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Clinical Trials - the basics

by Dr Cedric Nazareth


New drug development involves preclinical and clinical evaluation. During preclinical studies, the molecule is known as an investigational new drug (IND), and is evaluated for efficacy against the disease vector and for safety in animals. This stage of drug investigation last for 3 to 5 years and costs about $100-150 million. Then come the clinical studies, which take about 5 to 8 years and usually cost about $300 350 million. In India, these studies could be done at about one-tenth of the cost. Opportunities for clinical trials in this country will also open up because product patent protection will encourage Indian and multinational companies to develop new pharmaceutical products in India.

Here we will look briefly at some key aspects of clinical trials methodology.

Stages in clinical trials

Clinical studies of new drugs are divided into four phases. In Phase 1 studies, a new drug is administered to humans for the first time. A small number of about 20-100 healthy volunteers are involved. Phase 1 trials aim at getting a rough idea of the dose to be administered in humans and detecting harmful adverse effects. The initial dose is very low; perhaps one-hundredth of the lowest effective dose, per kilogram body weight, used in animal studies. The dose is gradually increased, but in Phase 1 the dose to be attained does not exceed that required to produce any detectable effect - desirable or undesirable. Single doses, and later multiple doses, are evaluated. Phase 1 studies include pharmacokinetic evaluation, and when all the necessary studies have been done in healthy volunteers, the drug may be administered to patients to demonstrate its pharmacodynamic effects.

In Phase 2 studies, more data is generated by administering the drug to a somewhat larger number (100-300) of patients for limited periods.

Phase 3 studies form the last group of pre-marketing trials and involve even larger and more varied patient populations. The drug is administered for a longer duration, extending to 6-12 months for drugs intended for long term treatment. Comparisons may be undertaken with proven treatments.

Phase 4 trials are those undertaken after the drug has become commercially available. Large numbers of patients may be involved, and these studies help detect adverse effects that may not have been recognised in earlier studies with smaller patients groups and shorter treatment durations. Newer uses and new patient categories may also be studied.

Types of studies

The design of a clinical trial is based on a set of rules called a protocol. The protocol spells out the materials and method for the study, including the types of patients who will participate in the trial (inclusion and exclusion criteria), tests and procedures to be employed, medications and their dosages, duration of the study and the end points.

Clinical trials are generally controlled. This means that the trial drug will be compared against a control medication, with one group of patients being given the drug under evaluation while a control group is given a standard treatment for the illness or a placebo. Patients are usually randomly assigned (randomised) to one or the other group.

Studies may also be open or blinded. In an open study, the participants know what they are getting, but in a blinded study, they do not know whether they are in the experimental or control group. A double-blind study is one in which neither the participants nor the study staff know which is the trial drug and which is the control. Such studies minimise bias. In some trials, patients who were initially given the control medication are later administered the trial drug and vice versa (crossover study).

Having conducted a clinical trial, statistical analysis can determine whether the data generated with a trial drug are indeed significantly different from those in the control group. The probability that differences between the two groups are not simply due to chance are reflected in the p values which are commonly mentioned in trial reports. Generally speaking, a p value of 0.05 or less reflects a statistically significant finding, and the lower the p value, the greater will be the significance.

November 2000 Pharma Marketing Page.
This article appeared in Pharma Business, December 22, 2000.
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