Clinical Research

Clinical Trial Phases in Drug Development

Clinical Trials are generally considered to be biomedical or health related research studies in human beings that follow a pre-defined protocol. Statistics say that only one molecule out of 5000 new discoveries reach the pharmacist shelf after undergoing various evaluation phases. Every new chemical entity discovered must pass through all the phases of clinical trials to enter into the market.
Once the new chemical entity has been discovered, an extensive laboratory research is conducted in-vitro and in-vivo, to evaluate the pharmacologic (pharmacokinetic and pharmacodynamic) and toxicological parameters. This laboratory research is considered as Pre-Clinical Trials. After the completion of pre-clinical studies, an IND (Investigational New Drug Application) is filed with the FDA in the United States. Once IND gets approved by FDA, depending upon the data obtained in pre-clinical phase; the drug is continued for further research and testing in human beings (Clinical Trial Phases).
Following are the four Clinical Trial Phases:
• Phase I: Human Pharmacology phase
• Phase II: Therapeutic Exploratory phase
• Phase III: Therapeutic Confirmatory phase
• Phase IV: Post Marketing Surveillance

Though Phase 0 studies are not very common and are not mandatory as of now as per regulations, we would describe them too:…
Phase 0: Micro-dosing Studies:
Recently FDA has approved testing of small quantities of experimental drugs in human beings to understand the path of drug in the body. US-FDA designated this phase as phase-0 in accordance with US-FDA 2006 Guideline on Exploratory Investigational New Drug Studies.
A phase-0 studies can be considered as micro-dosing studies. These studies give no data on safety or efficacy, being by definition, a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.

Phase I: Human Pharmacology phase:
Phase-I trials are conducted to determine the pharmacologic (pharmacokinetic and pharmacodynamic) parameters, initial safety and tolerability of drugs in human beings. Usually healthy volunteers participate in these trials, but in some special disease conditions like cancer, AIDS & similar conditions, the diseased population is targeted where participation of healthy volunteers is ethically not possible. Usually a less number of patients, generally 20-80 are included in these trials. These studies typically include both single and multiple dose administration studies.

Phase II: Therapeutic Exploratory phase:
Phase-II is the therapeutic exploration of the primary objective that is to explore therapeutic efficiency of drugs in patients. Once the pharmacologic parameters are determined for the experimental drug from phase-I studies, depending on the data obtained in phase-I, the dose regimen and drug efficacy is determined in two sub-phases:
• Phase-IIA: Dose regimen and dose requirements are assessed.
• Phase-IIB: Efficacy of drug at prescribed dose regimen is evaluated.
Phase-II plays a critical role in successful drug development process. If new drug fails to reach market, this usually occurs during this phase of clinical trial.

Phase III: Therapeutic Confirmatory phase:
Phase-III trials present a bridge between clinical research and the application of its experience in clinical practice. It is, therefore, essential that the experience from a phase III trial is applicable to a broad population of patients. A product that successfully comes through a phase-II trial may be put into a Phase-III clinical trial.
Phase-III studies are most often designed to compare currently available or standard of care treatment with the investigational agent over a large group of patient pool. In this phase, safety and efficacy parameters, side effects, risks and benefits of the investigational product are the main focus. Subjects are randomly assigned to any of the available treatment arms according to pre-defined protocol, hence this phase of clinical trials is also called as Randomized Clinical Trials. As the data obtained in phase-II is confirmed by the data obtained in phase-III, this phase is also called as Therapeutic Confirmatory Trial.
Phase-III trials may be “Double-Blinded”, where neither the investigator nor the subject knows which treatment is being used, or “Single-Blinded”, where only the investigator knows which treatment is being used. They are designed to answer the question of whether or not the new treatment works better, or has fewer side effects than the standard treatment.
If the results are promising, the sponsor of the product would use the trial and other information in its application to bring the product to the market. Thus the information from phase-III trials provides part of the foundation for the licensing application.
Once the phase-III data is obtained, NDA (New Drug Application) is submitted to FDA. The FDA reviews all the data submitted, and approves the drug for marketing if the data is found worth.

Phase IV: Post –Marketing Surveillance:
Post marketing research is an important element of commercialization that enables companies to expand existing markets, enter new markets, develop and deliver messaging that directly compares their products with the competition and secure a niche position in crowded markets.
Phase-IV trials are done to determine if a drug or treatment is safe over time (Safety Surveillance), or to see if a treatment or medication can be used in other circumstances. These studies are often important for optimizing drug’s use. The safety surveillance is designed to detect any rare or long term adverse effects over a much larger patient population and longer period of time than in phase I, II and III trials.
Phase-IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in these studies.

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