Chapter 2

Identify and classify different types of trial designs when reading a

clinical trial report
As we mentioned earlier, the efficacy and clinical safety of medical products must
be demonstrated by clinical trial with the guidance of International or national
agencies.
A large proportion of CT is sponsored by organization or companies in the field of
pharma or biotechnology, to develop a new disease management intervention:
drug, device or diagnostic strategy. There may also funds available for the
investigators in health care providing by Government sectors.
CTs are designed medical experiments. it must be designed in an ethical manner so
that patients are not denied the benefit of usual treatments. CTs are sets of test in
research of medical field and development of drug that give safety and efficacy for
heal the health interventions. These are based on drugs and therapy protocols. to
examine and evaluate the safety and efficacy of

new drugs or therapeutic

procedures using human subjects. Thus by using the CT, we can compare and
improve the efficacy of new drugs against the existing drugs.

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CT is a continuous process and it is essential to the society in evaluating therapies

for existing and new diseases. The primary purpose of the CT is to be providing an
unbiased evaluation. As a main goal of CT is to make conclusions about the
treatment process in a general population those who need treatment. as to be get
approval of a new drug , the FDA requires an evidence based trial. That evidence
of the effectiveness of the drug be provided through the conduct of adequate and
well-controlled CT. Such type of CT, includes appropriate methods for bias
reduction such as double blinding, randomization of treatment assignments as well
defined patient population and scientific and valid statistical methods for data
analysis.
For this purpose we need to identify and classify different types of trial design
when reading a trial report. Basically, there are several types of CT based on their
characteristics and application situations. they are not mutually exclusive. the
different types of CT include
1. Multi-central Trial
2. Superiority Trial
3. Sequential Trial
4. Active control and equivalence / Non-inferiorityTrials
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5. Dose-Response Trials
6. Combination trials
7. Bridging studies

and

8. Vaccine Clinical trial

These are all usually applied in different situations depending on the objectives of
the planned clinical trials.
A brief discussion on the above
1. Multi-central Trial:
Whenever we have a situation of study that involves with single study that involves
with signle-study site and it have
a. An adequate number of relative homogeneous patients as which referred as
targeted study
b. Sufficient capacity of resources and supporting staff.
As it being single study site, it provides it provides consistent assessment for
ecacy and safety in a similar medical environment. As a result, a single-study
site can improve the quality and reliability of the collected clinical data and
consequently the inference of the clinical results. The main dis advantages of this
method are the availability of patients and resources in a single site. If the intended
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clinical trial calls for a large number of patients, a single-site study may take a long
time to complete the study, since qualied patients may not be available at the
same time.
Goldberg and Kury (1990) indicate that a single-site study may not be appropriate
insituations where (1) the intended clinical trials are for relatively rare chronic
diseases and(2) the clinical endpoints for the intended clinical trials are relatively
rare (i.e., require alarge number of patients to observe an incidence).
To overcome the disadvantages of a single-site study, the multicenter study is
usually considered. A multicenter study is a single study involving several study
centers (sites or investigators). In other words, a multicenter trial is a trial
conducted at more than one distinct center where the data collected from these
centers are intended to be analyzed as a whole.
At each center an identical study protocol is used. Amulticenter trial is a trial
withacenter

or

site

as

natural

blocking

or

stratiedvariablethat

providesreplications of clinicalresults. Amulticenter trial should permit an

overallestimation of the treatment differencefor the targetedpatient population
across variouscenters. In what follows,we willdiscuss the impact of treatment-bycenter interaction and some practical issues when planninga multicenter trial.

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Treatment-by-Center Interaction
The FDA guideline suggests that individual center results should be presented for a
multi-center study. In addition, the FDA suggests that statistical tests for
homogeneity across centers (i.e., for detecting treatment-by-center interaction) be
provided. The signicant level used to declare the signicance of a given test for a
treatment-by-center interaction should be considered in light of the sample sizes
involved. Any extreme or opposite results among centers should be noted and
discussed.
The presentation of the data, demographic, baseline, and post baseline data as well
as ecacy data should be presented by center, even though the combined analysis
may be the primary one.
Gail and Simon (1985) classify the nature of interaction as either quantitative or
qualitative. A quantitative interaction between treatment and center indicates that
the treatment differences are in the same direction across centers but the magnitude
differs from center to center, while a qualitative interaction reveals that substantial
treatment differences occur in different directions in differentcenters.

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Figure 2.1
The above figures, depicts situations where there are quantitative and qualitative
treatment-by-center interactions. Consider the following examples which exhibit
quantitative and qualitative treatment-by-center interactions.
EXAMPLE 1
Recently a study was conducted to evaluate the hypothesis that exposure of
skeletal muscle to exercise-induced stress in combination with prior administration
of a study drug (e.g., drug A) will produce a greater increase in CK than the effects

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of exercise alone. This study was a randomized, two-arm parallel study comparing
the study drug A plus exercise and a placebo control plus exercise which was
conducted at two distinct study centers. Below table display the mean CK values at
24 hours post-treatment

