Clinical Trials

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Chapter: Essential pharmacology : Aspects Of Pharmacotherapy; Clinical Pharmacology And Drug Development

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.

 

Phase I: Human Pharmacology And Safety

 

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.

 

Phase II: Therapeutic Exploration And Dose Ranging

 

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.

 
Phase III: Therapeutic Confirmation/Comparison

 

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.

 

Phase IV: Postmarketing Surveillance/Studies

 

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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