Three Decades of Drug Regulation and Legislation

When Pharmaceutical Technology first appeared in 1977, the US Food and Drug Administration was a much smaller and less well-known government agency in the Department of Health, Education, and Welfare. Donald Kennedy, a prominent neurophysiologist from Stanford University, was the newly named commissioner. FDA was undergoing visible change as it strove to update the drug provisions in the Food, Drug, and Cosmetic Act. The act had been altered considerably by the 1962 Kefauver–Harris Amendments, which were generated in response to the thalidomide crisis that began in 1956. The amendments required drug manufacturers to submit clinical evidence of both safety and effectiveness before marketing a new medicine.

Eight commissioners have led FDA since then, presiding over a period that has witnessed the emergence of user fees, drug advertising, and drug-safety concerns. All these changes have increased the agency's oversight of drug development and market approval. They also have prompted more congressional attention to FDA and industry activities. Today FDA is struggling to assure the public and policymakers that it has the ability to ensure the quality and efficacy of medicines. It also is striving to modernize its regulatory programs and encourage pharmaceutical innovation, thereby addressing many of the challenges facing the pharmaceutical industry today.

1970s and 1980s: Growth and innovation

During the 1970s and 1980s, FDA launched many key initiatives, including a retrospective review of over-the-counter (OTC) drugs and an increased collection of adverse drug reports, and reorganized and expanded its Bureau of Drugs (see sidebar, "FDA builds drug oversight infrastructure"). Reports of AIDS in the 1980s spurred demands from patient advocates for faster access to promising therapies, prompting a general rethinking of regulatory attitudes. The thalidomide crisis had fostered a cautious approach at the agency, encouraging staffers to move slowly in reviewing new drug applications. The AIDS epidemic, though, spurred agency officials to adopt a less risk-averse attitude, acknowledging that their job was to facilitate patient access to needed treatment as well as to guard against unsafe products. Other important developments are described below.

The changing face of drug-oversight infrastructure

AIDS-influenced regulation. The first reports of AIDS expanded FDA collaboration with researchers and scientists to approve initial immunoassay tests. Several rule changes in the mid-1980s broadened access to experimental drugs for patients with serious diseases and no alternative treatment options. FDA approved AZT (azido-thymidine), the first drug to treat AIDS, in 1987, as well as treatments for opportunistic infections.

Human subject protections. In 1981, FDA and other federal agencies involved in medical research revised regulations to protect individuals participating in clinical research. The revisions were inspired by the 1979 Belmont Report, a broadly acclaimed document articulating the basic need to protect human subjects participating in biomedical research. During the following decade, more government agencies adopted the "Common Rule" governing human subject research, which: requires researchers to obtain and document informed consent; provides special protections for children, women, and prisoners; and sets policies for institutional review boards.

Milestone. 30 Years of Pharmaceutical Technology

Orphan-drug development. Congress passed the Orphan Drug Act in 1983, launching an innovative program that encourages industry to develop treatments for rare diseases, i.e., conditions affecting fewer than 200,000 people in the United States. The law provides extended market exclusivity for such drugs and medical products and awards grants to support orphan-drug clinical trials. These incentives have led to FDA approval of nearly 300 drugs and biological products under this program.

Generic-drug marketing. In 1984, Congress enacted the Drug Price Competition and Patent Term Restoration Act, commonly known as the Hatch–Waxman Act after its lead Senate and House sponsors. This act launched the modern generic-drug industry. The legislation allows FDA to approve abbreviated applications for generic versions of brand-name drugs that rely on much of the innovator firm's preclinical and clinical testing. An important provision permits generics companies to access innovator research data early to develop and test generics before patent expiration.

At the same time, brand-name companies gained as many as five years' additional patent protection for new medicines to make up for the time lost when their products went through FDA's approval process, which often lasted two or three years at that time. The legislation attracted some inexperienced operators to this fast-growing industry, leading to fraudulent activities and a subsequent enforcement crackdown. Congress approved legislation in 1992 that stiffened penalties for illegal acts involving abbreviated drug applications.

Curbs on illegal drug distribution. The Prescription Drug Marketing Act of 1988 provided FDA with added authority to prevent the diversion and resale of prescription drugs, including drug samples. FDA is just now implementing provisions requiring wholesalers to establish pedigree systems that track the movement of approved drugs through the distribution system, thus thwarting sales of adulterated and counterfeit products.

1990s: Expanded authority and resources

David Kessler became FDA commissioner in 1990 and promised to crack down on fraud and abuse, and to compel manufacturers of drugs and food products to meet regulatory requirements. As head of the agency until 1997, he engineered the first prescription-drug user-fee program and the resulting expansion of FDA staff and authority. Other key developments are outlined below.

International harmonization. Beginning in 1990, FDA joined regulators and manufacturers from Europe and Japan to establish the International Conference on Harmonization. In 1992, the group adopted a formal process for reaching agreement on common standards and policies for testing and registering new drugs and biologics in the three regions.

User fees. The Prescription Drug User Fee Act of 1992 requires manufacturers of drugs and biologics to pay fees to support a more efficient FDA review process for market applications and supplements. A five-year "sunset" provision required reauthorization of the user fee program in 1997 and 2002. The program must be renewed again by September 30, 2007.

