All drugs used for medical therapy in the United States must first be reviewed and approved by the FDA. The FDA is responsible for assuring that all drugs, before they are sold, are sufficiently safe and effective. Accordingly, the FDA dictates that certain steps be followed from the time a drug is discovered until it is finally licensed. The process of testing drugs has several stages: a drug is tested first in the test tube and in animals, then in a few people for a short time, and then in a larger group of people for a longer time. Preclinical trials-A new drug is first tested, not in people, but in test tubes and in animals. These first tests are called preclinical trials because they precede tests with people, which are called clinical trials. Preclinical trials determine the drug’s toxicity, its pharmacologic properties, and its effects against certain microbes. Of all the drugs tested in preclinical trials, only about one drug in a thousand is ever tested in people. If a drug shows promise in the preclinical trials, the FDA grants it the status of an Investigational New Drug (IND). IND status must be granted before the FDA allows the drug to be tested in humans. Phase one clinical trials. Phase one clinical trials are the first round of tests in humans. Phase one trials are designed to determine the safety and dosage of a new drug. These trials usually involve a relatively small number of people, usually between twenty and eighty. The drug is given only for a short time, usually for not more than a week or two, and sometimes only a single dose is given. Participation in a phase one trial may require staying in a research unit of the hospital, or the participant may visit an outpatient clinic which carefully monitors the trial. Participants in a phase one trial don’t benefit much when the trial is for an infection like HIV because the treatment lasts for such a short time. Therefore, people who participate in phase one trials are often paid for their services, or else they participate for entirely altruistic reasons. Phase two clinical trials. Phase two clinical trials are the second round of tests in people. Phase two trials usually involve one hundred to three hundred participants and last for months or years. The purpose of these trials is to determine the schedules for doses, to collect additional information on toxicity, and to test, at least preliminarily, the drug’s effectiveness. With HIV infection, the effectiveness of a drug may be determined by the effect on CD4 cell counts, by the numbers of HIV in the blood, by the delay in progression of disease as indicated by opportunistic infections or development of AIDS, and by how the participant feels. People often participate in phase two trials for access to the drug before licensing. Or if the trial is relatively short and benefits to the participant relatively brief, people participate for payment or altruism. Phase three clinical trials. Phase three clinical trials are the last phase before the FDA licenses the drug. Phase three trials often include two thousand to three thousand or more participants and run for months or years. In this phase, the drug is given to participants in the doses and at the intervals that the FDA is likely to consider acceptable. The purpose of these trials is to get additional information about the safety and effectiveness of the drug. People usually participate in phase three trials for access to the drug before licensing. NDA review. The next step is to take all the information gathered during the previous steps and submit it in a New Drug Application (NDA) to the FDA. The FDA reviews the NDA and decides whether to license the drug, what the dose should be, how the drug should be administered, which side effects require specific warnings in promotional material, and what conditions the drug is useful for. This and other information is available in the Physicians’ Desk Reference, or PDR. The PDR is published each year and is available in most bookstores for $30 to $40. There is also an edition for nonprescription drugs, like ibuprofen, cold remedies, or Dramamine, called PDR for Nonprescription Drugs. It should be noted that the FDA does not specify the exact conditions for which a physician can prescribe a drug. On the contrary, the FDA says that accepted medical practice often includes use of a drug for conditions not specifically approved in the labeling. Thus, licensing a drug means that the drug becomes available in pharmacies, and that physicians can prescribe the drug for virtually any condition. Phase four trials. Phase four trials may be conducted after the drug is licensed in order to determine new dosing schedules, or to collect additional information about effectiveness or toxicity, or to compare the drug to other drugs. People participate in phase four trials of drugs, even though the drugs are already available in the marketplace, in order to have access to the best medical care and (sometimes) in order to receive free care. Streamlining clinical trials-The process described above has established high standards for determining the safety and effectiveness of new drugs. Unfortunately, the process is also expensive and time-consuming. The average new drug in the United States costs $230 million to develop and requires an average of twelve years to move from the laboratory to licensing. Many people with HIV infection, however, have argued that they simply cannot wait twelve years for a potentially useful drug to make it to the marketplace. In response to this argument, the FDA has streamlined the testing process for drugs that might be useful in treating HIV infection. The process now goes faster. Drugs for HIV infection get an expedited review: this means that the FDA examines the IND and the NDA more rapidly, and the phase three trials require fewer participants (around three hundred instead of the usual two thousand to three thousand). Moreover, drugs are made available earlier in the testing process through a mechanism called a Treatment IND. Under the Treatment IND classification, the drug can be prescribed by physicians other than the investigators between the time the trial is completed and the time the FDA reviews the complete NDA application. A more recent attempt to streamline the process and make new drugs more quickly available is called the parallel program. The new drug may be prescribed to people with HIV infection who are not participants in the clinical trial during (and therefore parallel to) the phase three trials. AZT was the first drug to be evaluated under some of the provisions of this streamlined process. The phase two trial began in February 1986; in September 1986, the first analysis of data showed the drug was clearly beneficial; the drug was then made available to people with AIDS through a Treatment IND, and the drug was licensed in March 1987, just thirteen months after the trial began. Although the streamlined process provided access to the drug quickly, it must also be recognized that when AZT became available, the amount of information about it was limited. As a consequence, much of the work normally done in phase three testing was actually done during the phase four, post-licensing trials. These trials indicated that the original dose of the drug was probably too high and that the treatment was probably begun too late. Nevertheless, the experience with AZT showed the potential usefulness of streamlining clinical trials.*184\191\2*