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The diagram provides a preliminary investigation of a potential treatment-bycenter interaction. The plot shows that there is a potential quantitative treatmentby-center interaction. This was conrmed by an analysis of variance that includes
the terms of treatment, the center, and the treatment by center interaction ( p-value
0.08< 0.1). A subgroup analysis by center reveals that there is a signicant
treatment effect at the second center ( p-value 0.029< 0.05).
EXAMPLE 2
Consider a clinical trial for the assessment of a study drugs ecacy in treating
mild to moderate hypertension. The study was conducted as a randomized placebocontrolled multicenter trial that involved 219 patients in 27 study centers.
Below table lists the mean change in seated diastolic blood pressures after six
weeks of treatment

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A plot of mean change in seated diastolic pressures against study centers is given
in below figure

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In this gure the centers are grouped according to the magnitude of differences in
mean change from the baseline. That is, the center with a difference in mean
change from base-line of - 19.89 are labeled site 1 and the center with a difference
in mean change from baseline of 9.11 are labeled site 27. As can be seen, 19
centers (70.4%) show the difference in the positive direction, while 8 centers
(29.6%) are in the negative direction. An analysis of variance indicates that a
signicant qualitative interaction between treatment and group has occurred ( pvalue = 0.01). If we ignore the interaction and perform an analysis of variance, an
overall estimate of the treatment effect based on the difference in the mean change
from the baseline is given by -- 4.36 1.9 or (-6.26, -2.46) with a p-value less than

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0.01. This positive signicant result, however, is somewhat misleading because it

is not reproducible in those 8 out of 27 centers. In other words, there is a relatively
high chance that we may observe a totally opposite result if we are to randomly
select a center from a pool of centers and repeat the study with the same protocol.
Besides, the 8 centers involve 60 patients, who show different results, or about
27.4% of the patients under study.
Therefore the reproducibility and generalizability of the results to the targeted
patient population and the treatment setting is to be arise.
Practical Issues
1. A multicenter trial with a number of centers is often conducted to expedite
the patient recruitment process. Although these centers usually follow the
same study protocol to evaluate the ecacy and safety of a study drug, some
design issues need to be carefully considered. These design issues include
the selection of centers, the randomization of treatments, and the use of a
central laboratory for laboratory evaluations. The selection of centers is
important to constitute a representative sample for the targeted patient
population. However, in multicenter trials the centers are usually selected
based on convenience and availability. When planning a multicenter trial

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with a xed sample size, it is important to determine the allocation of the

centers and the number of patients in each center.
For example, if the intended clinical trial calls for 100 patients, the sponsor may
choose to have 5 study centers with 20 patients in each, 10 study centers with 10
patients in each, or 20 study centers with 5 patients in each. The chance for
observing a signicant treatment-by-center interaction for the selection of 20
centers is expected to be higher than those for the selections of 10 centers and 5
centers. If there are potential dropouts, the selection of 20 centers may result in a
number of small centers (i.e., with a few patients in the center).
2. For comparative clinical trials, the comparison between treatments is
usually made between patients within centers. If there is no treatment-bycenter interaction, the data can be pooled for analysis across centers.
Therefore, it is not desirable to have too few patients in each center. A ruleof-thumb is that the number of patients in each center should not be less than
the number of centers. In this case the selection of 10 sites for a xed sample
size of 100 patients may be preferable. Some statistical justication for this
rule can be found in Shao and Chow (1993). Once the centers are selected, it
is also important to assign treatments to patients in a random fashion within
each center. The issue whether a central laboratory will be used for the
laboratory testing of samples collected from different centers has a
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signicant impact on the assessment of ecacy and safety of the study drug.
A central laboratory provides a consistent assessment for laboratory tests. If
a central laboratory is not used, the assessment of laboratory tests may differ
from center to center depending on the equipment, analyst, and laboratory
normal ranges used at that center. In such a case possible confounding
makes it dicult to combine the laboratory values obtained from the
different centers for an unbiased assessment of the safety and ecacy of the
study drug.
3. Another practical issue of great concern in a multicenter trial is statistical
analysis of the collected data from each center. As was indicated earlier, if
there is no evidence of treatment-by-center interaction, the data can be
pooled for analysis across centers. The analysis with combined data provides
an overall estimate of the treatment effect across centers. In practice,
however, if there are a large number of centers, we may observe signicant
treatment-by-center interaction, either quantitative or qualitative. As
indicated by Gail and Simon (1985), the existence of a quantitative
interaction between treatment and center does not invalidate the analysis in
pooling data across centers. An overall estimate of the average treatment
difference is statistically justiable, and it provides a meaningful summary
of the results across centers. On the other hand, if a qualitative interaction
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between treatment and center is observed, the overall or average summary

statistic may be misleading and hence considered inadequate. In this case it
is preferable to describe the nature of the interaction and to indicate which
centers contribute toward the interaction.
In practice, if there are too many centers, the trial may end up with big imbalances
among centers, in that some centers may have a few patients and others a large
number of patients. If there are too many small centers (with a few patients in each
center), we may consider the following two approaches. The rst approach is to
combine these small centers to form a new center based on their geographical
locations or some criteria prespecied in the protocol. The data can then be
reanalyzed by treating the created center as a regular center.
Another approach is to randomly assign the patients in these small centers to those
larger centers and reanalyze the data. This approach is valid under the assumption
that each patient in a small center has an equal chance of being treated at a large
center.As was indicated before, for approval of a new drug, two well-controlled
clinical trials are conducted to provide substantial evidence of the effectiveness and
safety of the new drug. Since a multicenter trial involves more than one distinct
center, whether a single multicenter trial is equivalent to that of two separate trials
has become an interesting question. The FDA indicates that an a priori division of
a single multicenter trial into two studies is acceptable for establishing the
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reproducibility of drug ecacy to NDA approval. Nevius (1988) proposes a set of

