A Textbook of Clinical Pharmacology and Therapeutics

90 INTRODUCTION OF NEW DRUGS AND CLINICAL TRIALS

Patient groups who respond more or less well may be identi-
fied, 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 manufac-
turers will be setting up plant for large-scale manufacture and
undertaking further pharmaceutical studies on drug formula-
tion, bioavailability and stability. The medical advisers to the
company, in association with their pharmacological, pharma-
ceutical 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.

and may also help in the detection of previously unrecognized

adverse events (see Chapter 12).

Does the therapy have

unacceptable adverse effects?

Yes Yes

Yes

Yes

No

No

No

No

Does the therapy exhibit

potentially useful clinical effects?

Are the benefits statistically significant

over existing therapy/placebos in

well-designed clinical trials?

Are these benefits of useful

magnitude?

Useful Not useful Figure 15.3:usefulness of a new therapy.Flow chart for deciding

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 mar-
keting approval (the granting of a product licence). These may
assess the drug’s clinical effectiveness in a wider population

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 intro-

duced 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 manu-

facture 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 ver-

sion of the drug is ‘bioequivalent’ to the standard formulation.

The convention accepted for such ‘bioequivalence’ is gener-

ous, and the issue is the subject of current debate by biostatis-

ticians. In practice, the essential point is that clinically

untoward consequences should not ensue if one preparation

is substituted for the other.