When a compound deserving trial in man is identified by animal studies, the regulatory authorities are approached who on satisfaction issue an ‘investigational new drug’ (IND) licence. The drug is formulated into a suitable dosage form and clinical trials are conducted in a logical phased manner.
CLINICAL TRIALS
When a compound
deserving trial in man is identified by animal studies, the regulatory
authorities are approached who on satisfaction issue an ‘investigational new
drug’ (IND) licence. The drug is formulated into a suitable dosage form and
clinical trials are conducted in a logical phased manner. To minimize any risk,
initially few subjects receive the drug under close supervision. Later, larger
numbers are treated with only relevant monitoring. Standards for the design,
ethics, conduct, monitoring, auditing, recording and analyzing data and reporting
of clinical trials have been laid down in the form of ‘Good Clinical Practice’ (GCP) guidelines by an International Conference on Harmonization (ICH). Adherence to
these provides assurance that the data and reported results are credible and accurate,
and that the rights, integrity and confidentiality of trial subjects are
protected. The clinical studies are conventionally divided into 4 phases.
The
first human administration of the drug is carried out by qualified clinical
pharmacologists/ trained physicians in a setting where all vital functions are
monitored and emergency/ resuscitative facilities are available. Subjects
(mostly healthy volunteers, sometimes patients) are exposed to the drug one by
one (total 20–40 subjects), starting with the lowest estimated dose and
increasing stepwise to achieve the effective dose. The emphasis is on safety
and tolerability, while the purpose is to observe the pharmacodynamic effects in
man, and to characterize absorption, distribution, metabolism and excretion. No
blinding is done: the study is open label.
This is conducted by
physicians who are trained as clinical investigators on 100–400 patients selected
according to specific inclusion and exclusion criteria. The primary aim is
establishment of therapeutic efficacy, dose range and ceiling effect in a controlled
setting. Tolerability and pharmacokinetics are studied as extension of phase I.
The study may be blinded or open label and is generally carried out at 2–4
centres.
Generally these are
randomized double blind comparative trials conducted on a larger patient
population (500–3000) by several physicians at many centres. The aim is to
establish the value of the drug in relation to existing therapy. Safety,
tolerability and possible drug interactions are assessed on a wider scale,
while additional pharmacokinetic data may be obtained. Indications are
finalized and guidelines for therapeutic use are formulated. A ‘new drug
application’ (NDA) is submitted to the licencing authority, who if convinced give
marketing permission.
After the drug has
been marketed for general use, practicing physicians are identified through
whom data are collected on a structured proforma about the efficacy,
acceptability and adverse effects of the drug (similar to prescription event
monitoring). Patients treated in the normal course form the study population:
numbers therefore are much larger. Uncommon/idiosyncratic adverse effects, or
those that occur only after longterm use and unsuspected drug interactions are
detected at this stage. Patterns of drug utilization and additional indications
may emerge from the surveillance data.
Further therapeutic
trials involving special groups like children, elderly, pregnant/lactating women,
patients with renal/hepatic disease, etc. (which are generally excluded during
clinical trials) may be undertaken at this stage. Modified release dosage
forms, additional routes of administration, fixed dose drug combinations, etc.
may be explored.
As such, many drugs
continue their development even after marketing.
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