Food and Drug Administration

HOW THE FDA APPROVES NEW DRUGS

The process by which the Food and Drug Administration (FDA) approves drugs as safe and effective is generally long and complicated, though it may vary according to the type of drug and the nature of the illness for which it is being developed. The FDA refers to drugs under development as investigational new drugs, or INDs.

The evaluation of new drugs requires the skills of many different FDA scientists and professionals performing a wide variety of tasks. Biochemists and molecular biologists evaluate the basic chemistry and biology of new chemical compounds and molecular structures. Toxicologists assess the potential harm of proposed drugs, and pharmacologists study how these drugs affect the body and are broken down and absorbed by it. Computer scientists create electronic models that aid in the understanding of new chemicals. Physicians evaluate the results of clinical trials, assessing both the beneficial and adverse effects of the drugs. And statisticians evaluate the design and results of controlled studies.

It is an expensive and time consuming process, particularly for the company developing the drug, called a drug sponsor. A sponsor spends an average of $359 million for each new drug brought to market. Typically, the process takes eight and a half years and may be divided into roughly three stages: preclinical trials, involving animal and other laboratory tests (lasting one and a half years on average); clinical trials, involving tests on humans (five years); and FDA review (two years).

Preclinical Trials Once a sponsor has developed a drug, it must test the drug on animals in the laboratory. In doing so, the drug sponsor must follow FDA guidelines and regulations. These tests, also called preclinical trials, are usually done on more than one species of animals. FDA guidelines call for the inspection of animal laboratories every two years to ensure that they are being operated according to the administration's regulations.

After short-term lab testing has been performed and the sponsor has deemed its results adequate, the sponsor submits test data and plans for future clinical trials to the FDA. FDA scientists, together with a local institutional review board composed of scientists, ethicists, and nonscientists, then conduct a thirty-day safety review to decide whether to allow testing on humans. The vast majority of new drugs tested in the laboratory are rejected by either the sponsor or the FDA because they are unsafe or ineffective.

If the FDA indicates approval, the drug sponsor may begin clinical testing on humans. Even if a drug is approved for clinical trials, the sponsor continues animal testing of the drug in order to better understand the drug's long-term effects.

Clinical Trials Clinical trials are scientifically controlled studies in which the drug being tested is given to one group of patients, while another treatment, often a placebo (an inactive substance that looks like the drug being tested), is given to another group. Ideally, neither group of patients knows which is receiving the new drug and which is receiving the placebo.

The clinical trials, like the animal tests, examine what happens to the drug in the body, including whether it is changed, or metabolized, in the body, how much of it is absorbed into the blood, and how long it remains in the body. If human tests produce unexpected results, researchers may conduct further animal tests to better understand the drug.

Clinical trials proceed in three phases: Phase 1 involves testing primarily for safety and dosage level. Twenty to one hundred healthy patients are assessed over several months. If the results are within FDA safety guidelines, the trials proceed to phase 2.

Phase 2 involves a greater number of patients—up to several hundred—who have the condition that the drug is intended to treat. During this stage, which lasts from several months to two years, researchers attempt to determine the drug's effectiveness in achieving its stated purpose, as well as its safety. At the end of this phase, sponsors meet with FDA officials to discuss the best way to conduct the next phase of testing.

In phase 3, the most crucial stage of testing, the number of patients is expanded still further, to several hundred to several thousand, and the length of the study is increased to one to four years. This phase establishes the correct dosage of the drug and how it will be labeled, and provides further evidence regarding its safety and effectiveness.

Of one hundred drugs submitted for testing in humans, an average of seventy will pass phase 1. Of these seventy, on average, only thirty-three will remain after phase 2 testing, and twenty-five to thirty after phase 3. Finally, an average of only twenty will actually receive FDA approval.

Once the drug sponsor has completed clinical trials, it submits a new drug application (NDA) to the FDA, requesting approval to market the drug. This application consists of documentation detailing the chemical composition of the drug, the design of the trials, the results of the trials, and the means by which the drug is made and packaged.