four conditions under which evidence from a single multicenter trial would provide
sucient statistical evidence of ecacy.
These conditions are summarized below:
1. The combined analysis shows signicant results.
2. There is consistency over centers in terms of direction of results.
3. There is consistency over centers in terms of producing nominally signicant
results in centers with sucient power.
4. Multiple centers show evidence of ecacy after adjustment for multiple
comparisons.
To address the consistency over centers, Chinchilli and Bortey (1991) propose
the use of thenoncentrality parameter of an F distribution as a means of testing
for consistency thetreatment effect across centers.
As an alternative, Khatri and Patel (1992) and Tsai andPatel (1992) consider a
multivariate approach assuming random center effects. Huster andLouv (1992)
suggest the use of the minimax statistic as a method that can quantify
theamount of evidence for reproducibility of treatment ecacy in a single
multicenter trial.
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To describe the minimax statistic, we consider an example given by Huster and

Louv (1992). Suppose that there is a four-center clinical trial. Denote the four
centers by a, b, c , and d. Consider all possible divisions of these four centers
into two mutually exclusive sets of centers. The minimax statistic can then be
summarized as follows: First, for each of the seven divisions, nd the p-value
for the drug effect (adjusted for the center) for each study.
Then nd the maximum of these two p-values for each division.Second, nd the
minimum of these maximum p-values across all divisions. The rationale for
choosing the maximum at the rst step is that if a particular division is to show
reproducibility of a drug effect, then both studies within that division should
exhibit a signicant drug effect. On the other hand, the rationale for choosing
minimum at the second step is that the optimal division is one where the
evidence against the null hypothesis from both studies in the greatest. As
indicated by Huster and Louv (1992), the minimax statistic approach provides a
reasonable assessment for the amount of evidence for reproducibility of
treatment ecacy in a single multicenter trial. In addition it gives an objective
answer to the question whether a second conrmatory study is required.
Note that the analysis of a multicenter trial is different from that of a metaanalysis. The analysis of multicenter trials combines data observed from each

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study center; the data are generated based on the methods prospectively
specied in the same study protocol with the same method of randomization
and probably at the same time. In contrast, a meta-analysis combines data
retrospectively observed from a number of independent clinical trials, which
may be conducted under different study protocols with different randomization
schemes at different times. In either case the treatment-by-center interaction for
multicenter trials or treatment-by-study interaction for meta-analyses must be
carefully evaluated before pooling the data for analysis.
SUPERIORITY TRIALS
A superiority trial is dened as a trial with the primary objective of showing
that the response to the investigational product is superior to a comparative
agent - ICH E9 Guideline entitled, Statistical Principles for Clinical Trials.
Scientically, superiority trials can provide the most convincing evidence of
superior ecacy of the test drug product to that of comparative controls
A regulatory review/approval process point of view, the superiority of a test
drug product is in fact established in a two-step procedure.
Let T and C be the summary population parameters of some primary
ecacy end point for the test drug product and comparative control,
respectively. Here T and C can be the population means if the primary
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ecacy endpoint is a continuous variable, or the proportions if the primary

ecacy endpoint is a binary variable or survival function if the primary ecacy
endpoint is a censored variable.
In addition, a larger value of the summary population parameter represents a
superior ecacy. Then, the rst step is to establish the superior ecacy of the
test drug product by testing the following two-sided hypotheses at a
prespecied signicance level, say, :

After the null hypothesis is rejected at the level of signicance and if the
estimate of T- C is positive, the test drug product is then claimed to be
superior to the control agent in ecacy. The ICH E9 guideline indicates that
this two-step procedure is consistent with the two-sided condence intervals
that are generally considered an appropriate method for estimating the possible
size of the difference between the test drug product and the comparative
control. In other words, the superiority of the test drug product is established if
the lower limit of the (1 - )% two-sided condence interval for T- Cis
greater than 0.
This two-step procedure is actually equivalent to testing the following onesided hypotheses at the /2 signicance level
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It follows that this two-step approach establishes the superiority of the test drug
product atthe /2 signicance level rather than at the usual signicance level.
Hence, the issue ofone-sided or two-sided approaches to inference on
establishment of superior ecacy remains controversial and generates a lot of
discussions and debates. The rationale behind this controversial issue from a
regulatory viewpoint is that no one would know for sure during the clinical
development that there is a difference between the test drug product and its
comparative control.
Therefore, one should rst provide evidence of the difference between the test
drug product and comparative control at the usual signicance level. If there
is no such evidence, then no claim of superior ecacy for the test drug product
can be concluded. Once sucient evidence is provided to support the existence
of a difference between the test drug product and the comparative control, then
superiority of the test drug product can be claimed only when the difference is
in the positive direction. Otherwise, the ecacy of the test drug product is
inferior to the comparative control.