Rules for dietary supplements. The Dietary Supplement Health and Education Act of 1994 established specific labeling requirements for vitamins and other supplements. It gives FDA authority to establish good manufacturing practices (GMPs) for these products, which has drawn on GMPs for drugs.

Greater oversight of drug advertising. In 1996, FDA established the Division of Drug Marketing, Advertising, and Communications within the Center for Drug Evaluation and Research to oversee a growing volume of professional and consumer advertising. Regulation increased in 1999, when FDA issued a final guidance requiring balanced risk and benefit information in broadcast advertising.

Modernized drug regulation. In reauthorizing the user fee program in 1997, Congress enacted the FDA Modernization Act (FDAMA), which revised and extended many agency practices. Among its multiple provisions, it clarified and streamlined policies governing clinical research, application-review procedures, marketing rules, and postmarketing surveillance requirements.

Incentives for pediatric studies. A key provision in FDAMA granted a drug six months of added exclusivity if the manufacturer conducted additional studies to add pediatric information to the product's label. This initiative was expanded in 2002 under the Best Pharmaceutical for Children Act and again by the Pediatric Research Equity Act of 2003.

2000 to date: New challenges and opportunities

Jane Henney, FDA's only female commissioner, headed the agency from 1999 to 2001. She was succeeded by Mark McClellan in 2002. They undertook many initiatives to revise agency policies and practices that continue to shape FDA operations, including the following.

Updated GMPs. FDA launched a major initiative in 2002 to update the regulation of GMPs for drugs and biologics. The initative adopts a more risk-based system for inspecting manufacturing facilities and supports new approaches for ensuring product quality. The ultimate goal is to reduce agency oversight of manufacturing processes and postapproval changes, and to provide more regulatory flexibility for companies that establish quality-control systems.

Combination products. The continued squeeze on FDA resources prompted medical-device manufacturers to negotiate a user-fee program in 2002 to support more efficient review of medical-device applications. This has important implications for the growing number of drug-device combination products under development. FDA established the Office of Combination Products in 2002 to better manage market applications for these products.

Response to bioterrorism. In the wake of September 11, 2001, Congress approved legislation to strengthen controls on imported products. The Project BioShield Act of 2004 encouraged the development and regulation of drugs and vaccines to prevent or defend against bioterrorist attacks, a policy reinforced by additional legislation in 2006. FDA has played a lead role in spurring the development of new vaccines and updating production methods to address the need for more preventives and treatments for infectious diseases and biological attacks.

A call for innovation. FDA issued the Critical Path report in March 2004, urging new approaches for bringing new therapies to patients. This launched a major effort to encourage more FDA collaboration with industry to spur research and development and counter a decline in new drugs coming to market. Two years later, the agency issued an Opportunities List of a wide range of research and regulatory initiatives such as biomarker development and toxicity-testing standards that could potentially lead to more biomedical discoveries.

Stress on safety. Evidence linking COX-2 inhibitor painkillers to cardiovascular events caused a major outcry in 2004 that lax FDA policies were permitting unsafe drugs to be marketed. Manufacturers pulled certain products off the market, and FDA launched several initiatives to make oversight of drug safety issues more open and effective. The initiatives included establishing a Drug Safety Board in 2005 and reorganizing FDA's drug-safety offices. Earlier this year, FDA announced broader postmarket surveillance and product-evaluation policies and established a new advisory committee in this area.

Labeling changes. In 2005, FDA issued requirements for manufacturers to submit drug labeling in an electronic format to the Daily Med data bank. Eventually, all labels will follow the new format for professional labeling established by a long-discussed final rule. The rule revises the content and format of labeling for human prescription drugs and biological products. An important innovation is to establish a "highlights" section at the beginning of the label to make it easier for healthcare professionals to access, read, and use the information in approved labeling.

OTC access to Plan B. In August 2006, FDA approved an OTC version of the "morning after pill" Plan B. The three-year controversy over this birth-control product raised concerns about political interference in FDA decisions, but its resolution removed obstacles to the confirmation of cancer specialist Andrew von Eschenbach as FDA commissioner.

2007 and beyond: Building for the future

The need to renew the user-fee program this year provides an opportunity for Congress to increase FDA authority and establish programs that policymakers believe will enhance public access to needed medicines and ensure that medical products are safe and effective. Widely acknowledged as "must-pass" legislation, the user-fee bill may change regulatory programs and policies that will have a broad and serious effect on industry.

The Senate approved a measure in May that raises fees to cover a broader spectrum of FDA preapproval and postapproval activities. The House is expected to approve its version this month. The Senate bill also enables FDA to require more information about drug safety and more disclosure of clinical-trial activities and research results. In reauthorizing programs to encourage pediatric studies of new and approved drugs, the bill reduces the added exclusivity from six months to three months for drugs that reach "blockbuster" status based on sales. One unresolved issue is whether Congress will authorize FDA to approve applications for follow-on or "similar" biopharmaceuticals, a subject that has generated considerable controversy.

Despite proposals that threaten to increase the cost of drug development, regulators and manufacturers are optimistic that recent discoveries in genomic sciences and molecular biology create opportunities to develop entirely new classes of more effective and less toxic medicines, potentially at more affordable costs. Cooperative efforts to adopt new regulatory models in harmony with other nations' approaches have the potential to streamline drug development and registration, and accelerate global access to new therapies.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com

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