European Journal of
Eur J Clin Pharmacol (1988) 34:15-19
Dose-Finding Studies in Clinical Drug Development
R. Schmidt
Clinical Research Department, SANDOZ Ltd., Basel, Switzerland
Summary. A correct dose-finding study is of the ut-
most importance during clinical development of a
new drug. It must define the no-effect dose and the
mean effective and maximal effective doses. Then
taking tolerability into account, the optimal thera-
peutic dose range can be selected.
To define the dosage schedule the duration of
action in man must be tested, if possible together
with blood concentration measurements. An ade-
quate dose-finding study shows the optimal doses
for double-blind trials in Phase II and large scale
trials in Phase III, thereby saving time and effort
and reducing the number of patients required.
The tendency of clinical experts to try to demon-
strate superiority of one drug over another by using
doses higher than patients really need must be re-
sisted. The price paid in poor tolerability exceeds
any potential benefits.
Key words: dose-finding, drug development; clinical
trial, therapeutic dose range, proposed procedure,
dose optimisation
The clinical development of a new drug is usually
divided into three phases [1, 2]. Phase I is devoted to
tolerability testing and pharmacokinetic evaluation.
Trials in late Phase I or early Phase II are aimed at
elucidating clinical efficacy in the intended patient
population and to define the dosage and dosage
schedule. Controlled trials are performed subse-
quently to compare the new drug with the standard
medications. In Phase III, large scale trials are per-
formed to confirm the efficacy and safety of the
new drug in the target population.
Definition of the dosage and dosage schedule is
a key question during clinical development of a new
drug, and it is the objective of the so-called dose-
Clinical Pharmacology
© Springer-Verlag 1988
finding studies. The goal is to satisfy the require-
ment that patients be exposed only to the quantity
of drug that they really need [3]. It is mandatory that
the therapeutic dose-range be established prior to
initiation of double-blind studies, in which a fixed
dosage and dosage schedule are the rule. In spite of
the crucial importance of dose-finding studies, na-
tional and international guidelines as well as recom-
mendations for clinical drug development at the
best contain a few general suggestions on how to
perform such trials. In the following a proposal for
the procedure is described in more detail.
Selection of Subjects
Whether healthy human volunteers or patients are
selected depends largely on the indication [4].
Healthy Volunteers
The involvement of healthy volunteers in drug
studies is officially permitted in most countries and
is specifically mentioned in the Guidelines laid
down in the 1975 Tokyo Amendment of the 1964
"Declaration of Helsinki" [5]. In France the legal
situation neither prohibits the administration of
drugs to healthy volunteers nor does it make provi-
sion for it [6].
Studying healthy volunteers has the following
advantages [7]:
They are
1. in a steady-state condition showing
- no variation due to disease
- no different stages of disease
2. easy to recruit
3. easy to select for age, sex, race, etc.
16
4. tested under identical conditions (climate, food,
laboratory values)
5. not taking concomitant medication
6. easily prepared to consent in writing
7. in a condition in which the test can be repeated.
Dose ranging studies can be only performed in
normal volunteers when there is a reliable test mod-
el with high predictability for the therapeutic effect,
e.g. prevention of ergometer-induced tachycardia
for betablockers, prolactin-lowering effect for endo-
crine indications of dopaminergic compounds, his-
tamine flare test for antihistamines, etc.
The disadvantages of treating healthy volunteers
are that they cannot receive any potential benefit
and, in the case of pharmacodynamic studies, that
they do not show the symptoms of the disease. To
overcome this shortcoming "symptoms" can be pro-
duced by "provocation tests" [8], e.g. ergometer
tachycardia. In this way the new substance can be
tested with regard to whether and to what extent it
reverses the "provoked" effects in healthy volun-
teers in comparison with placebo a n d / o r a standard
drug. Another possibility is to compare the new sub-
stance with a standard drug which itself evokes typi-
cal changes or effects in normals, e.g. the decrease
in REM sleep evoked by classical antidepressants
[9]. In such cases the new compound is tested to see
if it produces the same changes and to compare
these changes qualitatively and quantitatively with
the effects of the standard drug. The new substance
is thus "identified" in terms of changes produced by
a standard drug, and such tests can be classified as
"identification tests" [8]. As mentioned above, only
those test methods should be used whose predicta-
bility for the foreseen disease has been clearly estab-
lished. In addition, the tests must be safe.
Patients
The performance of dose-ranging studies in patients
is
1. mandatory for drug groups for which potentially
harmful effects may be anticipated, such as cytos-
tatics, immunosuppressants, narcotics etc., and
2. necessary for drug groups for which there is no
valid test model in healthy volunteers, e.g. drugs
for senile dementia, parkinsonism etc.
