Clinical Pharmacology and Therapeutics

90 INTRODUCTION OF NEW DRUGS AND CLINICAL TRIALS
Does the therapy have
unacceptable adverse effects?
No
Does the therapy exhibit
potentially useful clinical effects?
Yes
Yes
Yes
Are the benefits statistically significant
over existing therapy/placebos in
well-designed clinical trials?
Are these benefits of useful
magnitude?
Yes
No
No
No
Useful
Not useful
Figure 15.3: Flow chart for deciding
usefulness of a new therapy.
Patient groups who respond more or less well may be identified,
patient exposure (both numbers and duration of therapy)
is increased, and less common type B (see Chapter 12) adverse
reactions may be identified. During this period, the manufacturers
will be setting up plant for large-scale manufacture and
undertaking further pharmaceutical studies on drug formulation,
bioavailability and stability. The medical advisers to the
company, in association with their pharmacological, pharmaceutical
and legal colleagues, will begin to collate the large
amount of data necessary to make formal application to the
MHRA or EMEA for a product licence. Marketing approval
may be general or granted subject to certain limitations which
may include restriction to hospital practice only, restriction in
indications for use, or a requirement to monitor some particular
action or organ function in a specified number of patients.
Doctors are reminded (by means of a black triangle symbol
beside its entry in the British National Formulary) that this is
a recently introduced drug, and that any suspected adverse
reaction should be reported to the MHRA or Commission on
Human Medicines.
Key points
Phase III studies:
• confirmation of effective doses;
• expanded tolerability profile;
• collection of data on a more varied patient population
with indication;
• data on overall benefit/risk;
• can be placebo or more usually active controls;
• multicentre;
• commonly 1000–5000 patients in total;
• usually double-blind.
PHASE IV
Phase IV studies are prospective trials performed after marketing
approval (the granting of a product licence). These may
assess the drug’s clinical effectiveness in a wider population
and may also help in the detection of previously unrecognized
adverse events (see Chapter 12).
Key points
Phase IV studies:
• performed after marketing approval and related to the
approved indications;
• exposure of drug to a wider population;
• different formulations, dosages, duration of treatment,
drug interactions and other drug comparisons are
studied;
• detection and definition of previously unknown or
inadequately quantified adverse events and related risk
factors.
POSTMARKETING SURVEILLANCE
The MHRA closely monitors newly licensed drugs for adverse
events through the yellow card reporting system (see Chapter
12). Direct reporting by patients of adverse events was introduced
in 2004. SAMM (Safety Assessment of Marketed
Medicines) studies may be initiated which can involve many
thousands of patients.
GENERIC DRUGS
Once the patent life of a drug has expired, anyone may manufacture
and sell their version of that drug. The generic drug
producer does not have to perform any of the research and
development process other than to demonstrate that their version
of the drug is ‘bioequivalent’ to the standard formulation.
The convention accepted for such ‘bioequivalence’ is generous,
and the issue is the subject of current debate by biostatisticians.
In practice, the essential point is that clinically
untoward consequences should not ensue if one preparation
is substituted for the other.