All new drugs are labeled as Investigational New Drugs (INDs) by UDFDA. All INDs undergo various stages of development. Clinical trials have been classically divided into four phases as described below in phases of the clinical trial. In addition, phase 0 has been added in recent years.
Phase 0 has been added by USFDA from 2006 guidance on exploratory IND studies. Phase 0 trials are known as human micro-dosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug behaves in human subjects as was expected from pre-clinical studies. Distinctive features of phase 0 trials include the administration of sub-therapeutic doses to a small number of subjects (10-15) to gather preliminary data on the pharmacokinetics of the drug.
Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Based on information from phase 0 studies, a decision regarding the progress of the drug in the next phases is taken.
Phase I trials were formerly called first-in-humans studies. Normally, a small group of 2-100 healthy volunteers is recruited in the phase I trial. These trials are conducted in a clinical trial clinic, where the subject can be observed by a full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug. Normally, phase I trials include dose-ranging, also called dose escalation studies so that the best and safest dose can be identified. Normally, phase I trials include dose-ranging, also called as dose escalation studies, so that the best and safest dose can be identified. The tested range of doses is usually a fraction of a dose that causes harm in animal testing. Although phase I trials are conducted on healthy volunteers, there are some circumstances when clinical patients are used for phase I. In such cases where treatment is likely to make healthy individuals ill, patients with terminal cancer or HIV are used for the trial. In addition to terminal patients, patients who have already tried and failed to improve on existing standard therapies may also participate in phase I trials. Volunteers are paid a variable inconvenience fee for their participation in the phase I trial. In addition, their health insurance premium is paid by the sponsor of the trial. Before beginning the phase I trial, the sponsor must submit an IND application to FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Three types of studies are included in phase I trials: single ascending dose, multiple ascending doses, and the effect of food.
Once a dose range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect on human beings. Phase II trials are performed on a relatively larger group as compared to phase I trials. Normally, 100-300 patients have included in phase II studies. Genetic testing is common, especially when there is evidence of variation in the metabolic rate of the drug. When the development process for an IND fails, it is usually during phase II trials. Conveniently, phase II trials can be divided into two sub-categories: phase II A and phase II B. Phase II A studies are pilot studies designed to demonstrate clinical efficacy or biological activity. It can be termed as “proof of the concept” studies. Phase II B studies find the optimum dose at which the drug shows biological activity with minimal side effects. They are also termed as “definite dose-finding” studies. Occasionally, phase I and phase II may be combined to test both efficacy and toxicity.
Phase II studies historically have recorded the lowest success rate. In 2010, the percentage of phase II trials that proceeded to phase III was 18 %. During 2006-2015, only 37% of developmental drugs advanced from phase II to phase III.
This phase is designed to assess the effectiveness of the IND. Phase III studies are randomized controlled multicentre trials on large patient groups ranging from 300-3000. These studies are aimed at being the definitive assessment of the effectiveness of the drug. Phase III trials are the most expensive, time-consuming, and difficult trials to design and run, especially in chronic diseases. Phase III trials of chronic diseases often have a short follow-up period of evaluation, relative to the period of time during which intervention might be used in clinical practice. Phase III studies are also called as “pre-marketing phase”. During this stage, sub-groups of patients like those having hepatic, renal or cardiac failure may also be exposed to appropriate modifications in dosages. If proof of adequate safety is available, then pediatric and geriatric patients may also be included. In the case of pediatric patients, a separate clinical study is suggested by the regulatory authority.
It is expected that at least two successful phases III trials, demonstrating a drug’s safety and efficacy are necessary in order to obtain approval from appropriate regulatory agencies like USFDA, EMA, etc. Once a drug has proved satisfactory in phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the regulatory submission which is provided for review to appropriate regulatory authorities in different countries. The regulatory authorities review the submission, and if found appropriate, give approval for marketing the drug to the sponsor.
By 2010, about 50% of the INDs fail during phase III trials or are rejected by national regulatory agencies. An estimate of phase II/III trials depends on various factors, a therapeutic area being studied, and types of clinical procedures as key drivers. It is indicated that phase II studies may cost about $ 20 million (` 130 crores), and phase III studies $ 53 million (` 345 crores ).
By the end of phase III studies, after review, regulatory authorities provide marketing permission to the sponsor. Thus, a phase IV trial is also known as post-marketing surveillance trial/confirmatory trial. Phase IV trials involve surveillance of safety and ongoing technical support of a drug. Phase IV studies may be required by regulatory authorities or may be undertaken by the supporting company for competitive or other reasons. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the phase I-III clinical trials. If an adverse drug effect is rare, then it may be detected only in phase IV studies. The minimum time period mandatory for a phase IV clinical trial is of two years. During this period, if a serious adverse reaction is observed, then the use of the drug may be appropriately restricted. If the adverse reaction is too serious, probably causing death, then the drug may be withdrawn from the market during phase IV studies.
The entire process of developing a new drug from pre-clinical research to marketing can take 12-18 years and may cost over $ 1 billion (` 6500 crores). The life of the patent of a drug expires 20 years after its registration. The figures indicate big financial risks in developing a new drug.
A summary of different phases of trials is presented in table 1.1.
Table 1.1: Summary of trial phases
|Sr. No.||Phase||Primary goal||Dose||Typical number of participants|
|1.||Pre-clinical||Testing of the drug in animals to gather efficacy, toxicity, and pharmacokinetics||Unrestricted||Not applicable (in-vitro and in-vivo only)|
|2.||Phase 0||Pharmacokinetics, oral bioavailability, and half-life||Very small, sub-therapeutic||10 healthy volunteers|
|3.||Phase I||Testing on healthy volunteers for dose ranging||Sub-therapeutic with ascending doses||20-100 healthy volunteers (cancer patients for anti-cancer drugs)|
|4.||Phase II||Testing of the drug on patients to assess efficacy and side effects||Therapeutic dose||100-300 patients with specific diseases|
|5.||Phase III||Testing on patients to assess efficacy, effectiveness, and safety||Therapeutic dose||300-3000 patients of diverse sub-groups|
|6.||Phase IV||Post-marketing surveillance watching drug use in public||Therapeutic dose||Anyone seeking treatment from a physician|
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