Regulatory Beat: Biologics Oversight Challenges Federal Regulators

Although the Food and Drug Administration is celebrating its 100th birthday this year, federal government regulation of biologics is even older. FDA's Center for Biologics Evaluation and Research (CBER) dates its origins to Congressional approval of the Biologics Control Act of 1902, following a wave of deaths from tainted diphtheria antitoxin. The law established CBER's predecessor, the Hygienic Laboratory of the Public Health and Marine Hospital Service, and gave it authority to license and inspect manufacturers of smallpox and rabies vaccines, diphtheria and tetanus antitoxins, and various serums to protect against bacterial infections such as scarlet fever.

Jill Wechsler

Four years later, Congress passed the 1906 Pure Food and Drugs Act, which established FDA's predecessor, the Drug Laboratory in the Bureau of Chemistry of the Department of Agriculture. This law authorized testing drug product strength and purity, but did not establish premarket approval requirements and gave the government little authority to remove even ineffective drugs from the market. FDA was established around 1930, at the same time that the Hygienic Laboratory became the National Institutes of Health (NIH); biologics control remained part of NIH until it was transferred to FDA in 1972 (see Coordination Challenges).

FDA did not gain any real teeth for regulating unsafe and ineffective products until another national health disaster roused 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 such catastrophes in the future, the new law required manufacturers of drugs and biologics to test the safety of new products and submit the results in a new drug application (NDA) before marketing (biologics still had to submit a biologics licensing application, or BLA). The law authorized inspections of drug manufacturing facilities and established requirements for product labels.

Coordination Challenges

Congress further expanded FDA's responsibilities in 1941 by requiring premarket testing of all batches of insulin for purity, strength, quality, and identity. The Public Health Service Act of 1944 updated the 1902 biologics policy. And a Penicillin Amendment passed in 1945 mandated similar testing requirements for that drug.

Vaccine development rapidly moved forward during this period. In the 1940s, government researchers developed methods to determine vaccine potency, which led to improvements in vaccines for pertussis (whooping cough) and influenza. A major success was realized with the development and testing of the Salk polio vaccine in the mid-1950s. And in 1966, agency researchers developed the first effective experimental vaccine for rubella (German measles). The safety of blood and blood plasma products also improved during World War II and beyond with the development of tests to detect hepatitis.

A major regulatory change occurred in 1962 when the dangers of Thalidomide use prompted Congress to adopt the Kefauver-Harris Amendments. The new law required manufacturers to prove that drugs are safe and effective before marketing; it also formalized good manufacturing practices, required adverse event reporting, and called for sponsors of clinical trials to obtain informed consent from study participants.

AIDS SPARKS REVOLUTION

The 1980s was a time of important social and biomedical change in the US, with major consequences for FDA and biotech companies. The first reports of HIV/AIDS cases appeared in 1981, prompting coordinated efforts to develop and approve immunoassay tests and test kits to screen donated blood for the AIDS virus. AZT, the first drug to treat AIDS, was approved by FDA in 1987, along with additional treatments for certain opportunistic infections. Demands from AIDS advocates for quicker access to promising therapies also spurred a more risk-averse attitude at FDA, leading to rules expanding access to experimental drugs for seriously ill patients, and permitting FDA approval of AIDS and cancer treatments based on early clinical results.

At the same time, policy makers encouraged development of innovative treatments for rare diseases by enacting the Orphan Drug Act of 1983. The legislation provided extended market exclusivity for therapies that treat diseases affecting less than 200,000 people in the US, which has led to approval of nearly 300 drugs and biological products. These policies spurred development of new therapeutic proteins and monoclonal antibodies able to target cancer cells more effectively, clear clots from coronary arteries, and prevent anemia in ill patients.

The modern generic drug industry also emerged with Congressional approval of the 1984 Drug Price Competition and Patent Term Restoration Act, or Hatch-Waxman Act. The bill allowed FDA to approve identical versions of brand-name drugs based on innovator preclinical and clinical testing. In return, brand-name companies gained up to five years additional patent protection to compensate for time spent waiting for FDA to approve a new drug. Because this legislation applies only to drugs, a major legal battle to authorize "similar" versions of biotech therapies has erupted as significant biologics are beginning to lose patent protection.

INDUSTRY ANTES UP

All of these new programs greatly increased FDA's responsibilities and made it difficult for staffers to review applications and inspect manufacturing facilities in a timely manner. The resulting delays generated support for the Prescription Drug User Fee Act of 1992, which required pharmaceutical and biotech companies to pay fees to support a more efficient FDA review process for NDAs and BLAs.

A global initiative to accelerate drug development by harmonizing product testing standards also was launched at this time.

In 1992, FDA joined regulators and manufacturers from Europe and Japan to establish the International Conference on Harmonization, which produced numerous guidelines for assessing drug quality and for conducting preclinical animal tests and clinical studies.

In reauthorizing the user fee program in 1997 (PDUFA II), Congress enacted the FDA Modernization Act (FDAMA) that revised many agency practices. A key section of this law 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 streamline FDA regulatory processes have become even more visible in recent years. In the wake of 9/11, Congress approved the Project BioShield Act of 2004, which encourages development of drugs and vaccines to prevent or treat bioterrorist threats. FDA launched a major project in 2002 to update the regulation of good manufacturing practices for drugs and biologics that advocates a more risk-based approach for inspecting manufacturing facilities and ensuring product quality.

Another key initiative champions new approaches and new tools to encourage pharmaceutical innovation. FDA's Critical Path report of 2004 urges additional agency collaboration with industry to spur R&D, and a subsequent Opportunities List describes a range of research and regulatory initiatives with potential to lead to more biomedical discovery.

At the same time, drug safety has emerged as a major public concern. Evidence linking Cox-2 inhibitor painkillers to cardiovascular events spurred a major outcry in 2004 that lax FDA policies were exposing patients to unsafe drugs. Manufacturers pulled a number of products off the market, and FDA launched several initiatives to make drug safety oversight more open and effective, with more changes still to come.

Today, FDA has some 10,000 staffers and a $2 billion annual budget. Agency leaders strive to promote patient access to needed therapies as well as to keep unsafe products off the market. Globalization has transformed how FDA monitors regulated products; user fees have altered the agency's relationship with pharmaceutical and biotech manufacturers; and new technologies continually change how FDA conducts business, developments that will continue in FDA's next hundred years.

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634 jwechsler@advanstar.com