Indication
In patients the indication should be defined qualita-
tively and quantitatively. Not only the disease for
which the drug is foreseen must be carefully de-
R. Schrnidt:Dose-FindingStudies
fined, but also its gravity and stage. The more in-
novative a drug, the more prepared are the clinical
expert in the company and the investigator in the
clinic to select end-stage patients rather than those
in an early stage of the disease. This may result in
the recommendation of a too high a dosage for the
study population in Phases II and III trials. There-
fore the involvement of patients with different but
well defined stages of the disease is essential in
dose-finding studies, and interpretation of the re-
suits must take into account the various degrees of
the disease state.
Study Design
Whether several doses can be tested in the same in-
dividuals (intrapatient comparison) or whether a
parallel group design, i.e. one dose per group,
should be chosen depends on the nature of the dis-
ease, and on the condition of the patients. Only
when the disease is in a steady state is a stepwise in-
crease in dose in the same patient allowed. If the
disease is expected to show variation over the peri-
od of the trial, a parallel group design is preferable.
If objective and measurable parameters of the
disease process can be chosen an open design may
be sufficient. When subjective symptoms or syn-
dromes must be assessed, treatment must be blind-
ed. In both cases the performance of the study
should be controlled ("controlled trial").
Definition of the Optimal Dosage
Dose-finding studies should define
- the no-effect dose range
- the minimum effective dose
- the mean effective dose
- the maximum effective dose
- the optimal dose range
The minimum effective dose is the dose which has
only a borderline effect in a small number of sub-
jects, and the maximum effective dose will produce
a marked effect in a large proportion of patients.
Since it is the goal with most developmental drugs
to produce a greater therapeutic activity and a larg-
er proportion of responders than competitor drugs,
there is a real risk of choosing a dose that is far
above the optimal level for use in further studies.
Another possibility contributing to recommendation
of too high a therapeutic dose is, as mentioned
above, the selection of severely disabled or end
stage patients in early clinical trials. It is essential al-
R. Schmidt: Dose-Finding Studies
ways to keep in mind the general rule that the high-
er the dose the higher the incidence of side effects.
As dosage and tolerability are inversely correlated,
it is of the utmost importance to define the position
of the "optimal dose range" between the minimal
and maximal effective doses. Within the optimal
dose range, the desired therapeutic effect should be
associated with good tolerability. For a promising
new drug this means that efficacy and/or tolerabili-
ty will show advantages over competitor drugs, i.e.
that the new drug is superior. The definite proof of
any claim of superiority will be provided later in
the controlled (if possible double-blind) trials in
Phases II and III.
During tolerability studies in Phase I, the high-
est well-tolerated dose will have been defined. In
practice this highest, well-tolerated dose should be
used as the initial dose in dose-finding studies. If
this dose has a weak or only a borderline effect, the
further development of the drug for the selected in-
dication becomes questionable. If the highest well-
tolerated dose produces a clear effect, lower doses,
e.g. 50% and 25% of it, should be tested in order to
establish the dose-effect relationship. In addition,
the dose range must be defined which gives the zero
value, i.e. which has no therapeutic effect. When-
ever possible a placebo should be included to dem-
onstrate the placebo response, which varies for dif-
ferent indications and populations.
The correlation between efficacy and toterability
is illustrated in Fig. 1.
Curve Eft shows the increase in efficacy and
curve Tol the inverse decline in tolerability with in-
creasing dose (d). In the middle, between the "maxi-
mal effective dose" and the "minimal effective
dose" on curve Eft lies the "mean effective dose".
The distance between the maximal and minimal ef-
fective doses is the "therapeutic dose range", which
includes all effective doses. Above the maximal ef-
fective dose lie the supramaximal doses, which do
not further increase efficacy but only worsen tolera-
bility. Below the minimal effective dose lies the no-
effective dose or placebo range. That is the range
where effects or side-effects occur which should not
be attributed to the drug, as they are also observed
to the same extent and with the same incidence after
placebo. This is the reason why the effect curve
starts above the zero point and the tolerability curve
below the 100% point.
For some indications the placebo response is re-
markably strong, as in hypertension and analgesia.
An analgesic produces "effects" at dosages clearly
below the minimal effective dose. It is important to
be aware of the differing placebo range for different
indications and populations [10], and to perform
t7
%Eff, m
E. TO[ Eft I
l
1
I
I
I
I i
I I
I t 1 I
I I I I
optimal dose range I supramax
i
ther. dose range
Fig. 1. Interrelation between efficacy (Eft) and tolerability (Tol)
in a dose-finding study, d = dose
dose-finding studies strictly as "controlled trials",
especially when the placebo range is large.
