Principles and Practice of Pharmaceutical Medicine

9.8 Objectives and prerequisites

of phase II studies

Gallenical forms

A good rule of thumb is that pivotal clinical trials
for registration purposes ought to be conducted
with the same formulation and manufacturing pro-
cess that is proposed to be taken to market.
Although the nuances of pharmaceutical con-
structs are described in Chapter 5, it is important
to understand the sometimes grave consequences
when this rule of thumb is not observed.
Most regulatory authorities will want reassur-
ance that the pharmacokinetic (PK) properties of
the marketed product closely resemble those in
which the pivotal studies are carried out. This is
not unreasonable: if the PK properties differ, then
so may dose size and frequency. Occasionally, a
phase III study will be ‘bridged’ to the marketed
formulation by the demonstration, for example,
that two different tablets have the same PK profile.
However, the risk is that different formulations will
not turn out to possess the same PK profile: either
new pivotal studies will have to be conducted with
the new formulation or registration will be delayed
until the new formulation is adapted so that it does
match the phase III test material. For inhaled drugs,
this is especially difficult. Time and money is often
lost in both cases. It is a risky gamble to leave
development of the final formulation until the end
of a clinical development plan.

Informed consent

This is considered in detail in Chapter 7. The
clinical trialist should remember, however, that
he or she ultimately carries the ethical responsibil-
ity for this document, regardless of what corporate
lawyers and others may wish to do with it. Typi-
cally, Institutional Review Boards in the United
States are more likely to be tolerant of long forms
than ethics committees in Europe.
Toxicological coverage is covered in more detail
in Chapter 6. However, the clinical trialist is
encouraged to consider this for every protocol. A
useful method is to start with the general case:

What is the relationship between duration and

dose sizes of animal studies and the clinical proto-

col-specified dose size and duration? This exercise

ought to be conducted using methods that standar-

dize both for body weight and body surface area

across species. Next, review closely all the prior

human exposure to the test drug (if any) to see

whether any unexpected signals for investigation

may be found. Lastly, consider from the known

pharmacology of the drug whether there are likely

to be any particular tolerability issues for which

special monitoring methods are needed, andthink

laterally.

For example, what is likely to be the adverse

effects of a potassium channel-blocking drug being

investigated for a central nervous system indica-

tion? The answer may lie in all the excitable tissues

that contain potassium channels. Is there any pre-

clinical evidence that the drug discriminates

between potassium channels in different tissues?

Are there changes in the EEG or ECG that may be

found in the nonhuman database or among prior

human exposures to the test agent that escaped

being reported because ‘not thought to be clinically

significant’?

9.9 Common phase II/III study

designs

Many initial studies are conducted in an uncon-

trolled fashion. Eminent professors will treat a few

of their patients with a test medication (perhaps

under an investigators’ IND in the United States)

and form opinions about the worth (or otherwise)

of a new therapy. Although this may be grist for the

mill of press releases and fund raising for small

companies, these uncontrolled observations often

mistakenly become a cast-iron credo for the spon-

soring company. An observed effect – any effect –

is viewed as better than none, and the relative lack

of scientific controls permits large biases to arise.

The first risk from this haphazard start to clinical

development is that potentially good options for a

test compound may be needlessly rejected. The

professor’s patient population may not include a

disease state or disease subtype for which the new

drug is actually well suited. Equally, efficacy and

106 CH9 PHASE II AND PHASE III CLINICAL STUDIES