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EXAMPLE
Chelation Therapy for Ischemic Heart Disease Chelation therapy using EDTA
is a widely used alternative therapy for ischemic heart disease. In 1993, Grier
and Meyers estimated that more than 500,000 people in the United States are
treated with EDTA therapy each year. Knudtson et al. (2002) also projected one
million U.S. residents will adopt chelation therapy with an annual expenditure
of approximately $400 million U.S. Unfortunately; its ecacy is never fully
established. Knudtson et al. and the Program to Assess Alternative Treatment
Strategies to Achieve Cardiac Health (PATCH) Investigators (2002) conducted
a double-blind, randomized, placebo controlled trial to determine whether the
most commonly used EDTA protocols have a favorable impact on exercise
ischemia threshold and quality-of-life measures in patients with stable ischemic
heart disease. Random intervention included infusion with either weightadjusted (40 mg/kg) EDTA chelation therapy or placebo for 3 hours per
treatment, twice weekly for 15 weeks and once per month for an additional
three months. In addition, patients in both groups also took oral multivitamin
therapy.

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The PATCH is a double-blind, randomized, placebo controlled trial to

evaluate whether the EDTA chelation therapy is superior to placebo on exercise
ischemic threshold and quality of life in patients with stable ischemic heart
disease.
The primary ecacy endpoints for this study are change from baseline to 27week follow-up in time to ischemia (1-mm ST depression), and mental and
physical component summary of Health Status Survey Short Form-36 (Ware et
al., 1994). The sample size of 40 patients per group for this study was chosen to
provide a 90% power for detection of a difference of 60 seconds in mean
change in exercise time from baseline to 27-week follow-up, assuming a
standard deviation of 80 seconds in both groups.
The results of these two primary endpoints are summarized in Table 3.1. The pvalues for treatment comparisons given in Table 3.1 are for the two-sided
hypotheses given in table. The mean change in exercise time to ischemia at the
27-week follow-up for the chelation and placebo groups were 63 seconds (95%
CI: 29 to 95, p-value < 0.001) and 54 seconds (95% CI: 23 to 84, p-value <
0.001), respectively. Although improvement of the exercise time to ischemia is
highly statistically signicant for both groups, the difference in mean change at
27-week follow-up between the chelation and placebo group is only 9 seconds

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with a 95% condence interval from -36 to 53 seconds. As the p-value for the
two-sided hypothesis in (7.3.1) is 0.69> 0.05 and the lower limit of the 95%
condence interval is -36 seconds less than 0, then based on the exercise time to
ischemia, there is no evidence to support that EDTA chelation therapy provides
superior ecacy to placebo. A similar conclusion can be reached based on the
results on the mental and physical component summaries of SF-36. Because the
standard deviations of these primary ecacy endpoints and other variables
were comparable between the chelation and placebo groups, this trial is
considered a well-conducted trial.

As mentioned in the ICH E9 guideline for regulatory settings, the approach of

setting type I errors for one-sided tests at half the conventional type I error used in
two-sided test is preferable for superiority. However, such a requirement is not
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necessary for other research environments in which superiority can be proved in a

one-step procedure by performing a one-sided hypothesis presented in table above
at the traditional level of signicance.
4. ACTIVE CONTROL AND EQUIVALENCE/ NONINFERIORITY TRIALS

In guide line entitled Choice of Control Group in Clinical Trials, indicate that
there are ve kinds of control, including placebo concurrent control, dose-response
concurrent control, active (positive) concurrent control, no treatment concurrent
control, and external or historical control (ICH, 1999).
A control is usually referred to as active or positive if it is a known active
treatment or drug. Therefore, an active control (positive control) trial is dened as
an adequate and well controlled trial in which a test drug product is compared
concurrently with a known active drug. Here, an active control trial is referred to as
a two-arm study in which subjects are randomly assigned to the test drug product
or to the known active drug.
From a regulatory prospective, the effectiveness of a drug product should be
established by demonstrating its superior ecacy to the placebo concurrent control
in superiority trials. However, ethical use of a placebo concurrent group in
assessment of ecacy and safety of new treatments in clinical trials has been
continuously questioned and challenged.
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As a result, it may not be ethical to conduct a placebo controlled trial for serious
illness or patients with severe or life-threatening diseases for establishment of the
ecacy of a new drug product. On the other hand, as many drug products have
been approved by regulatory agencies due to substantial evidence of ecacy and
safety generated from placebo-controlled superiority trials for the treatment of a
number of diseases, attention has focused on a search of new therapeutic
modalities to compete with the standard and known effective drug products
currently available on the market.
These new products may offer some specic advantages over the standard drugs.
These advantages include a better safety prole such as reduction of risk of
intracranial hemorrhage, or of some grade 3 or 4 toxicities in some cancer
treatments, an easy administration route such as from IV infusion to oral
administration, a short duration of treatment, an improvement on quality of life,
and most importantly, reduction of cost. Due to these reasons, the use of active
concurrent control has recently become increasingly popular.
However, despite their recent popularity, the use of active control trials is not
without unresolved problems, issues, and challenges that have to do with the
objectives of the active control trials.