Each patient will have an individual optimal
therapeutic dose. That dose is only valid for that
patient and not for a study population. For the lat-
ter an optimal dose "range" must be defined, which
is effective and well tolerated by the majority of re-
sponders. From the two curves in Fig. 1 it is evident
that it is exceptional for the optimal dose range to
be centered around the mean effective dose. It lies
around the point of intersection of the two curves,
clearly taking into account not only the efficacy but
also the tolerabitity curve [11]. If the optimal thera-
peutic dose range is broad, more than one dose
should be selected for double-blind trials, or it may
even be necessary to treat patients with individual
dosages, as is usually the case for psychotropics and
antiparkinsonism drugs. In order to keep the num-
ber of patients low, as well as for reasons of time
and capacity, the numbers of doses in comparative
trials should be as small as possible, and should not
usually exceed three. Whenever possible a individu-
al dose titration must be avoided.
Duration of Administration
For some compounds (analgesics, diuretics, dop-
aminergics in endocrinology etc.) a single dose or
single day application will permit definition of the
optimal dose range as well as the dosage schedule,
but for other drugs several days or even weeks of
treatment are necessary, e.g. psychotropics and an-
tiphlogistics.
18
Definition of Dosage Schedule
The duration of action should be determined during
the dose-finding study, as it will allow definition of
the dosage schedule. Unfortunately, for some sub-
stances (nootropics, immunoactive drugs, etc.) the
duration of action is difficult to determine during
early clinical trials, as there is no easily measurable
and reliable pharmacodynamic parameter. Other
parameters instead must be taken into considera-
tion, which may suggest a tentative dosage sche-
dule; for example,
1. half-lives in plasma and urine in man and various
test species
2. the duration of side-effects or signs of accumula-
tion in the Phase I tolerability tests
3. receptor binding in vitro, e.g. as for betablockers,
where a short half-life but high receptor binding
is likely to lead to a prolonged duration of action.
4. pharmacodynamic data in vivo in animals.
Whenever possible measurement of the duration of
a pharmacodynamic action in man should lead to
the definition of the dosage schedule. A study
planned to define the "plasma concentration-re-
sponse curve" is one of the best means to define the
duration of action, as it takes into account both the
duration of action and the pharmacokinetic behav-
iour of the substance.
Blood Concentration-Response Curve
"Pharmacokinetic studies" in healthy volunteers
and patients and "plasma concentration measure-
ments" during therapeutic trials have different
goals. Pharrnacokinetic studies give information on
the fate of the administered drug in the organism
and allow definition of its pharmacokinetic parame-
ters. Plasma concentration measurements in healthy
volunteers and patients correlate the plasma con-
centration with the quality and quantity of desired
or undesired effects (therapeutic plasma concentra-
tion monitoring).
Performing plasma concentration measurements
during dose-finding studies permits a concentration
range to be defined within which the desired effects
or side-effects occur. This will show whether there is
a correlation between effectiveness and blood level,
and "whether blood level predicts response" [3].
A properly designed plan of the timing of blood
sampling and effect measurements will provide a re-
liable answer about the "blood concentration-re-
sponse curve". A few (about 3-5) blood samples
R. Schmidt: Dose-Finding Studies
drawn during the day will suffice to provide the in-
dividual blood concentration profile. Effect and tol-
erability assessments should be made at the same
time points to reveal the correlation between blood
level and activity. Usually, at least the zero (basal)
value, the maximal concentration (Cmax) and the
trough level are determined. The results of the ini-
tial pharmacokinetic study must be used to help to
design this part of the dose-finding studies.
Conclusions
The dose-finding study occupies a key position in
clinical drug development. If properly designed and
accurately performed it will save time and effort
during the comparative and large scale trials of
Phases II and III, and it will help to minimize the
numbers of patients required. It must be done early
during the clinical studies, i.e. at the end of Phase I
or at the beginning of Phase II. It must include
measurement of the desired effects as well as side-
effects. For its design and during its practical per-
formance the following notes for guidance should
be observed:
1. dearly define the study population
2. select the appropriate patients and avoid includ-
ing only end-stage patients
3. define:
3.1. optimal dose range
include the minimal and maximal effective
doses as well as the no-effect dose or placebo
range
3.2. duration of action and dosage schedule
3.3. provisional blood concentration-response
curve
4. avoid '*superior" efficacy if it is due solely to use
of higher doses than patients need
5. select one or at the most three doses for compara-
tive trials, and avoid whenever possible individual
dose titration
6. confirm tolerability.
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R. Schmidt: Dose-Finding Studies 19

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Received: May 15, 1987
accepted: June 29, 1987
Dr. R. Schmidt
SANDOZ Ltd.
CH-4002 Basel, Switzerland