A novel drug or medical device treatment must pass through five primary stages of development before approval. Many good ideas for novel treatments don't even make it through these stages due to various factors, such as incomplete paperwork or lack of funding. A collaboration involving researchers, doctors, regulators, and the private company that owns the patent on the medication or device determines how the trials are set up.
The five stages of development
The five key stages of clinical trials that a novel drug or medical device must pass through before and after it reaches the market include the following:
Stage 1: Preclinical
The safety and effectiveness of experimental medications or devices are evaluated in test tubes, computer models, and often on animals. For medicines, this involves assessing how the compounds move through living organisms and their impact on the disease target. Likewise, devices must also be evaluated for their compatibility with the human body and how they work within the body.
The main goal of preclinical studies is to rigorously assess safety before human tests begin; this is why preclinical studies often take three to six years (or longer) to conduct. Some preclinical safety tests continue even after the start of clinical trials to help identify any long-term adverse effects.
Stage 2: Pilot (Phase 1)
Once ready for testing on humans, the researcher or scientist must file an investigational medicine or device application with the U.S. Food and Drug Administration (FDA) before human testing may begin. The application must show the following:
- Results of preclinical experiments
- The chemical structure of the compound or design of the device
- How it’s thought to work in the body
- Any side effects found in animal studies
- How will it be manufactured
The application must also include a detailed plan of how, where, and by whom the clinical trial will be conducted.
Researchers first test an experimental medication or device in a small group of people to evaluate its safety, determine a safe dosage range, and identify side effects. To establish the safety profile of an experimental medication and determine how it moves through the body, a pilot study may involve 20 to 100 healthy volunteers. Somewhat fewer participants (a dozen or more) are needed for devices. This process can take from six months to a year to complete.
Stage 3: Feasibility (Phase 2)
The experimental medication or device is given to a larger group of patients to assess for basic efficacy and to further evaluate the safety of the experimental treatment. These trials can involve up to 500 subjects. In this phase, it is possible that the experimental treatment will be compared against either the standard of care (e.g., the device or medication that is usually used to treat the disease) or to placebo treatment. In the case of drug trials, a placebo treatment would be an inactive substance or a "sugar pill." In the case of device trials, placebo treatment might involve undergoing a "sham" procedure in which the steps leading up to device use are performed. Still, the device itself is not actually used. These studies typically take up to 1 year to complete.
Stage 4: Pivotal (Phase 3)
The pivotal stage is the phase of clinical trials designed to evaluate safety and effectiveness (efficacy) on a broad sampling of participants—from hundreds to 5,000 or more—of the target patient group. For medications, these are large, randomized (i.e., the participants are randomly assigned to one of two or more treatment "arms" or groups), placebo-controlled trials that generate statistically significant data. This means the results are unlikely to have been reached by chance or coincidence.
Researchers closely and regularly monitor patients to confirm their effectiveness and identify adverse events or side effects. They compare the safety and effectiveness of the new therapy to treatments already in everyday use for the targeted disease or condition. These studies can take one to four years to complete, depending on the study's design and how long it takes to recruit enough patients to meet the minimum size requirements established for the trial.
For any phase 1, 2, or 3 clinical trials to be performed at a hospital, they must first be approved and monitored by an Institutional Review Board (IRB). This committee reviews biomedical and behavioral research involving humans. An IRB is typically set up by academic institutions and medical facilities, but it can also be created by for-profit companies and is called an independent or commercial IRBs. The IRB aims to protect the rights and welfare of those involved in the study. Progress reports on clinical trials must be submitted annually to IRBs and the FDA.
Once the preclinical, pilot, feasibility, and pivotal trials are complete, all data are analyzed to determine if the experimental medication or device is safe and effective. If it is, a new medication or device application is filed with the FDA.
FDA scientists review the study results and determine whether the medication or device is safe and effective enough to be "cleared for marketing." In some cases, an Advisory Committee composed of FDA-appointed experts is convened to review the application and recommend whether the new drug or device should be approved and, if so, under what conditions. The FDA is not required to accept an Advisory Committee's recommendations, but it typically does accept them.
The FDA’s approval process strives to review and act on at least 90% of new drug approvals no later than 10 months after applications are received and six months for priority drug reviews.1 From 2011–2016, the FDA approved 81% of drugs during the first cycle of reviews.2
Stage 5: Post-marketing (Phase 4)
Patients participating in a clinical trial are followed for a year or more—sometimes many years— after a medication or device receives regulatory approval to monitor for safety and effectiveness and to gather additional information about risks, benefits, and optimal use. Since a much more extensive and diverse group of patients is now likely to take medicine or have the device, researchers may detect side effects or adverse events that weren’t apparent during clinical trials. This is why researchers must submit regular reports to the FDA detailing their observed complications. These studies also help researchers better assess how the medication or device affects a particular group of patients based on such criteria as age, sex, race, or condition.
Types of studies
Studies are conducted using varying methods and are commonly classified as observational or interventional. Common study classifications include the following:
- Observational studies – In these studies, researchers only observe study participants and don’t intervene in their care or treatment program. These studies are not considered clinical trials.
- Observational retrospective cohort studies – These studies collect past data and information from the medical records of two groups of similar human populations who differ in only one key characteristic to measure a specific outcome. An example of this would be looking for the prevalence of lung cancer in a population of 40-year-old white women (assigned female at birth) where half of the population smokes tobacco, and half don’t smoke.
- Prospective cohort studies – These studies follow a specific population over a specific time period and observe how key differentiating factors amongst study subjects result in different outcomes.
- Registry studies – These studies observe and collect clinical data about the effectiveness and use of a medication or medical device in a human population that’s already received the medication or device. These studies are typically broad and don’t exclude participants based on age, gender, race, etc.
- Case-control studies – These studies compare a population with a particular medical condition to a similar population without the medical condition to determine factors that may lead to the condition.
- Interventional studies – In these studies, researchers give participants a particular medicine or medical device to assess the outcome. Most clinical trials of a new drug or device are classified as interventional studies because the new treatment is classified as an intervention.
- First-in-man – These studies involve testing on humans for the first time once a medication or device has been previously tested on a nonliving organism or animal.