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The new drug user-fee program will define how FDA does business over its next 100 years.
The US Food and Drug Administration is 100 years old this year. Its origin dates to June 1906 when President Theodore Roosevelt signed the Pure Food and Drugs Act into law. The agency began as the Drug Laboratory in the Bureau of Chemistry of the US Department of Agriculture, and its main task was to test whether drug products and ingredients met standards for strength and purity. Most medicines were ineffective, and some even dangerous. The Pure Food and Drugs Act had no premarket approval requirements and gave the government little authority to remove fraudulent drugs from the market.
It took another 50 years and several health crises for Congress to require evidence of a drug's safety, quality, and efficacy. Today, FDA has some 10,000 staffers and a $2-billion annual budget but is hard pressed to keep up with expanding responsibilities. Agency leaders consider it their public-health responsibility to help speed patient access to needed therapies as well as to keep unsafe medical and food products off the market. This mandate has stimulated a host of initiatives to streamline regulatory policies and procedures. Globalization has transformed how FDA monitors regulated products; user fees have altered the agency's relationship with manufacturers; and new technologies continually transform FDA operations.
Many of these themes will continue during FDA's next hundred years, commented Deputy Commissioner for Operations Janet Woodcock at the annual meeting of the Drug Information Association in June. FDA needs a more formal focus on bioinformatics and improvements in how it processes huge volumes of information, she pointed out. Unfortunately, the agency is plagued by inadequate funding, Woodcock said, noting a perennial "mismatch between resources and expectations."
Challenges for CDER
FDA's future resources will be up for discussion during the next year as part of negotiations for renewing the drug user-fee program, added Murray Lumpkin, deputy commissioner for international and special programs. How policymakers revise that program "will define how FDA does business going into its second 100 years," he commented.
In its early years, the main work of the Bureau of Chemistry's Drug Laboratory, which became the Drug Division, was to examine and test samples of synthetic and natural drug ingredients and products. Some 2000 domestic and imported items were sampled in 1910. Most of the staff were chemists and pharmacologists who assessed drug manufacturing, formulation, and purity and helped develop methods to improve pharmaceutical analysis.
But, this office didn't have enough clout to stop Johnson's Mild Combination Treatment for Cancer from making false claims of effectiveness. Patients died from impure anesthetics, and improperly packaged chloroform decomposed into a dangerous substance. In the 1920s, the Bureau began collaborating with the US Pharmacopeia to study and develop reference standards for bio-assayed drugs such as digitalis.
The agency, however, did not gain any real teeth for regulating unsafe and ineffective products until a national disaster raised a public outcry. Congress approved the Food, Drug, and Cosmetic Act of 1938 after more than 100 people, including many children, died in 1937 from a poisonous ingredient in elixir sulfanilamide. To prevent more catastrophes of this sort, the new law required manufacturers to test the safety of new drugs and submit the results in new drug applications (NDAs) before marketing. It authorized inspections of drug manufacturing facilities and set requirements for product labels.
In the first year of the preapproval requirement, FDA received more than 1200 applications. Congress expanded FDA's responsibilities further in 1941 by requiring premarket testing of all batches of insulin for purity, strength, quality, and identity. And, a 1945 Penicillin Amendment established similar testing requirements for that drug.
Effective as well as safe
Throughout the 1950s, various experts and advisors developed new strategies for improving and expanding drug regulation. FDA launched an adverse drug reaction reporting system in 1955. A major reorganization in 1957 established a Bureau of Medicine and a Bureau of Biological and Physical Sciences.
A fast-expanding pharmaceutical industry also was attracting public attention because of high drug prices, fairly rudimentary clinical-research activities, and increasingly bold claims in drug labeling and advertising. Senator Estes Kefauver began to hold hearings in 1960 on proposals to strengthen FDA oversight, including new rules for monitoring manufacturing practices.
The bill was going nowhere, though, until the horrifying effects of thalidomide on newborns became known in 1962. FDA reviewer Frances Kelsey had qualms about the NDA for the product, and her hesitation made her a hero overnight. The narrowly avoided tragedy prompted Congress to adopt the Kefauver–Harris Amendments, which required drug manufacturers to prove that products are both safe and effective before marketing. The measure also formalized good manufacturing practices (GMPs), required adverse-event reporting, and called for sponsors of clinical trials to obtain informed consent from study participants.
These new requirements prompted a major expansion of FDA's Division of New Drugs, forming separate branches to evaluate NDAs and to monitor clinical trials, manufacturing controls, and adverse-reaction reports. The National Center for Drug Analysis opened in St. Louis in 1967 to conduct large-scale tests of drug products. The Bureau of Drugs became the Bureau of Drugs and Biologics in 1980 to coordinate agency oversight better, but the combination proved unwieldy and lasted only a few years (see sidebar, "Challenges for CDER").
Another major initiative was to assess the safety and efficacy of the vast number of drugs already on the market that never had been formally evaluated for efficacy. The resulting Drug Efficacy Study Implementation (DESI) review of some 3500 products lasted almost 20 years. In 1972, FDA launched a similar retrospective review of over-the-counter drugs that led to monographs on the safety and efficacy of some 1000 active ingredients.
The 1980s were a time of important social and biomedical change in the United States that entailed major consequences for FDA. The first reports of AIDS appeared in 1981, prompting coordinated efforts by FDA and researchers to develop and approve immunoassay tests. Azidothymidine (AZT), the first drug to treat AIDS, was approved by FDA in 1987, along with additional treatments for certain opportunistic infections.
