Principles and Practice of Pharmaceutical Medicine

of the nuances and challenges of conducting phase
IV trials.
The type of investigator that one seeks during
phase IV development must clearly correspond to
the nature of the study. Usually, larger numbers of
investigators who each contribute fewer patients
than the phase II and III investigators are sought. If
such individuals are local or national thought lea-
ders, who will eventually advocate for the product,
then so much the better. But even at the local level,

it is these investigators who might be found on

hospital formulary committees, develop local

treatment algorithms, see high volumes of patients

and are active in local medical societies.

Comparative superiority trials

Well-designed, head-to-head, active comparator

studies are also always to be preferred over the

Table 10.1 Typical goals and tactics of phase IV clinical trials

Extension of tolerability information Wider range of patients than in

NDA/PLA database

Larger numbers of patients

Competitive efficacy claims Active comparator study designs

New indications Supplemental efficacy studies

Ethnopharmacology Additional approvals in non-ICH countries

Outcomes assessment Pharmacoepidemiology and pharmacoeconomics

in particular healthcare environments

Pharmacovigilance Post-marketing commitments

Market expansion All of the above

The draft ICH Guidance on pharmacovigilance (ICH E2E, 11 November 2003) is likely to cause greater

emphasis on the penultimate item in this list.

Table 10.2 Practical aspects of phase IV clinical trials

Type of study Challenges

Active comparators Obtaining active comparator drug

Blinding, reformulations and bioequivalence

Disclosure of trade secrets to competitors

Placebo-control justifications

Use of appropriate dose ranges

Risks demonstrating superiority of competitor

Equivalence trials Usually large patient populations needed

Cannot demonstrate superiority

Scientific demonstration of a negative

‘Standard of care’ context challenged

Mega-trials Statistical complexity

Few inclusion/exclusion criteria

Representativeness to treated population known

only toward the end of the trial

Open-label Prescriber and patient biases

Scientifically limited

New indication Similarity to phase III designs (q.v.)

Drug interactions Almost unlimited alternatives

Special patient populations See other chapters

New formulations Bioequivalence

120 CH10 PHASE IV DRUG DEVELOPMENT: POST-MARKETING STUDIES