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Primary Objectives
For the development of a test drug product, the primary objectives of an active
control trialcould be
1. To establish the ecacy of the test drug product.
2. To demonstrate that the test drug product is superior to the active control agent.
3. To show that the test drug product is similar to an active control agent or
4. To verify that the test drug product is no worse than the active control.
Because the placebo concurrent control is not included in the two-arm active
control trials, the ecacy of the test drug product cannot be established due to lack
of direct evidence of effectiveness of the test drug product against placebo .
Although the hypotheses in above example for superiority trials can be used to
assess objective (2) for demonstration of superior ecacy of the test drug product
to the active drug product, it still cannot establish the ecacy of the test drug
product because the two-arm active control trials do not include a placebo
concurrent control. Without inclusion of a placebo concurrent control in a two-arm
active control trial, the ecacy of a test drug product may be inferior to or

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indistinguishable from that of placebo even though it is superior to the active

control.
Objective (3) can be achieved through a two-sided equivalence trial with the
primary goal of showing that the response to two or more treatments differs by an
amount that is clinically unimportant (ICH E9, 1998). This objective can be
usually veried regardingwhether the true treatment difference is to lie between a
lower and an upper equivalencelimits of clinically acceptable differences. It
follows that the hypotheses corresponding toobjective (3) as interval hypothesis
given:

where L and U are some prespecied clinically meaningful lower and upper
equivalencelimits.
Average bioequivalence trials based on pharmacokinetic proles of plasma
concentrations of the active ingredients required for approval of generic drug
products are typicaltwo-sided equivalence trials as mentioned in Section 2.7 (FDA,
2001a). However, whendrugs are not absorbed and plasma concentrations of their
active ingredients are negligible,two-sided equivalence trials are also undertaken to

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demonstrate a two-sided clinical equivalence of the generic drug product to the

innovators product.
On the other hand, because of other advantages provided by the active control,
manyactive control trials are designed to show that the ecacy of a test drug
product is not clinicallyinferior to that of the activecomparator.
Atrial with objective(4) is referred to as anoninferioritytrial. Thecorresponding
hypotheses to a noninferiority trial is givenas

ICH

E9

(1998)

indicates

equivalence/noninferiorityis

that

statistical

generally

based

analysis
on

for
the

evaluation
use

of

of
a

condenceinterval.Two-sidedequivalencebetweenthetest drug product and the

activecontrol is concluded if the lowerand upper limit of thecondenceintervalfor
T -C is completely contained within (L, U). On the other hand,if the lower limit
of the condence interval for C -T is greater than L, then noninferiorityof the
test drug product is concluded. Again,both two-sided equivalence trials andonesided noninferiority trials cannot provide direct evidence of the effectiveness of
thetest drug product because they do not include a placebo concurrent group.
Issues in Active Control Equivalence Trials
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Issues, diculties, and controversies surrounding the active control equivalence

trials (ACET). A set of criteria for evaluation of the quality of active control
equivalence trials is presented in the table below

The number one problem of any two-armed clinical control trials without a
placebo concurrent control is the verication of the fundamental assumption of
active control equivalence trialsthe effectiveness of the active concurrent
control. This fundamental assumption been true, then the effectiveness of the test
drug product could have been established if it is shown to be equivalent to or not
inferior to the active concurrent control. However, without a placebo concurrent
control, the fundamental assumption of active control trials cannot be proven
directly by the present active control trial. However, if this fundamental
assumption is not true and cannot be veried, when the test drug product is

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equivalent to or not inferior to the active control, they can be both ecacious and
both inecacious.
ICH E10 guideline lists the following factors that can reduce ACET assay
sensitivity:

5. DOSE-RESPONSE TRIALS
All drugs are potent and poisonous. Only at the right doses, the benet provided by
the drug exceeds its inherent risk and only then the drug is useful. Therefore,
Moore (1995) pointed that the difference between a drug and a poison is the dose.
Information of the relationship among dose, drug concentration, and clinical
responses is extremely important for the safe and effective use of the drug. A
common wrong impression about the dose response information is only aimed at
the relationship on ecacy or benet.
However, it should be emphasized that the dose-response relationship on safety is
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response information on both ecacy and safety can help identify an appropriate
starting dose, the proper way to adjust dosage to the need of a particular patient,
and a dose beyond which increases would be unlikely to provide additional benet
or would induce unacceptable adverse events (ICH E4, 1994). Determination of the
dose and dosing range is the most dicult and challenging task during the clinical
development of a test drug product. The issue of whether the dose-response
relationship has been suciently characterized is one of the frequently asked
questions at the U.S. FDA advisory committee.. Trials conducted to characterize
the dose-response relationship of the test drug product are referred to as dose
response trials.
The following objectives of dose-response trials are given by the ICH E9 guideline
(1998):

