How Pharmaceutical Companies Test Drugs in Clinical Trials

Before the US Food and Drug Administration (FDA) will allow a new substance to be sold in the United States, it requires pharmaceutical firms to document that the drug substance is safe and effective. To do so, the company must conduct clinical trials of the drug in healthy individuals and patients who have the condition or disease the drug will treat.

The expenses and risks of testing a drug in clinical trials are considerable. It can cost hundreds of millions of dollars to conduct the clinical trials required to market a drug. And the vast majority of drugs entering clinical trials fail, making attrition of drugs in clinical trials an important contributor to the high cost of pharmaceutical R&D.

To minimize monetary and safety risks, and because the FDA requires it, pharmaceutical companies conduct clinical trials in stages. Firms are also required to conduct efficacy and safety studies in vitro (in laboratory tests or assays) and in vivo (in living organisms) before starting human studies. Companies usually conduct preclinical toxicology, pharmacology, and efficacy (a measure of how well the drug works) studies in animals.

Many pharmaceutical firms do not dose patients themselves in studies. Instead, they hire a contract research organization to conduct the clinical trials or fund academic medical researchers who carry out the clinical studies at a teaching hospital or medical center.

Before a company can begin testing the drug in humans, it must file an Investigational New Drug (IND) application with the FDA. This application identifies the substance to be tested and how it will be manufactured. The IND lists planned indications, plans for how the clinical trials will be conducted, what criteria will be used to judge success or failure of the drug in each clinical trial, and clinical testing procedures. The IND remains open through the entire course of the clinical studies of the new drug. The firm updates the IND periodically as more becomes known about the drug through clinical studies.

Pharmaceutical companies may begin clinical trials outside the US without filing the IND. Studies in developing countries, Europe, and Asia are common because they facilitate patient enrollment and reduce costs. International harmonization, or standardization of requirements to market a drug throughout the world, enables companies to use data collected in one country to gain approval to market the drug in a country other than the one in which the clinical studies were conducted.

Most clinical trials are conducted as controlled clinical studies. People participating in a controlled clinical trial are assigned to a group that receives the study medication (study group) or an alternative treatment (the control group). The control group often receives a placebo, but this is not the only option. For drugs that treat life-threatening conditions, such as cancer or heart disease, the drug is usually added to a regimen of FDA-approved medicines or treatments. Ethical guidelines do not allow patients who have life-threatening diseases to receive a placebo (no treatment) when therapies are available.

Often, information about who is receiving the control treatment and who is receiving the study medication is concealed. Studies of this type, called "double-blind" studies, are considered more rigorous than those in which researchers know who receives what treatment, called open-label studies. Open-label studies may be subject to experimental biases. If the researchers or patients know they are receiving the study treatment instead of the control, they may judge the result of the drug treatment differently than if they do not know.

Phase 1 clinical studies test the safety of the drug in a limited number of healthy volunteers and establish initial guidelines for dosages. Study volunteers receive various amounts of the drug or a placebo. The study researchers, or clinical investigators, monitor them for possible adverse reactions to the drug, which might affect its safety, and monitor for possible side effects of the active ingredient. Although animal studies can predict many possible problems, a drug may be processed differently in the human body than in animals. Study investigators may also monitor the people receiving the drug or collect samples to determine how the drug is absorbed, processed by the body (metabolized), and eliminated from the body.

If a drug shows no adverse events in healthy volunteers, the company conducts Phase 2 clinical studies in patients. The company recruits a limited number of patients to show that the drug has the expected therapeutic benefits (efficacy studies) in people with the condition or conditions to be treated. Usually the company must show that the treatment results in improvement, not that it is better than drugs that are already sold to treat a disease. If the firm plans to market the drug for multiple conditions, for example, breast cancer and prostate cancer, they conduct separate studies for each condition.

If the Phase 2 results are promising, the FDA gives the go-ahead, and the drug has commercial potential, the firm begins Phase 3 studies. This is the most expensive part of clinical trials. During large efficacy and safety studies conducted for Phase 3 clinical trials, firms and the researchers they have contracted with collect and keep detailed information about large numbers, sometimes thousands, of patients. Firms record how many people and which people achieve specific study results, called "endpoints."

Phase 3 clinical studies track the prevalence of known side effects and problems with the drug, called adverse events. They also look for serious and rare adverse events, such as stroke or liver damage that might affect drug safety. No drug is entirely without side effects and adverse events, and the number considered reasonable for a marketed drug can vary with the seriousness of the condition it treats and the availability of other therapy options.

The final stage before approval of a new substance is to file a New Drug Application (NDA) with the FDA. The NDA covers all that is known about a drug: clinical trial results for every patient studied, how the drug will be manufactured, its properties, what exactly will be in the labeling information, and anything else that needs to be specified. In the days before electronic submissions, pharmaceutical firms rented trucks to deliver application materials, and filled them. NDA submissions could run to hundreds, or more, of volumes. Now, electronic submission of study data helps streamline the application process.

The FDA staff and its advisory panels are expected to review the material in an unbiased manner before making a decision. The FDA relies on its advisory panels to provide expert advice regarding the approval of drugs and medical devices. Although it usually does not go against the advice of the experts, it is not required to follow their advice in making approval decisions.