The long road to drug approval

Before prescription drugs are allowed to be sold to the public, they must undergo clinical trials. The four phases of trials are designed to ensure that drugs are safe and effective.

What is a clinical trial?

A clinical trial is a research study to answer specific questions about a new drug or procedure that has not yet been approved for use in general medical practise, or about new ways of using known treatments. Clinical trials (also called medical research and research studies) are used to determine whether new drugs or treatments are both safe and effective, what dosages are most effective, and what side effects a drug may cause in people. Carefully conducted clinical trials are the fastest and safest way to find treatments that work.

What happens before a clinical trial?

Before a clinical trial is conducted, researchers perform laboratory testing on animal and human cells. They may also conduct research on animals. Only if the results of these initial studies demonstrate potential benefits and no serious safety concerns will a clinical trial be considered.

What are clinical trial phases?

Clinical trials of experimental drugs proceed through four phases:

  • In Phase 1 clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to determine what happens to the drug in the human body (how it is absorbed, metabolized, and excreted), evaluate its safety, determine the best way to provide it (injection, orally etc.) and a safe dosage range, and to identify side effects as dosage levels are increased. This initial phase of testing typically takes several months. About 70 per cent of experimental drugs pass this initial phase of testing.
  • In Phase 2 clinical trials, the study drug or treatment is given to a larger group of people, to see if it is effective and to further evaluate its safety. This second phase of testing may last from several months to two years, and involve up to several hundred patients. Most Phase 2 studies are randomized trials. One group of patients will receive the experimental drug, while a second "control" group will receive a standard treatment or a placebo. Often these studies are "blinded" — neither the patients nor the researchers know who is getting the experimental drug. In this manner, the study can provide the pharmaceutical company and the government regulators comparative information about the relative safety of the new drug, and its effectiveness. Only about one-third of experimental drugs successfully complete the first two phases of study.
  • In Phase 3 studies, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare the new drug or treatment with existing drugs or treatments — to determine if the new procedure is better than the existing one — and to collect information that will allow the drug or treatment to be used safely. This large-scale testing provides the pharmaceutical company and government regulators with a more thorough understanding of the drug's effectiveness, benefits, and the range of possible adverse reactions. Most Phase 3 studies are randomized and blinded trials. Phase 3 studies typically last several years. Seventy to 90 per cent of drugs that enter Phase 3 studies successfully complete this phase of testing. Once a Phase 3 study is successfully completed, a pharmaceutical company can request government approval for marketing the drug.
  • Phase 4 studies are done after the drug or treatment has received approval from the government and is available to the public. These studies continue testing the study drug or treatment to collect information about their effect in various populations, any side effects associated with long-term use, and its impact on quality of life.

What happens to the results of clinical trials after they are finished?

Once a clinical trial is completed, the research results are analyzed and often subjected to "peer review." Peer review ensures that research is evaluated by experts in a particular field before being published and accepted by the scientific community as valid research. Results from clinical trials are also used to support an application by a pharmaceutical manufacturer for market approval.

What protections are there for people who participate in clinical trials?

When a sponsor — generally a pharmaceutical company — wants to conduct a clinical trial in Canada, it must apply to Health Canada. The applicant submits a "protocol" that outlines the objectives, methods and rules by which the researchers will function during the trial. The applicant must also justify that a clinical trial is worth whatever potential risks the drug might have and that the patients will not be exposed to undue risk.

Health Canada reviews the application to make sure all the necessary components have been included in the trial and that the scientific methods are sound. The application is also reviewed by an independent committee of physicians, statisticians, community advocates, and others, called a Research Ethics Board (REB), who examine the clinical trial procedures to ensure that the trial is conducted appropriately, ethically, and to protect patients' rights.

All institutions that conduct or support biomedical research involving people must, by federal regulation, have an REB that initially approves and periodically reviews the research.

What is a protocol?

All clinical trials are based on a set of rules called a protocol. Protocols are sets of procedures that ensure the research objectives can be accomplished and make it possible for others to replicate the study. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages, and the length of the study. While in a clinical trial, participants are supposed to be seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.

What is informed consent?

Informed consent is the process of learning the key facts about a clinical trial before you decide whether to participate.

These facts include:

  • Why the research is being done.
  • What the researchers want to accomplish.
  • What will be done during the trial and for how long.
  • What risks are involved in the trial.
  • What benefits can be expected from the trial.
  • What other treatments are available.
  • The fact that you have the right to leave the trial at any time.

If you are considering joining a clinical trial, the research staff should give you informed consent documents that include the details about the study.

Who can participate in a clinical trial?

All clinical trials have guidelines about who can get into the program. Guidelines are based on such factors as age, type of disease, medical history, and current medical condition. Before you join a clinical trial, you must qualify for the study. Some research studies seek volunteers with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. Healthy volunteers participate in Phase 1 trials, vaccine studies, and trials on research on preventive care for children or adults.

The factors that allow you to participate in a clinical trial are called inclusion criteria. The factors that keep you from participating are called exclusion criteria. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study. You should read them carefully to determine if you may be eligible.

If you believe that you meet the listed criteria, it is essential that you discuss the trial with your family doctor or specialist. Your doctor can double-check to make sure you meet the inclusion/exclusion criteria, and also help you to understand the potential risks and benefits of participating. You may then contact the trial co-ordinator, who will provide you with further information. Keep in mind that even if you meet the inclusion/exclusion criteria, there is no guarantee that you will be selected for the clinical trial.

Who sponsors clinical trials?

Clinical trials are sponsored by government agencies, pharmaceutical companies, individual physician-investigators, and organizations that develop medical devices or equipment. Trials can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics. The sponsor of the research hires physicians, who may work in a wide variety of health-care settings, to conduct the clinical trial.

Physicians are typically paid on a per-patient basis. The medical care is often provided free to the patient. Patients may also be paid a small fee to participate in a clinical trial.