From the above objectives of dose-response trials, it is extremely important to

identify the dosing range of a test drug product and to describe the relationship of
the dose and clinical ecacy and safety responses within that range. Therefore,
there are at least two types of dose-response curves with respect to the responses.
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The rst is the dose-ecacy curve that describes the relationship between dose and
some primary ecacy endpoints. The other is the dose-safety curve that
characterizes the relationship between dose and safety endpoints, such as incidence
of some adverse event or changes in some important laboratory evaluations. The
dose-response curve can also be classied as the population average dose response
curve (PDRC) and individual dose-response curve(IDRC). ThePDRC is
usefulfordescription of the shape and location of the response curvebased on the
averagefor theentirepatient population. On the other hand,the IDRC is extremely
important for selectionof an initial starting dose and subsequent dose adjustment
for an individual patient becausemany factors can contribute to differences in
pharmacokinetics of the test drug products among patients, including demographic
factors such as age, gender, race; concurrent illness such as renal or hepatic failure;
diet, concomitant therapy, or characteristics of individual patients such as weight
or genetic differences.
The dosing range or therapeutic window is determined jointly by the dose-ecacy
curve and the dose-safety curve. The lower bound of the dosing range is referred to
as the minimum effective dose (MED). The MED is then dened as the lowest
dose level of a test drug product that provides a clinically signicant response in
average ecacy that is also statistically signicantly superior to the response
provided by the placebo (Rodda et al., 1988; Ruberg, 1995a). In addition, the MED
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should also present a safety prole that is no worse than the placebo. According to
this denition, the MED must produce a response with a magnitude of clinical
superiority over placebo because a small but statistically signicant response
resulting from either large sample sizes or small variability can be of no clinical
application. On the other hand, the MED must also provide a statistically
signicant clinical response. This is because a large clinical response, yet
statistically insignicant from the placebo response produced at a dose level,
cannot establish the scientic evidence of the effectiveness at that dose level.
Similarly, the maximum tolerable dose(MTD) is the highest possible but still
tolerable dose level with respect to a prespecied clinical limiting toxicity (Storer,
1989; Korn et al., 1994). The maximum useful dose (MUE) is referred to as the
highest dose beyond which increases would unlikely provide additional ecacy.
The dosing range or therapeutic window is then dened as the range of the dose
levels from the MED to the minimum of MTD and MUE. If the difference between
the maximum of MTD and MUE and MED is large, then the corresponding test
drug product is said to have a wide therapeutic range. On the other hand, if the
maximum of MTD and MUE is very close to or even smaller than the MED, then
the product is practically of little therapeutic value.
The dose-response curve is usually estimated based on the data of primary ecacy
endpoints collected from dose-ranging or dose-response clinical trials conducted
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during phase II clinical development of a drug product. These dose-response

studies are usually randomized, double-blind, parallel-group designs comparing
several doses to a concurrent placebo. Occasionally, a crossover design such as
Williams design (Chow and Liu, 2000) is employed. Many clinicians, however,
nd a variety of titration designs either with or without a concurrent parallel
placebo group for dose-ranging studies that are useful due to the impression that
they mimic the clinical practices in the real world. The ICH E4 guideline (ICH,
1994) classies the dose-response designs as (1) parallel does-response design, (2)
crossover dose-response design, (3) forced titration design, and (4) optional
titration design (placebo-controlled titration to endpoints).
1. Randomized parallel dose-response design (RPDRD) is a straightforward
application of the parallel group design described here to investigate the
dose-response relationship. It is simple in concept and easy to implement
with straightforward analyses and interpretation of the results. RPDRD has
had extensive use and considerable success in obtaining and characterizing
the dose-response relationship. For RPDRD, patients are randomly assigned
to receive one of several xed-dose groups. The xed dose here is referred
to as the nal or maintenance dose. Patients in RPDRD may initially be
placed on a starting dose and gradually titrated to the nal dose according to
a prespecied schedule. The study period of the nal dose should be long
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enough for the full effect of the test drug product to realize and to allow
dose-response comparison. However, PRDRD provides only the population
averagedose response but not the distribution or shape of the individual
dose-response curve.
2. Crossover Dose-Response Design
3. Forced Titration (Dose-Escalation) Design
The forced titration design, all subjects move through the series of escalating
doses. This design is similar to the crossover dose-response trials. However,
assignment of subjects to receive different dose levels is ordered, not random.
Therefore, a critical drawback of this design is that the dose effects of individual
periods, time, and carryover effects (effects of cumulative doses) are all
confounded together. No valid and unbiased statistical inference for the doseresponse relationship based on continuous endpoints from this design is currently
available. Forced titration trials may be the poor choice for collecting the doseresponse information on adverse events because of their time-dependent nature.
Other problems that make this design unattractive for the dose-response studies,
including the poor choice for delayed response and spontaneous improvement over
time. Consequently, the higher doses under this design may nd very little room to
show an incremental effect. Similar to the crossover dose-response design,
nonetheless, the forced titration design can provide a reasonable rst
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approximation of both the population average dose-response curve and the

distribution of individual dose-response relationships if the carryover effect is
minimal and the number of dropouts is not excessive. In addition, if a placebo
concurrent group is included in the forced titration trials, it allows a series of
comparisons of an entire randomized group given several doses with a placebo
concurrent control. In addition, because of inclusion of a placebo concurrent
control, the forced titration design can provide evidence of effectiveness of the test
drug product. Because the inference from this design may be based only on
intrasubject variability, the forced titration design requires fewer patients than does
the RPDRD. Because it can be used to investigate a wide range of doses, the forced
titration design with a placebo concurrent group is a reasonable rst dose-response
study for helping selection of the doses for the subsequent randomized, parallel
dose-response trials.
4. Optional Titration Design (Placebo-Controlled Titration to Endpoint)
The optional titration design is the application of the titration design to investigate
the dose-response relationship of the test drug product. The difference between the
optional titration design and the forced-titration design, is that the subjects in the
optional titration design are titrated up to the next higher doses if they fail to
respond at the current dose level with respect to some prespecied ecacy criteria.

