Clinical trials

DEFINITION: Research studies that test new drugs or treatments on human subjects to determine whether and at what dosage they are safe, effective, and better than similar products already in use.

ANATOMY OR SYSTEM AFFECTED: All

Indications and Procedures

Clinical trials offer the most reliable process for bringing new drugs and medical treatments into public use. The process has features that attempt to protect human participants, avoid biases, ensure that patient improvements are due to the experimental treatment and not to other factors, and allow accurate comparison of the experimental treatment with others on the market. Clinical trials are usually initiated and managed by academic institutions (often with grant funding), companies, or government research agencies, such as the National Cancer Institute.

In 1998, it was estimated that the cost of developing a new drug was, on average, $500 million, and the process could take twelve to fifteen years—from discovery and laboratory testing, through clinical trials, to Food and Drug Administration (FDA) approval, and finally getting the drug to market. By the late 1990s, a new drug might go through sixty-eight clinical trials. The average number of patients enrolled in a trial was 3,800.

Clinical trials fit into one of four types. Phase I trials, which usually involve only twenty to one hundred seriously ill patients, try to determine how to administer a new drug, the maximally tolerated dose (MTD), how the human body processes the drug, and any significant side effects. Phase II trials, which are usually randomized, treat up to several hundred patients who all have measurable rates of disease. These trials study the effectiveness of the drug. Phase III trials, which are usually randomized and blinded and which treat hundreds or thousands of patients, have more relaxed criteria for inclusion and are usually multicenter (held simultaneously at more than one site). These trials try to determine whether the new drug is better than current, standard ones. Phase IV trials, conducted once a drug is on the market, are often informal. Pharmaceutical companies may simply ask physicians to submit reports on how their patients are responding to the drug.

Uses and Complications

The 1979 Belmont Report detailed three ethical principles to guide clinical trials. They include respect for persons (abiding by their opinions and choices as autonomous agents), (doing no harm and maximizing the possible benefits while minimizing possible harm), and justice (distributing the benefits and burdens of research fairly).

Two standard features of clinical trials help ensure that ethical principles are being followed. First, all clinical trials in the United States must be approved and monitored by an Institutional Review Board (IRB), which includes both scientists and laypersons. Multicenter trials must also have a data safety and monitoring board composed of independent experts. This group monitors data from the trial regarding the treatment’s effectiveness and any adverse reactions. Second, parents must carefully consider and sign the detailed informed consent document in all categories. Most importantly, anticipated physical risks, discomforts and financial risks are explained. Similar practices occur globally.

Perspective and Prospects

In October 1948, The British Medical Journal published an article reporting on what was probably the first study using all the methodological features of the randomized clinical trial. Since then, the randomized has come to be regarded as perhaps the most important medical achievement of the twentieth century. It transformed biomedical research and allowed physicians to make treatment choices based on scientific evidence rather than on personal opinion and experience.

The National Cancer Institute (NCI) and other sources reported a low participation rate in clinical trials—ranging in the late 1990s from 3 to 20 percent of patients. One of many causes was that insurance companies and managed care providers frequently refused payment for experimental treatments. Their concerns were that they might be liable for adverse reactions or additional care after the trial ends and that clinical trials are more costly than conventional treatments. Because so many insurers would not cover the costs of clinical trials, researchers had trouble finding patients willing to participate, thus slowing the development of more effective drugs and treatments. Insurers gradually realized that more widespread coverage of the costs of trials might speed the development of better drugs, which could ultimately save them money. In 1998, US states began to pass laws requiring insurers to cover the routine medical costs (such as tests and office visits) of treatment in clinical trials of drugs for life-threatening diseases.

Criticism has been leveled at clinical trials for insufficient inclusion of women, children, people of color, and the aged. When these groups are underrepresented, there is no certainty that a drug will be effective or without side effects for them. However, there are ethical issues that come into play with clinical trials involving children and older adults.

In June 2000, the FDA added a regulation that would place a clinical hold on a phase I trial of a drug or treatment for a life-threatening disease affecting both women and men if either gender was excluded because of risk to their reproductive potential. That same month, President Bill Clinton signed an executive memorandum directing Medicare to reimburse senior citizens for routine medical costs incurred in clinical trials. A major impetus for this change came from reports that only 33 percent of cancer clinical trial participants were over sixty-five, while 63 percent of all cancer patients are over sixty-five.

During the outbreak of the COVID-19 pandemic, the importance of clinical trials of drugs became apparent through the development of the vaccine to slow the spread of the virus. Patients, nurses, doctors, and researchers played a vital role in stopping the spread of COVID-19 through their participation in clinical trials of the vaccine. Further, to determine the safety and efficacy of the vaccine on children, many parents consented to allow their children to participate in clinical trials for the good of public health. Clinical trials continued in the early 2020s as researchers looked for ways to treat patients suffering from the extended effects of COVID-19 through Long COVID.

Bibliography

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