug law are:

Food and Drugs Act (1906): This first drug law required only that drugs meet standards of strength and purity. The burden of proof was on FDA to show that a drug's labeling was false and fraudulent before it could be taken off the market.

Federal Food, Drug, and Cosmetic Act (1938): A bill was introduced into the Senate in 1933 to completely revise the 1906 drug law--widely recognized then as being obsolete. But congressional action was stalled. It took a tragedy in which 107 people died from a poisonous ingredient in "Elixir Sulfanilamide" to prompt passage of revised legislation that, for the first time, required a manufacturer to prove the safety of a drug before it could be marketed. Among other provisions, the law also eliminated the Sherley Amendment requirement to prove intent to defraud in drug misbranding cases, provided for tolerances for unavoidable poisonous substances, authorized factory inspections, and added the remedy of court injunction to previous remedies of seizure and prosecution.

Durham-Humphrey Amendment (1951): Until this law, there was no requirement that any drug be labeled for sale by prescription only. The amendment defined prescription drugs as those unsafe for self-medication and which should therefore be used only under a doctor's supervision.

Kefauver-Harris Drug Amendments (1962): News reports about the role of FDA medical officer Frances O. Kelsey, Ph.D., M.D., in keeping the drug thalidomide off the U.S. market aroused public interest in drug regulation. Thalidomide had been associated with the birth of thousands of malformed babies in Western Europe. In October 1962, Congress passed these amendments to tighten control over drugs. Before marketing a drug, firms now had to prove not only safety, but also effectiveness for the productÕs intended use. The requirement was applied retroactively to 1938, when the FDC Act was passed. (Pre-1938 drugs were "grandfathered"--allowed to be sold because they were generally recognized as safe and effective, provided no evidence to the contrary developed.) To help implement the amendments, FDA contracted with the National Academy of Sciences/National Research Council to review the efficacy of drugs approved solely on the basis of safety since 1938. Firms were required to send adverse reaction reports to FDA, and drug advertising in medical journals was required to provide complete information to doctors--the risks as well as the benefits. The amendments also required that informed consent be obtained from study subjects.

Orphan Drug Act (1983): "Orphans" are drugs and other products for treating rare diseases. They may offer little or no profit to the manufacturer, but may benefit people with the rare diseases. To foster orphan product development, this law allows drug companies to take tax deductions for about three-quarters of the cost of their clinical studies. Firms also are given exclusive marketing rights for seven years for any orphan products that are approved.

Drug Price Competition and Patent Term Restoration Act (1984): This law expands the number of drugs suitable for an abbreviated new drug application, or ANDA. ANDAs make it less costly and time-consuming for generics, which are often sold at lower prices than brand-name drugs, to reach the market. "Patent Term Restoration" refers to the 17 years of legal protection given a firm for each drug patent. Some of that time allowance is used while the drug goes through the approval process, so this law allows restoration of up to five years of lost patent time.

Generic Drug Enforcement Act (1992): This law imposes debarment and other remedies for criminal convictions based on activities relating to the approval of ANDAs.

Prescription Drug User Fee Act (1992): Manufacturers must now pay user fees for certain new drug applications and supplements, an annual establishment fee, and annual product fees. Using these funds, FDA plans to hire some 700 new staff by the end of fiscal year 1997, when the act will expire unless renewed by Congress.

Though not involving changes in law, the following changes in drug regulations are noteworthy:

Protection of Human Subjects; Informed Consent; Standards for Institutional Review Boards (1981): These standards clarify FDA requirements for informed consent and provide protection of the rights and welfare of human subjects involved in research within FDA's jurisdiction. They also establish standards governing the composition, operation and responsibility of institutional review boards that review clinical investigations. In 1991, other federal agencies adopted a revised version of these regulations, resulting in a "common federal rule."

Revision of New Drug Application Regulations (1985): These changes provide for safety reports after an application for a new drug is submitted, more focused and better organized data, use of summaries and tables for easier review, earlier problem solving, and allowance of approval on the basis of foreign studies alone. It also strengthens the monitoring of adverse reactions from marketed drugs.

Revision of Investigational New Drug Application Regulations (1987): The revision encourages problem-solving meetings with FDA, requires deadlines in safety reports, and increases sponsor control over initial human test design so long as subjects face no unreasonable, significant risks.

Treatment Use of Investigational New Drugs (1987).

Procedures for Subpart E Drugs (1988): Intended to speed availability of new drugs to patients with life-threatening or severely debilitating illnesses, these procedures encourage sponsors to work with FDA early on to develop the most time-efficient, well-designed animal and human studies. FDA expects this cooperative effort will allow approval after phase 2 clinical trials. "Subpart E" refers to the section of the Code of Federal Regulations governing this new drug classification.