The U.S. National Institutes of Health (NIH) defines a clinical trial as: “A research study, in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”
Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see whether they should be approved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine, blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine potential toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promise are then moved into clinical trials. Clinical trials are often used to learn if a new treatment is more effective and or has less risk (side effects) than the standard treatment. There are four phases in clinical trials, after first three phases, the researchers find a drug or other intervention to be safe and effective, the FDA approves it for clinical use and continues to monitor its risks and effects.
The 4 phases of biomedical clinical trials are:
Phase 1 Trials:
This phase occurs directly after lab testing. Based on the lab testing, researchers have determined that the drug, device or other treatment may provide a benefit to humans. However, at this point, it has not yet been determined how the drug will affect or react to a human’s biology, or whether it’s safe or even effective. Phase 1 usually consists of a very small number of participants — either mostly healthy subjects or patients, such as terminal cancer patients — and is conducted to evaluate the drug’s overall safety and determine the safest dose of the drug. The phase 1 studies examine the pathways through which the drug is absorbed, distributed in the body, metabolised and eliminated and the maximum tolerable dose. They can also study proposed formulas and dosage (frequency and scheduling) for further trials. Phase I studies might typically require 12 months to complete and involve comparatively few subjects.
Phase 2 Trials:
After appropriate dosing is established in Phase 1, the clinical trial moves on to Phase 2. In this phase, the experimental drug or treatment is tested on a larger group of people (up to several hundred), lasting several weeks or months and often uses a double blind design where a standard of care comparator product or placebo is used to benchmark the investigation product’s safety and efficacy. These trials aim to study the drug as administered to patients who already have the disease which the drug may have the potential to treat. The objective is to determine the optimal dose and dosing regimen, one which delivers maximal efficiency alongside acceptable adverse effects. If results from this phase show that the new drug or device may be just as beneficial or more beneficial than the existing drug or device to treat the same or similar ailments, then researchers can move to Phase 3.
Phase 3 Trials:
These trials test drugs that have been successful in Phase 1 and 2 trials. In this phase, the experimental drug or treatment being studied is given to large groups of people involves hundreds or even thousands of patients and may require several years for completion. Researchers will use these trials to confirm the drug’s efficacy, monitor side effects, compare it to other commonly used treatments or to a placebo, and collect information to ensure safe use of the drug or treatment. The aim is to gain statistically significant scientific proof of a positive benefit-risk profile of the medicinal product which is required for regulatory approval and often the favoured design is again double blind with randomised allocation of patients to receive active drug or placebo or active comparator treatment.
Phase 4 Trial:
This phase occurs post-marketing, meaning after a drug has been shown to work and the treatment has received FDA approval. Studies done at this stage are designed to evaluate the long-term risks and benefits of a medication. This phase can also determine more about the side effects, interactions with other drugs, and how well it works when it’s more widely used.
Who conducts Clinical trials?
Clinical trials are overseen by a principal investigator, who is typically a medical doctor. A research team made up of doctors, nurses, pharmacists, social workers and other health care professionals will also aid in carrying out the clinical trial protocol and recording of data.
The sponsoring and funding of clinical trials often comes from the pharmaceutical companies manufacturing the drugs, devices and other treatments. Academic medical centers, voluntary specialty groups and governmental agencies, such as the National Institutes of Health, as well as doctors and other health care providers, can also sponsor trials.
Who Regulates Clinical trials?
The U.S. Food and Drug Administration requires certain clinical trials to register with and submit results information to the ClinicalTrials.gov databank. Clinical trials that are subject to these requirements include trials conducted on both drugs and devices. Every clinical trial that receives funds from the NIH is automatically required to register and submit results information to ClinicalTrials.gov. The goal of sharing the information is to avoid unnecessary and duplicative trials.
Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.
In the IND application, developers must include:
- Animal study data and toxicity (side effects that cause great harm) data
- Manufacturing information
- Clinical protocols (study plans) for studies to be conducted
- Data from any prior human research
- Information about the investigator
What Happens After a Clinical Trial?
Once a clinical trial is completed, the researchers carefully examine all of the collected data before making a final determination as to the meaning of the findings or whether further testing may be needed. Following Phase 1 and Phase 2 trials, researchers have to decide whether to stop testing if it is determined that the new drug, device or other treatment being tested was found to be unsafe or ineffective. After Phase 3 trials, researchers make conclusions regarding the medical importance of the new treatment approach to certain diseases or conditions.
Clinical trial results are often published in a peer-reviewed scientific journal. Peer review refers to the evaluation of a manuscript by experts in that particular field to determine if it is appropriate for publication. Peer review is vital for maintaining the quality of scientific literature.
If a drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file a New Drug Application (NDA) to market the drug. The FDA review team thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve it.
A NDA tells the full story of a drug. Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied. A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include:
- Proposed labeling
- Safety updates
- Drug abuse information
- Patent information
- Any data from studies that may have been conducted outside the United States
- Institutional review board compliance information
- Directions for use
References:
FDA drug development process