- Clinical research
Clinical research is a branch of medical science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use. These may be used for prevention, treatment, diagnosis or for relieving symptoms of a disease.
The term clinical research refers to the entire bibliography of a drug/device/biologic, in fact any test article from its inception in the lab to its introduction to the consumer market and beyond. Once the promising candidate or the molecule is identified in the lab, it is subjected to pre-clinical studies or animal studies where different aspects of the test article (including its safety toxicity if applicable and efficacy, if possible at this early stage) are studied.
In the United States, when a test article is unapproved or not yet cleared by the FDA, or when an approved or cleared test article is used in a way that may significantly increases the risks (or decreases the acceptability of the risks), the data obtained from the pre-clinical studies or other supporting evidence, case studies of off label use, etc. are submitted in support of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) for review prior to conducting studies that involve even one human and a test article if the results are intended to be submitted to or held for inspection by the FDA at any time in the future (in the case of an already approved test article, if intended to submit or hold for inspection by the FDA in support of a change in labeling or advertising). Where devices are concerned the submission to the FDA would be for an Investigational Device Exemption (IDE) application if the device is a significant risk device or is not in some way exempt from prior submission to the FDA. In addition clinical research may require Institutional Review Board (IRB) or Research Ethics Board (REB) and possibly Other institutional Committee reviews, Privacy Board, Conflict of Interest Committee, Radiation Safety Committee, Radioactive Drug Research Committee, etc.]] approval whether or not the research requires prior submission to the FDA. Clinical research review criteria will depend on which Federal regulations the research is subject to (e.g., [(Department of Health and Human Services (DHHS) if Federally funded, FDA as already discussed) and will depend on which regulations the institutions subscribe to, in addition to any more stringent criteria added by the institution possibly in response to state or local laws/policies or accreditation entity recommendations. This additional layer of review (IRB/REB in particular) is critical to the protection of human subjects especially when you consider that often research subject to the FDA regulation for prior submission is allowed to proceed, by those same FDA regulations, 30 days after submission to the FDA unless specifically notified by the FDA not to initiate the study.
In the European Union, the European Medicines Agency (EMA) acts in a similar fashion for studies conducted in their region. These human studies are conducted in four phases in research subjects that give consent to participate in the clinical trials.
Phase 1 trials
This phase is also called as first in humans. Phase 1 trials usually deal with investigating the studied drug in a minor number of research subjects (e.g. 10) who are healthy volunteers. This phase is mainly targeted at identifying the safety, tolerability, and the general mechanism of the action of the drug in humans.
These studies are usually conducted in tightly controlled clinics called CPUs (Central Pharmacological Units), where participants receive 24-hour medical attention and oversight. In some diseases in which the therapy under study is known to be too toxic for healthy subjects (some cancer medications, for instance), phase 1 trials are performed in patients with diseases to test these parameters.
Phase 2 trials
The goal of phase 2 trials is to grasp additional understanding of the studied drug's safety and efficacy. It also determines the appropriate dose to be administered to deliver the desired treatment effect while minimizing the safety risk of future research subjects. This usually requires more than 100 patients to demonstrate relevant results, although the actual number of subjects varies widely based on the disease under study. Thus, multiple clinics are utilized to recruit subjects with the disease under study to sufficiently enroll the study(ies) in a reasonable period of time.
Phase 3 trials
This is also called pre marketing. Multiple phase 2 studies are often required to define the appropriate patient population to study during phase 3. Once the drug is deemed a potentially safe and effective candidate in Phase 2, it is then studied in Phase 3 trials. This phase often exposes more than 1000 research subjects with the disease, and is usually performed at many clinics (sometimes well over 100) to enroll the trial (or trials). There is a focus on the effectiveness of the study drug in a variety of demographic and socioeconomic subjects with variants of the disease under study. A comparison is usually made with standard drugs available on the market. It is imperative that the drug is shown to be effective and safe in this phase.
When phase 3 trials are completed (as well as the data demonstrating safety and efficacy of the study drug), a New Drug Application (NDA) containing all manufacturing, pre-clinical, and clinical data is filed with the FDA for review. If deemed safe and effective, the FDA grants approval of the NDA, which then allows the company to market the product. This approval usually comes with strict requirements for the company to conduct additional studies to keep the NDA active (usually involving pediatric trials and additional safety trials).
Phase 4 trials
This phase is also called as post-marketing surveillance phase.In phase 4, the aim is to further characterize the safety of the drug through the identification of unknown adverse reactions and to potentially research new therapeutic indications. Companies often use this phase to gain exposure to different physicians and clinics, which aids in the marketing of their product. The entire process of a drug from lab to market may take approximately 12 to 18 years (but not always), costing billions of dollars.
Clinical research continues throughout the lifetime of the test article to include post marketing surveillance where a periodic 'progress report' is submitted to the regulatory authorities once every 2 years after the test article is released into the market, and such as pharmacovigilance where the safety of marketed drugs, biologics or medical devices are monitored.
The focus of clinical research is wide enough to include important items such as data management, medical writing, regulatory consultation, and biostatistics.
The clinical trials are regulated by country specific Health Regulatory Agencies such as the Food and Drug Administration (FDA) in the U.S. and the European Medicines Agency (EMEA) in the European Union.
Biomedical research: Clinical study design / Design of experiments Overview Controlled study
(EBM I to II-1; A to B)
(EBM II-2 to II-3; B to C)
occurrence: Incidence (Cumulative incidence) · Prevalence (Point prevalence, Period prevalence)
association: absolute (Absolute risk reduction, Attributable risk, Attributable risk percent) · relative (Relative risk, Odds ratio, Hazard ratio)
other: Virulence · Infectivity · Mortality rate · Morbidity · Case fatality · Specificity and sensitivity · Likelihood-ratios · Pre/post-test probability
Trial/test types Analysis of clinical trials
Interpretation of results
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