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Pharmaceutical company

Regulatory authority

Pharmaceutical company

Regulatory authority

Purpose of therapeutic To select best candidate evaluation for development and registration

To satisfy the regulatory authority on efficacy, safety and quality

To promote drug to expand the market

To add to indications (by variation to licence) arid to add evolving safety information

The process of therapeutic evaluation may be divided into pre- and postregistration phases (Table 4.1), the purposes of which are set out below.

When a new drug is being developed, the first therapeutic trials are devised to find out the best that the drug can do (and how it looks) under conditions ideal for showing efficacy, e.g. uncomplicated disease of mild-to-moderate severity in patients taking no other drugs, with carefully supervised administration by specialist doctors. Interest lies particularly in patients who complete a full course of treatment. If the drug is ineffective in these circumstances there is no point in proceeding with an expensive development programme. Such studies are sometimes called explanatory trials as they attempt to 'explain' why a drug works (or fails to work) in ideal conditions.

If the drug is found useful in these trials, then it becomes desirable next to find out how closely the ideal may be approached in the rough and tumble of routine medical practice: in patients of all ages, at all stages of disease, with complications, taking other drugs and relatively unsupervised. Interest continues in all patients from the moment they are entered into the trial and it is maintained if they fail to complete, or even to start, the treatment; what is wanted is to know the outcome in all patients deemed suitable for therapy, not only in those who successfully complete therapy.16 The reason some drop out may be related to aspects of the treatment and it is usual to analyse these according to the clinicians' initial intention (intention-to-treat analysis), i.e. investigators are not allowed to risk introducing bias by exercising their own judgement as to who should or should not be excluded from the analysis.

16 Information on both categories (use effectiveness and method effectiveness) is valuable. Sheiner L B et al 1995 Intention-to-treat analysis and the goals of clinical trials. Clinical Pharmacology and Therapeutics 57:1.

In these real life, or 'naturalistic', conditions the drug may not perform so well, e.g. minor adverse effects may now cause patient noncompliance, which had been avoided by supervision and enthusiasm in the early trials. These naturalistic studies are sometimes called 'pragmatic' trials.

The methods used to test the therapeutic value depend on the stage of development, who is conducting the study (a pharmaceutical company, or an academic body or health service at the behest of a regulatory authority), and the primary endpoint or outcome of the trial. The methods include:

• Formal therapeutic trials

• Equivalence and noninferiority trials

• Safety surveillance methods

Formal therapeutic trials are conducted during Phase 2 and Phase 3 of preregistration development, and in the postregistration phase to test the drug in new indications. Equivalence trials aim to show the therapeutic equivalence of two treatments, usually the new drug under development and an existing drug used as a standard active comparator. Equivalence trials may be conducted before or after registration for the first therapeutic indication of the new drug (see p. 61 for further discussion). Safety surveillance methods use the principles of pharmacoepidemiology (see p. 68) and are mainly concerned with evaluating adverse events and especially rare events, which formal therapeutic trials are unlikely to detect.

Need for statistics

In order truly to know whether patients treated in one way are benefited more than those treated in another, is essential to use numbers. Statistics may be defined as 'a body of methods for making wise decisions in the face of uncertainty'.17 Used properly, they are tools of great value for promoting efficient therapy.

Over 100 years ago Francis Galton saw this clearly.

In our general impressions far too great weight is attached to what is marvellous ... Experience warns us against it, and the scientific man takes care to base his conclusions upon actual numbers. The human mind is ... a most imperfect apparatus for the elaboration of general ideas ... General impressions are never to be trusted. Unfortunately when they are of long standing they become fixed rules of life, and assume a prescriptive right not to be questioned. Consequently, those who are not accustomed to original enquiry entertain a hatred and a horror of statistics. They cannot endure the idea of submitting their sacred impressions to coldblooded verification. But it is the triumph of scientific men to rise superior to such superstitions, to devise tests by which the value of beliefs may be ascertained, and to feel sufficiently masters of themselves to discard contemptuously whatever may be found untrue ... the frequent incorrectness of notions derived from general impressions may be assumed...18

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