Testing in 'real people.' - drugs, includes related articles

Testing in "Real People'

No part of the drug development process is more critical than clinical trials--testing a new drug in humans to find out whether it is really useful in fighting disease. Usually the answer is no. One major U.S. drug company says that of every 20 compounds it submits to clinical trial, only one may be sufficiently safe and effective to merit FDA approval for marketing. In drug development, unfortunately, failure is the norm.

According to an industry official involved in planning and evaluating clinical research, "Most compounds that look interesting in animal and other laboratory studies never even make it to clinical trial. They're either ineffective, too toxic, too difficult to produce in quantities sufficient for human testing (let alone marketing), or of such limited usefulness that the cost of development can't be recovered.' Those that do show genuine promise in preclinical research and development face the most rigorous, costly, and time-consuming stage of drug development, evaluation first in healthy human volunteers and later-- maybe--in patients who actually have the condition the drug is intended to remedy.

There's a common misconception that FDA is responsible for testing drugs before they're approved for sale. While the agency does a great deal of testing to check on the purity and potency of drugs, it's the drug sponsor--a pharmaceutical company, a research organization, a public or private agency, even an individual--that is required to initiate studies to assess drug safety and effectiveness. FDA's role is to examine the design and conduct of those studies, and, of course, the results, as part of the process of deciding whether a new drug can be approved for marketing.

Basically, FDA wants to be sure that the welfare of participants in clinical studies will be protected and that the studies will be planned and carried out by qualified experts. The method used to study the drug and the way the results are interpreted have to be scientifically valid and free of subjective bias. The investigators have to identify and analyze all their results, including those they didn't expect, and they must follow up any problems, especially those involving people who, for whatever reason, dropped out of the study.

But before an investigational drug can be given to the first patient, the sponsor has to provide FDA with the results of laboratory and animal research, plus information, if there is any, about previous use of the drug in humans in this country and abroad. The sponsor must describe in detail how the clinical trials will be conducted--how many people will be involved, how they will be selected, where the studies will be done and by whom, how the drug's safety and effectiveness will be evaluated, and what findings would require the study to be changed or halted. This material is sent to FDA in the form of an investigational new drug application, or IND. Clinical trials can begin 30 days after FDA receives an IND unless the agency approves an earlier start or orders a "clinical hold' because of questions about the request.

Normally, clinical trials are carried out in three phases involving progressively larger numbers of people. Drug sponsors arrange with physicians and hospitals to actually conduct the studies.

Clinical trials are normally done in three phases. Phase 1 trials are concerned primarily will learning more about the safety of the drug, though they may also provide some information about effectivenes. Phase 1 testing is normally done on healthy volunteers. The volunteers are usually paid for their services, which consist chiefly of submitting to a variety of tests to learn what happens to the drug in the human body-- how it's absorbed, metabolized (broken down), and excreted; what effects it has on various organs and tissues; and what side effects occur as the dose is increased. Evidence of toxicity at doses too small to produce any beneficial effect is one of the chief causes of failure in phase 1 drug testing.

These initial studies are critical to the design of later clinical trials. They provide essential information about how much of the drug a patient should receive, how often it should be used, and what precautions need to be taken to make sure the drug is being used safely. Phase 1 studies usually involve fewer than 100 subjects--sometimes as few as 20--who receive the drug for a month or so. To complete this phase normally takes from six months to over a year.

If the results of phase 1 testing present no unacceptable safety problems, phase 2 trials can begin. (Actually, in some cases, phase 2 studies may begin before all the phase 1 trials are completely evaluated.) Only about 13 or 14 out of 20 drugs that enter phase 1 clinical trials go on to phase 2. This stage of clinical testing may take somewhat longer than phase 1 studies. It normally involves a few hundred patients and is designed to show whether the drug is effective in treating the disease or condition for which it's intended. Phase 2 studies also attempt to disclose short-term side effects and risks in people whose health is impaired.

Most phase 2 studies are randomized controlled trials. A group of patients receiving the drug, a "treatment' group, is matched with a group that is similar in important respects, such as age, sex, disease state, and other factors that could affect the course of their illness and the effect of the investigational drug. This latter "control' group receives a standard treatment or a placebo (an inactive substance.) Comparison of the two groups tells both the investigators and FDA a great deal about the drug. Often these phase 2 studies are "blinded'--designed and carried out so that neither the patients nor the researchers know who is getting the experimental drug. Blinded studies help avoid errors in interpreting results caused by over-enthusiasm or other kinds of bias among patients and investigators.

There is some controversy over whether it is ethical to give a placebo to some patients in certain drug studies, especially when their condition is a serious or even life-threatening one, such as AIDS (acquired immune deficiency syndrome). Some people think that in such cases all patients should be given the experimental drug, since it offers at least some hope, where the placebo offers none.

But to do so would defeat the purpose of the clinical trial, making it impossible to learn whether the experimental drug does, in fact, have any more effect than no treatment at all. And that knowledge is crucial in the battle against diseases such as AIDS, allowing more lives to be saved in the long run. It is generally agreed, for example, that the clinical trials of the anti-AIDS drug zidovudine (formerly known as azidothymidine, or AZT) were actually shortened by testing it against a placebo. The studies showed dramatically better results for zidovudine, compared to a placebo, and FDA was able to approve the drug for marketing in March 1987, only four months after receiving an application from the drug's manufacturer, Burroughs Wellcome Co., of Research Triangle Park, N.C.

About 30 percent of the drugs studied in phase 2 are abandoned. Thus, of 20 drugs that enter phase 1 clinical trials, only about nine survive to go into phase 3 testing.

By the time the drug is ready for phase 3 studies, both the sponsor and FDA, which has been receiving reports on the progress and results of the clinical trials, know quite a bit about the drug's safety and effectiveness. They know by now from the results of the carefully controlled studies that the drug does have a therapeutic effect. They have a fairly good picture of its short-term side effects and adverse reactions. And they also know that the sponsor is very likely to apply to FDA for approval to put the drug on the market.

There is, however, much yet to be learned about how to use the drug properly. For example, phase 1 and phase 2 testing usually aren't designed to provide information about optimum dose rates and schedules. And, of course, scientists aren't likely to have data on long-term safety in humans. The comparatively small number of patients involved in phase 1 and 2 trials and their short duration generally mean that only the most common, frequent side effects and adverse reactions will have been seen. A more complete understanding of the drug's safety, along with verification of its usefulness in treating disease, has to await the far more extensive testing that constitutes phase 3 clinical trials.