In addition, demands from well-informed AIDS patient advocates for faster access to promising therapies spurred a general rethinking of FDA regulatory attitudes. The thalidomide crisis had fostered a cautious approach at the agency, but the AIDS epidemic engendered a less risk-averse attitude. FDA revised rules to expand access to experimental drugs for severely ill patients and to permit market approval of AIDS and cancer treatments based on preliminary clinical results.
The need for biomedical innovation also built support for an innovative program to encourage the development of treatments for rare diseases. Congress approved the Orphan Drug Act in 1983, which extends market exclusivity for drugs and medical products that treat diseases affecting less than 200,000 people in the United States and has led to the approval of nearly 300 drugs and biologics.
Generics spur competition
In 1984, Congress established the basis for the modern generic drug industry with the enactment of the Drug Price Competition and Patent Term Restoration Act, commonly known as the Hatch–Waxman Act. The bill allowed FDA to approve abbreviated applications for identical versions of brand-name drugs on the basis of preclinical and clinical testing performed by the innovator firm. Early access to innovator research data allows generics companies to develop and test generics before patent expiration.
The trade-off for brand-name companies is as many as five years of additional patent protection for new medicines to make up for time lost while their products went through FDA's approval process, which often ran for two or three years at that time. Unfortunately, the legislation attracted some inexperienced operators to this fast-growing industry, leading to fraudulent activities and a subsequent enforcement crackdown.
Monitoring distribution. In addition to illegal generic-drug activities, policymakers were increasingly concerned about questionable drug distribution and marketing activities. Congress approved the Prescription Drug Marketing Act of 1988, which gave FDA added authority to prevent drug diversion and resale by requiring industry to establish systems for tracking drugs and product samples. Specific approaches for implementing the legislation have been hard to negotiate, however, and FDA is only now requiring some wholesalers to establish pedigree systems to thwart sales of adulterated and counterfeit products.
A tiger with teeth. These developments set the stage for a tougher regulatory stance when David Kessler became FDA commissioner in late 1990. Determined to erase FDA's "paper tiger" image, he beefed up agency compliance staffs and launched a campaign to halt industry promotion of off-label drug uses through educational programs and the fast-growing Internet.
The enforcement crackdown also extended to vitamins and dietary supplements: Congress approved legislation giving FDA authority to halt unsubstantiated health claims and to establish GMPs for these products. Here again, agreement on an implementation plan has been delayed by debate and legal battles.
Commissioner Kessler also launched a campaign in 1994 to extend FDA regulation to tobacco products. The effort was halted by a 2000 Supreme Court ruling that FDA lacked authority in this area, but the initial attack led to hefty industry payments to state governments and curbs on tobacco marketing and sales.
Industry antes up
All these new programs greatly increased FDA's responsibilities and made it difficult for the staff to keep up with assignments, including timely review of NDAs and inspection of drug manufacturing facilities. The delays generated support for the Prescription Drug User Fee Act of 1992, which required pharmaceutical companies to pay fees to support a more efficient application review process, among other services. The program's five-year "sunset" provision has required reauthorization of user fees in 1997 and 2002. It is up for renewal again in 2007, and negotiations between FDA, industry, and interest groups are well underway.
A global initiative to accelerate drug development and streamline registration also was launched at this time. In 1992, FDA joined with regulators and manufacturers from Europe and Japan to establish the International Conference on Harmonization. The program has produced common standards in all three regions for testing and registering new drugs and biologics, with a focus on assessing drug quality through stability testing, and for conducting preclinical animal tests and clinical studies.
In reauthorizing the user-fee program in 1997, Congress enacted the FDA Modernization Act, which revised many agency practices. Its numerous provisions clarify and streamline clinical research and application-review policies and revise marketing rules and postmarketing surveillance requirements. A key section of the bill provides six months of added exclusivity on a drug if the manufacturer conducts additional studies to add pediatric information to the product's label.
New challenges for the new century
Efforts to support biomedical innovation and to streamline FDA regulatory processes have become even more visible in recent years. In the wake of the Sept. 11, 2001 terrorist attacks, Congress approved the Project BioShield Act of 2004, which encourages the development of drugs and vaccines to prevent or treat bioterrorist threats.
In 2002, FDA launched a major initiative to update the regulation of GMPs for drugs and biologics. It advocates a more risk-based regulatory approach for inspecting manufacturing facilities and ensuring product quality. The GMP modernization plan also encourages manufacturers to adopt more innovative approaches to monitoring production processes and includes efforts to revise policies governing electronic data submissions to the agency.
Critical initiatives. Another major initiative champions new approaches and tools likely to encourage pharmaceutical innovation. FDA's Critical Path report of March 2004 urges more agency collaboration with industry to spur research and development, including innovation in drug manufacturing and quality assessment. A subsequent Opportunities List describes a wide range of research and regulatory initiatives with the potential to spur biomedical discovery.
Drug safety also has emerged as a major public concern. In 2004, evidence linking Cox-2 inhibitor painkillers to cardiovascular events spurred major protests that lax FDA policies were exposing patients to unsafe drugs. Manufacturers pulled several products off the market, and FDA launched several initiatives to make drug safety oversight more open and effective. This movement included establishing a Drug Safety Board in 2005 and reorganizing drug safety offices. More changes are still to come.
An important milestone this year was the publication of a long-debated final rule revising the content and format of drug labeling. The new format includes a highlights section at the beginning of the label that aims to make it easier for healthcare professionals to access, read, and use information in approved labeling.