9 Phase II and Phase III

Clinical Studies

Anthony W. Fox

9.1 The phases of drug

development: an obsolete

model

In former times,it was assumed thatdevelopmental
drugs proceeded in stepwise fashion from phase I,
through phase II, to phase III, prior to filing a PLA
or NDA. Phase I was conducted in ‘normal volun-
teers’ (although some medical students might
hardly characterize this term!). Phase II trials
were initial studies in selected patients, and phase
III was seen as wide-scale studies in broader
patient populations. After approval, certain stu-
dies, to find new indications, address special
patient subpopulations, for marketing purposes or
to otherwise broaden product labeling might or
might not be conducted. All postapproval studies
were termed stage IV.
In modern practice, the distinctions between
phases I, II, III, and IV are very often blurred.
Three principal and interlocking pressures have
caused this blurring: time, finance and an evolving
regulatory environment.
Of these three pressures, the most important is
time. Strategies such as the overlapping of devel-
opment ‘phases’, as well as the use of early dose-
ranging studies as pivotal, and choosing doses

based on surrogate end points are technical

responses to this challenge.

Financial pressures, even for the largest pharma-

ceutical companies, are generally much greater

than in the past. The technical response is to max-

imize resources, avoiding any and all redundant

clinical studies.

The regulatory pressures come both from

the regulatory authorities and from within the

pharmaceutical companies themselves. Regula-

tory authorities have increased their scientific

sophistication during the last 30 years. The ques-

tions that are now asked of companies, and the

earlier stages of drug development when these

questions are asked, have driven change in

clinical study design. Increasingly sophisticated

data are now developed at earlier stages of drug

development.

In the later stages of the development of success-

ful drugs, the interval between PLA or NDA filing

and product launch is not wasted. The term ‘phase

IIIb’ has been invented for the conduct of phase IV-

type studies during the pre-approval period.

Furthermore, in some companies, the old ‘phase

IV’ is now divided into phases IV and V, without

any generally agreed definitions except, perhaps,

that the studies are run by different teams.

Principles and Practice of Pharmaceutical Medicine, 2nd Edition Edited by L. D. Edwards, A. J. Fletcher, A. W. Fox and P. D. Stonier
#2007 John Wiley & Sons, Ltd ISBN: 978-0-470-09313-9