In the previous set of blogs, we explained different terms involved in a clinical trial (listed later), in this post we write about the different phases of the clinical trials.
Clinical trials can be defined as an interventional research studies that explore the safety and effectiveness of a medical treatment or device in humans. Clinical trials are carried out before any drug, treatment or therapy is marketed. If a particular intervention for e.g. a drug is not beneficial or is toxic to the patient, it should not be marketed. The intention being to avoid any inconvenience to the patients at large.
Since clinical trials are performed in humans, it is mandatory that number of experiments, collectively known as pre-clinical studies, are carried out prior to starting the experiments in humans. These pre clinical studies involve various in silico (computational experiments), in vitro (cell culture) and in animals experiments. Each experiment should follow stringent guidelines and the experimentation in human should be completely justified. Once the regulatory body analyses all the results of the pre-clinical studies, and finds it satisfactory, the experiments in human can begin.
Clinical trials are divided into different phases, each having better statistical power than the previous phase. Please read on to know about these phases:
The Phases of Clinical Trial:
Clinical trials testing new drugs are normally classified into four phases. Each phase is treated as a distinct study (no carry over of data in next phase). If the drug passes successfully through Phases I, II, and III, it will usually be approved by the national regulatory authority for marketing and is available for the physicians to prescribe. Phase IV are ‘post marketing’ studies. All the phases take many years altogether.
Sometimes a Phase 0 is performed before Phase 1. This is an exploratory and not therapeutic phase. A limited number of low doses are administered (nanogram, picogram, femtogram) to the healthy volunteers. Therefore, the phase is also known as human micro-dosing studies.
This phase is designed to study the pharmacodynamic, pharmacokinetic, useful biomarkers and measures of mechanism in human. This phase gives information very early in the study, if the drug works human subjects as estimated from the preclinical studies.
Example: Read this paper on PET Study Using the Human Mini Antibody F16SIP in Head and Neck Cancer Patients.
Phase 1 (toxicity)
Prior to exploring the benefits from the drug, it is important to know the risks (toxicity). That’s the goal of Phase 1. The data obtained in this phase helps prevent severe toxicity later. During this phase, maximum tolerated dose and the safe clinical dosage range are determined. Many predictable toxicities are detected in this phase. Pharmacokinetic measurements of absorption, half-life, and metabolism are often done.
A small number (20–100) of healthy volunteers or volunteer patients with the disease are used in phase 1. Phase 1 studies are usually performed in research centers by specially trained clinical pharmacologists. This phase may take several months.
These trials may be non-blind (open) or may be “blinded” and placebo controlled. The choice of design depends on the drug, disease, goals of investigators, and ethical considerations.
Example: Phase 1 Dose-Finding Study Of Rebastinib (DCC-2036) In Patients With Relapsed Chronic Myeloid Leukemia And Acute Myeloid Leukemia.
Phase 2 (efficacy & dose)
The aim of this phase is to determine the efficacy of the drug and the suitable doses for the following trials. Subjects are the patients with the target disease. The sample size can be around 100–200 patients. A single-blind design may be used. The control group may receive placebo or the active/ standard drug (positive control). This phase is usually carried out in special clinical centers (eg, university hospitals). A broader range of toxicities may be detected in this phase.
Phase II studies are sometimes divided into Phase IIA and Phase IIB. Phase IIA usually involves determination of the dose range (how much drug should be given). Phase IIB involves estimating the efficacy aspect (how well the drug works at the prescribed dose/s).
Phase 2 trials have the highest rate of drug failures, and only around 25% of novel drugs move on to phase 3.
Read an example: here
Phase 3 (safety and efficacy)
The sample size is much greater with 300 to 3000 or more patients with the target disease. This phase further establishes and confirms the safety and efficacy of the drug. Phase 3 trials are designed such that the errors are minimized (bias, etc) caused by placebo effects, variable course of the disease, etc. Therefore, double-blind and crossover techniques are most preferred.
Phase 3 trials are usually performed in situations similar to the ones, where the drug is used in real world. The formulation of the drug is similar to the one intended for the market. The investigators are generally the specialists in the disease. Certain toxic effects, may appear in phase 3 for the first time. This is the most expensive phase.
During this phase an extensive data is collected and analysed. If phase 3 results meet expectations, application is made for permission to market the new agent.
Here’s an example.
New Drug Application (NDA)
Once the three phases are passed successfully, application is submitted to the Regulatory Authority for an approval to market the drug.
These applications are termed New Drug Application (NDA) for drug or a Biological License in case of biologicals. (Regulatory Authority: FDA in US and Drug Controller General of India (DCGI) works under Central Drugs Standard Control Organization (CDSCO).
The application contains full reports of all pre-clinical and clinical data pertaining to the drug under review. Time required in different cases differ, according to the urgency and novelty of the drug. For e.g. for some life-threatening diseases, controlled marketing even before phase 2 studies have been completed may be permitted.
Phase 4 (Post marketing)
Once the Regulatory Authority gives approval, the drug can be marketed and is available for the physicians to prescribe. Any toxicity that arises, is reported by the physician. This phase involves monitoring the safety of the new drug, under actual conditions of use in large numbers of patients after marketing. The data is collected from patients or physicians through different websites, published paper or through questionnaires.
The objectives met in this phase are to:
- Identify new toxicity after the product is already in market (interaction, etc)
- Understand the usage.
- Detect unidentified use
- Recognize any potential error in prescription and the possible safety measures.
The rare possible event (with incidence of 1 in 10,000 or less) induced by the drug are reported in this phase, as the sample size is very large. The toxicity arising after chronic dosing may also be detected. Phase 4 has no fixed duration.
Example: here’s a paper about post marketing reports of high doses of loperamide been associated with TdP and other serious cardiac adverse events.
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Read more posts by The Biotech Notes:
Previous posts on Clinical trials:
- Katzung, B. G., Masters, S. B., & Trevor, A. J. (2012). Basic & clinical pharmacology. New York: McGraw-Hill Medica