FDA Review In assessing an NDA, the FDA undertakes its closest scrutiny of all during the drug approval process. Its principal goal during review is to determine whether the benefits of the new drug outweigh the risks. To reach this determination, the FDA examines the documentation provided by the sponsor and looks at samples of the drug.

If inadequacies are discovered in the NDA, the FDA may require additional information, further testing, or modified labeling. In cases where it is difficult to establish clearly whether the benefits of the drug outweigh the risks, a panel of outside experts is often consulted.

If the FDA approves the drug, the sponsor may begin manufacturing and marketing the drug immediately.

The FDA does not stop monitoring a drug once it has been marketed. It continues to evaluate the drug's safety and effectiveness through its program of postmarket surveillance. This program consists of surveys, the testing of product samples, and the analysis of reported adverse reactions.

Speeding Drugs to Those Who Need Them The FDA has longstanding policies allowing what it calls the compassionate use of new drugs for those in desperate need. Innovative cancer treatments, for example, have been made available to patients since the 1970s through the National Cancer Institute.

However, during the 1980s, the FDA came under increasing fire for its slow approval of new drugs. Particularly with the emergence of AIDS during the 1980s, the public outcry for fast delivery of innovative new drugs strengthened. As science produces ever more pharmaceuticals, the FDA is called on to review drug applications as quickly as is reasonably possible.

In response to the growing demand for speedy drug evaluation, the FDA has made significant changes in its review protocols. In 1987, for example, the agency adopted "expanded access" regulations, which permit certain drugs to be designated as treatment INDs. A treatment IND may be administered to patients even while it is still undergoing clinical trials. This program allows patients with no other alternatives to undergo a treatment that may benefit their health. By August 1994, twenty-nine agents had been designated treatment INDs, and by 1995, more than seventy-five thousand patients had received access to new therapies through this program. New drugs used to treat patients with AIDS are made available through a similar process known as the parallel track approach.

Identifying priorities is another method the FDA uses to provide more rapid access to promising new treatments. AIDS drugs, drugs that treat life-threatening or severely debilitating illnesses, and drugs that appear to offer significant improvements over existing therapies are classified as priority drugs and receive faster review than those classified as standard drugs. With priority drugs, the FDA typically becomes involved earlier in the development process, and is thereby able to more quickly review the relevant applications.

Drugs are also classified as to chemical type, so that those closely similar in structure to existing drugs will receive less intensive review than those with a molecular structure that has never been marketed before.

Accelerated approval is another mechanism for faster review of promising new drugs. Under this program, created in 1991, a product may be approved for limited use if it has been shown in trials to achieve particular results—such as lowering blood pressure or cholesterol. Drugs approved under this program include didanosine for AIDS, interferon beta-1B for multiple sclerosis, and DNase for cystic fibrosis.

The Prescription Drug User Fee Act of 1992 (Pub. L. 102-571, Title 1, Oct. 29, 1992, 106 Stat. 4491 to 4500) has also enabled the FDA to speed drug review. Under this law, fees paid by drug manufacturers are used by the agency to hire hundreds of additional review staff and buy improved equipment, including computers that make review more efficient.

The FDA is also attempting to streamline red tape and bureaucracy. In 1995, President BILL CLINTON and Vice President ALBERT GORE, Jr., announced that twenty-one separate product license applications used by the FDA would be consolidated into one simplified form. This form would also be available in an electronic format, making it easier to distribute, prepare, and review.

Results indicate that these changes have led to faster approval of important new drugs. One signal success of FDA reform was the prompt approval of taxol, a treatment for advanced ovarian cancer that was approved in December 1992 after a record 5 months. By 1994, all new drugs were being approved by the FDA in a median time of 19 months, and priority drugs with important therapeutic uses were approved in an average of 10.4 months. In the late 1980s, by comparison, the FDA took an average of 27 months to approve new drugs.

In 1995, President Clinton established even more ambitious new goals for FDA approval. These goals, to be met by 1997, require the FDA to approve priority drugs within 6 months and standard drugs within 12 months.