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Therefore, individual dose-response information is very important in real clinical

practice for both physicians and patients. Therefore, if a drug effect develops
rapidly and patients return to baseline conditions quickly after termination of
therapy, and if responses are not irreversible, a randomized multiple-period
crossover study of different doses using Williams design (Chow and Liu, 2000)
can be successful. Because for this design each individual patient receives several
different doses of the test drug product, in addition to the population average doseresponse curve, the distribution of the individual dose-response curves can be
estimated.
Because the statistical inference for the population dose-response curve is based on
theintrasubject variability, it may require fewer patients than the RPDRD. In
addition, if thestudy is adequately designed and is well conducted with washout
periods of sucientlength, dose and time will not be confounded together, and
unbiased inference about thedose-response relationship can be obtained even in the
presence of carryover effects. However,this design suffers the same shortcomings
of all crossover designs. The duration ofthe study could be very long for each
individual patient. Consequently, the likelihood of apatients withdrawal during the
studies is higher than RPDRD. In addition, there is oftenuncertainty about the
carryover effects and about baseline comparability among differentperiods for

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potential

period-by-treatment

interaction.

All

of

these

in

turn

create

analyticnightmares and questionable interpretation of the results.

From a practical viewpoint, if the endpoints are continuous or
categorical variables for some indications (e.g., blood pressure, analgesia,
bronchodilation) that can be quickly obtained after the treatment is started and is
rapidly dissipated after treatment is terminated, a wider range of designs can be
used, and simple and small studies can provide useful dose-response information.
Under these circumstances, the optional titration design with a placebo concurrent
group is the typical design selected for many dose-response trials during early
phase II clinical development to provide guidance for more denitive, randomized,
parallel dose-response trials. In contrast, crossover or various titration designs are
not applicable when the endpoints for some indications are delayed, persistent, or
irreversible, e.g., stroke, asthma prophylaxis, survival in cancer, or treatment of
depression. A randomized, parallel dose-response design is usually required for
these indications. In addition, RPDRD offers protection against missing an
effective dose because of an umbrella or bell-shape dose response curve, where
higher doses are less ecacious than are lower doses (ICH E4, 1994).
It is prudent to conduct dose-responses studies at the early stage of clinical
development to reduce the number of failed phase III trials because of poor choice

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of the dose, or to avoid accumulation of a database that consists mainly of

exposures at ineffective or excessive doses. It can also speed up the drug
development process, and save development resources and cost. However, the
endpoints of the dose-response studies may be different during different stages of
clinical development. For example, as indicated by the ICH E4 guideline, in
treatment of heart failure, a pharmacodynamic endpoint such as cardiac output,
pulmonary capillary wedge pressure might be used in the early stage. An
intermediate endpoint such as exercise tolerance and symptoms might be employed
in the later development. However, a mortality or irreversible mortality endpoint
such as survival or new infarction may be used for the nal assessment.
6. COMBINATION TRIALS
A treatment is dened as a combination therapy if it consists of more than one
active ingredient. A treatment is called a combined product if it is a combination of
different pharmaceutical entities such as drugs, biologics, and/or medical devices.
Since the general principles of statistical designs and analyses for the assessment
of the effectiveness and safety are the same for both combination therapy and
combined product, in this section our discussion will be focused on the evaluation
of a xed dose for the combination of two or more active ingredients.
In recent years the search and development of combination therapy for various
diseases have become a popular issue in the pharmaceutical industry (e.g., see
Lasgana, 1975; Mezey, 1980). In clinical practice it is not uncommon to observe

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an enhanced therapeutic effect for a combination drug in which each component

(at a certain dose) acts through a different mechanism when applied alone.
For instance, the combination of a diuretic with a beta-blocker has an enhanced
therapeutic effect for the treatment of patients with hypertension. In practice, each
component of the combination drug must be administered alone at a high-dose
level in order to achieve the desired therapeutic effect. In this case the component
drugs may cause severe and/or sometimes fatal adverse events. Therefore it is
desirable to control the synergistic effect among these components so that a
combination at the lower-dose levels will reach the same or better effectiveness
with less severe clinical toxicity.
For example, below table presented with lists the conventional maximum tolerable
doses for chemotherapeutic agents in the treatment of patients with advanced
ovarian cancer. Each of these drugs induces serious organ-specic dose-limiting
toxicity that jeopardizes the ecacy when they are administered alone. It is
therefore imperative to search for different combinations of these agents at lower
doses so that a higher equivalent cytotoxic dose can be achieved to provide a
clinically meaningfully improvement in response rate and overall survival.

