Clinical Trials: The Phases of Drug Testing and Approval
Discovering and developing new medicines is a long, complex, and costly process, but biopharmaceutical researchers devote their careers to this often frustrating but tremendously gratifying task. The research and development (R&D) process is the road to new medicines—and more often than not it entails many turns, stops, and starts. Substantial progress typically occurs in increments over time, as advances build on each other.
The first step in developing a new medicine is to understand the disease or condition as thoroughly as possible. The entire biomedical research community contributes to this body of knowledge. In the United States, we are fortunate to have a have a dynamic, collaborative research ecosystem that includes researchers from government, industry and academia.
Basic research provides clues about how to treat diseases and potential ways to target the symptoms or underlying causes. Armed with an idea, researchers work to understand biological targets for a potential medicine. A drug target can be a protein, RNA, DNA or other molecule that is somehow involved in the disease. The investigators conduct studies in cells, tissues and animal models to determine whether the target can be influenced by a medicine. Then researchers look for a lead compound—a promising molecule that could influence the target and, potentially, become a medicine.
The drug discovery phase whittles down thousands of compounds to a few hundred promising possibilities that are ready for preclinical testing. In this stage, scientists conduct laboratory and animal studies to determine whether a compound is suitable for human testing. At the end of this process, which can take several years, approximately five compounds move to the next stage, clinical trials in humans. Before beginning a clinical trial, the pharmaceutical research company files an Investigational New Drug Application with the Food and Drug Administration (FDA).
During this stage, a compound is tested in human volunteers. The clinical trials process occurs in several phases and takes on average six to seven years. A potential medicine must successfully complete all of the phases before being submitted to the FDA for review.
Because this process involves both benefits and risks, companies take great care to protect the safety of trial participants and to ensure that they are thoroughly informed about the trial and its potential risks and can give their informed consent to participate, as required by federal regulations. Companies also ensure that the trials are conducted correctly and with integrity, including that the clinical trial results are disclosed at the appropriate time.
The study design and the informed consent are reviewed, approved and monitored by an Institutional Review Board (IRB). The IRB is made up of physicians, researchers, and members of the community. Its role is to make sure that the study is ethical and the rights and welfare of participants are protected. This includes making sure that research risks are minimized and are reasonable in relation any potential benefits.
Following is a general description of the three primary phases of clinical research:
- Phase 1 trials test a compound in a small group (e.g., 20 to 100) of healthy volunteers to determine the safety of the compound.
- Phase 2 trials test the compound in a somewhat larger group (e.g., 100 to 500) of volunteers who have the disease or condition the compound is designed to treat. Phase 2 trials determine effectiveness of the compound, examine possible short-term side effects and risks, and identify optimal dose and schedule.
- Phase 3 trials test the compound in a much larger group (e.g., 1,000 to 5,000) of participants to generate statistically significant information about safety and efficacy and to determine the overall benefit-risk ratio.
PhRMA members have had a longstanding commitment to sponsoring clinical research that fully complies with all legal and regulatory requirements as well as international agreements. In addition, PhRMA has set out voluntary principles to fortify member companies’ commitment to the highest standards for ethics and transparency in the conduct of clinical trials. PhRMA’s Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results are designed to help ensure that clinical research conducted by America’s pharmaceutical research and biotechnology companies continues to be carefully conducted, and that meaningful medical research results are communicated to healthcare professionals and patients.
FDA Review and Approval
If the results of all three clinical trials phases indicate that the compound is safe and effective, the company submits a New Drug Application or Biologics License Application to the FDA. This application, which includes reams of data from all stages of testing, is a request for FDA approval to market the new medicine.
Scientists at the FDA carefully review all the data from all of the studies on the compound and, after weighing the benefits and risks of the potential medicine, decide whether to grant approval. Occasionally, the FDA will ask for additional research before granting approval or convene an independent expert panel to consider data presented by the FDA and the company. The panel will then advise the agency on whether to approve the application and under what conditions.
Approved medicines may be used by millions of people or a small, specific population. Medicines often are in the marketplace for many years. As a result, manufacturing facilities must be carefully planned so that medicines can be consistently and efficiently produced.
Manufacturing facilities must be constructed to the highest standards to ensure that safety and quality are built into each step of the manufacturing process. Companies must adhere to FDA’s Good Manufacturing Practices regulations, and they also must constantly update, overhaul, or even rebuild facilities when new medicines are approved as each new medicine is manufactured differently.
Post-Approval Research and Monitoring
Research on a new medicine does not end when the discovery and development phases are over and the product is on the market. On the contrary, companies conduct extensive post-approval research to monitor safety and long-term side effects in patients using the medicine. The FDA requires that companies monitor a medicine for as long as it stays on the market and submit periodic reports on safety issues. Companies must report any adverse events that occur from use of the medicine.
FDA sometimes requires companies to conduct phase 4 clinical trials, which evaluate long-term safety or effects in specific patient subgroups. Companies may conduct post-approval studies to assess the benefits of a medicine for different populations or in other disease areas. In some cases, they may also develop improved delivery systems or dosage forms.
This research phase is critical to improving researchers’ and clinicians’ understanding of a medicine’s potential uses and its full benefits for health and quality of life. Continued research can show whether a medicine has a greater impact on an outcome when it is used earlier in a disease, in combination with other medicines, in different disease indications, or in combination with specific biomakers.