- Clinical Trials

A new drug must be tested first in the test tube, then animal models, and then in patients. Clinical trials are research studies involving unapproved drug and volunteer patients. Clinical trials assess the safety and efficacy of the potential therapy — under highly controlled circumstances. Clinical trials usually last two to four years and go through at least three separate phases.

Three Phases of Drug Testing in Humans

Phase 1 Number of Patients: 20-100 Length: Several months Purpose: Mainly safety Percent of Drugs Successfully Tested*: 70 percent Phase 2 Number of Patients: Up to several hundred Length: Several months to 2 years Purpose: Some short-term safety but mainly effectiveness Percent of Drugs Successfully Tested*: 33 percent Phase 3 Number of Patients: Several hundred to several thousand Length: 1-4 years Purpose: Safety, dosage, effectiveness Percent of Drugs Successfully Tested*: 25-30 percent

At the successful completion of lengthy human clinical trials, (This takes about two years) the innovator files a New Drug Application (NDA) submission with the FDA seeking to bring the new compound to market. The process required to establish safety and efficacy can take as long as 10-12 years, and cost in excess of $250 million. In order to recapture this investment, the innovator is typically granted a period of market exclusivity.

Pharmaceutical companies will benefit from a more industry-friendly regulatory environment with the Food and Drug Administration (FDA) since President Clinton signed in November 1997 the renewal of 1992 Prescription Drug User Fee Act (PDUFA). Under the original program, drugmakers paid the FDA some $327 million from 1993 to 1997. These funds helped the FDA hire 600 new drug reviewers, speeding up new drug approvals and making the approval process more efficient. As a result, approval times for new drugs declined from an average of 29.2 months in fiscal 1992 to 11.7 months in fiscal 1998 for new drugs and the biologics reviewed in an average of 13.5 months.

The number of new medicines (both pharmaceutical and biotech) approved increased from 26/yr in 1992 to a record 53/yr in 1996. For 1998, there were 30 new drugs and 9 new biologics approved by the FDA. The goal of the renewal is to modernize the agency in an era of rapid scientific discovery, and find ways of getting health products to patients quickly without compromising safety.

Clinical Trials: In a controlled trial, patients in one group receive the investigational drug. Those in a comparable group--the controls--get either no treatment at all, a placebo (an inactive substance that looks like the investigational drug), a drug known to be effective, or a different dose of the drug under study. Usually the test and control groups are studied at the same time. In fact, usually the same group of patients is divided in two with each subgroup getting a different treatment. That is the best way to be sure the groups are similar.

It is important that the treatment and control groups be as similar as possible in characteristics that can affect treatment outcome. For instance, all patients in specific groups must have the disease the drug is meant to treat or same stage of the disease. In a clinical trial of a drug to treat angina (chest pain associated with cardiovascular disease), for example, if one group of patients being studied actually had sore ribs rather than angina, their differing response to the drug could not be assumed to be due to its effectiveness or lack thereof.

Treatment and control groups should also be of similar age, weight, and general health status, and be similar in other characteristics that could affect the outcome of the study, such as other treatment being received at the same time.
Two principal methods have been used to achieve this all-important comparability. One is to carefully pair each person in the treatment group with a control patient who has closely matching characteristics. This method is rarely used today because even in the best of circumstances, it's difficult to match pairs of patients for the myriad factors that could have a bearing on results.

In the more common approach, called randomization, patients are randomly assigned to either the treatment or control group, rather than deliberately selected for one group or the other. When the study population is large enough and the criteria for participation are carefully defined, randomization yields treatment and control groups that are similar in important characteristics. Because assignment to one group or another is not under the control of the investigator, randomization also eliminates the possibility of "selection bias," the tendency to pick healthier patients to get the new treatment.

In clinical trials, bias (a "tilt" in favor of a treatment) can operate like a self-fulfilling prophesy. The hope for a good outcome can skew patient selection so that the treatment group includes a disproportionate number of patients likely to do well whatever their treatment.

The same kind of inadvertent bias can lead both patients and investigators to overrate positive results in the treatment group and negative findings among controls, and cause data analysts to make choices that favor treatment. Clinical trials that include such biases are likely to be incapable of assessing drug effect. In conjunction with randomization, a design feature known as "blinding" helps ensure that bias doesn't distort the conduct of a study or the interpretation of its results.

Single-blinding consists of keeping patients from knowing whether they are receiving the investigational drug or a placebo. In a double-blind study, neither the patients, the investigators, nor the data analysts know which patients got the investigational drug. Only when the closely guarded assignment code is broken to identify treatment and control patients do the people involved in the study know which is which.

Testing experimental drugs in people inevitably presents ethical questions. For example, is it ethical to give patients a placebo when effective treatment is available? Not all authorities agree on the answer. But the generally accepted practice in the United States, and one increasingly being adopted abroad, is that well and fully informed patients can consent to take part in a controlled-randomized-blinded clinical trial, even when effective therapy exists, so long as they are not denied therapy that could alter survival or prevent irreversible injury. They can voluntarily agree to accept temporary discomfort and other potential risks in order to help evaluate a new treatment.

In any trial in which a possible effect on survival is being assessed, it's important to monitor results as they emerge. That way, if a major effect is seen, positive or negative, the trial can be stopped. This happened in the first clinical study of the AIDS drug zidovudine (AZT), when a clear survival advantage for patients receiving zidovudine was seen well before the trial was scheduled to end. The trial was then ended early, and within a week the FDA authorized a protocol allowing more than 4,000 patients to receive zidovudine before it was approved for marketing under the brand name Retrovir.

Compassionate use The FDA has a "compassionate use" exception under which companies can give experimental drugs to dying patients without including their statistics. But many more patients want the drugs than receive them.

The AZT saga is an example of the ethical principle that if a lifesaving or life-extending treatment for a disease does exist, patients cannot be denied it. In some cases, a new treatment can be compared with established treatment, so long as the effectiveness of the latter can readily be distinguished from placebo and the study is large enough to detect any important difference. It is also possible to evaluate new drugs in this situation in "add-on" studies. In this kind of trial, all participants receive standard therapy approved for treating the disease, but those in the treatment group also get the investigational drug. The control group gets either no added treatment or placebo. Any difference in results between the treatment and control groups can be attributed to the investigational drug. It is common to study new anti-seizure drugs in this way, as well as new agents intended to reduce mortality after a heart attack.

On the other hand, newer drugs can also pose unknown risks - Some doctors are preferentially prescribing news drugs rather than older more established ones. Only when a drug is on the market for several years, and used by hundreds of thousands of people are its risks truly well understood.

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