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For example, McGuire et al. (1996) report that paclitaxel and cisplatin provided
not only a signicantly higher response rate than a standard therapy of cisplatin
plus alkylating agent cyclophosphamide (73% versus 60%, p-value = 0.01) for
stage III and stage IV ovarian cancer but also a signicant improvement in median
survival (38 vs. 24 months, p-value < 0.001).
After the initial successful culture of Helicobacter pylori (or H. pylori) in
gastricbiopsyspecimens

from

patients

with

histologic

gastritis

in

1982

(Warren,1982), it wasrecognized that more than 95% of patients with duodenal

ulcers and more than 80% ofpatients with gastric ulcers are infected with H. pylori
(Walsh and Peterson, 1995).Recently the Consensus Development Conference on
the U.S. National Institute of Healthrecommended that antimicrobial therapy be
used to treat patients with ulcers who are alsoinfected with H. pylori (NIH
Consensus Development Panel, 1994). However, it is not easyto identify effective
agents to eradicate the infection of H. pylori. The standard agents suchas Hreceptor antagonists and sucralfate have no effect on H. pylori. In addition,
bimuthsuch as pepto-mismol and numerous antibiotics including erythromycin,
amoxicillin, andmetronidazole have not been proved to provide satisfactory longterm eradication rate(Peterson, 1991).
As an alternative, a different regimen for the combination of antimicrobial agents
and the combination of antimicrobial and antisecretory agents has been proposed
for the treatment of patients with peptic ulcer disease who are infected with H.
pylori.Table6.2

displays

variouscombinations

of

antimicrobial

and

antisecretoryagentsin the eradication of H.pylori.

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The table displays various combinations of antimicrobial and antisecretory agents

in the eradication of H. pylori. As can be seen from Table 7.6.2 these different
combinations consist of different microbial and antisecretory agents at different
dose levels.
The duration for the treatment of these combinations and the corresponding
radication rates of H. pylori vary from one combination to another with different
overall incidence rates of adverse events. In addition to the eradication rate of H.
pylori, other important ecacy endpoints to be evaluated include the rate of
complete healing of the ulcer and the recurrence rate as documented by endoscopy.
Note that although the FDA has a specic policy for the approval of combination
therapy, the assessment of the effectiveness and safety for the combination therapy
is rather dicult and yet challenging because of its complexity. The development
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of a combination therapy involves the determination of the optimal joint region of

therapeutic dosing ranges, the duration of treatment for each different drug, and the
order of administration of these agents, while the assessment of the combination
therapy is usually based on multiple ecacy and safety clinical endpoints. This
complexity may limit the chance of a combination therapy being approved by the
FDA.
Fixed-Combination Prescription Drugs
The FDA has specic regulations thatare described in Section 300.50 in Part 21 of
CFR regulation states that Two or moredrugs may be combined in a single dosage
form when each component makes a contribution to the claimed effects and the
dosage of each component (amount, frequency, duration)is such that the
combination is safe and effective for a signicant patient population.
A xed-combination prescription drug is dened as a single dosage formulated
from differentpharmacological agents. Accordingto the FDAsregulation,the xedcombinationdrugs are conned to a class in which different drugs can be
formulated into one dosageform. However, different drugs may be administered in
separate and/or different dosageforms either simultaneously or sequentially.

For example, the Second International Studyof Infarct Survival (ISIS-2, 1988)
evaluated the effectiveness of the combined therapy ofone-hour intravenous
infusion of 1.5 MU of streptokinase up to 24 hours from the onset ofchest pain
followed by one month of oral enteric-coated aspirin at a dose of 150 mg per
dayfor patients with suspected myocardial infarction. The dosage forms and routes
of administrationof the twotherapeutic agents considered in ISIS2 are differentand
are givensequentially.
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It should be noted that current regulationsfor xed-combinationdrugs do not

coverthecombination therapywith differentdosage forms and time of administration
though,inprinciple, the statistical design and analysis are the same for both xedcombination prescriptiondrugs and combination therapy.
A combination therapy, the FDA also requires the evidence forwhich each
component must make a contribution to the claimed effects of the combinationbe
provided. The contribution is referred to as the contribution based on a single
clinical endpoint. Onthe other hand, for approval of a xed-combination
prescription drug, the FDA requiresevidence to be provided of the superiority of
the combination over each of its components.It, however, should be noted that the
combination might increase the risk of adverse eventsdue to the unnecessary
exposure of patients to some components that may not have additionalclinical
benet.
In addition the FDAregulationstates the relationship of the combinationand its
constituents in terms of the claimed effects.However,it does not specify thetype,
form, and magnitude of the contributions of each component to the claimed
effects,nor does it require the claimed effects to be contrasted with a concurrent
placebo control

Let A and B be the components of a combination drug, denoted by A B,

each at axed dose. Let A, B, and AB be the average of the distributions
of the clinical endpointssuch as reduction in seated diastolic blood pressure,
eradication rate, vascular mortalityrate within a certain time interval, or
median survival.Since the FDA requires that the ecacyof the combination

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be superior to those of each component,the hypotheses can beformulated as

follows

A larger value of indicates a better ecacy. Twoone-sided hypotheses:

and

.
The rst set of one-sided hypotheses is to verify that the combination drug A
B is superior to component A. If the combination drug is indeed superior to
component A, then component B does make a contribution of the claimed effect of
the combination. Similarly the second set of one-sided hypotheses is to
demonstrate that the combination A + B is superior to componentB.

As a result, the null hypothesis is a union of the two null hypotheses and which
include all points in quadrants two, three, and four as well as all axes. On theother
hand, the alternative hypothesis is the intersection of the two alternative
hypotheses,which consists of all points in the rst quadrant excluding the positive
axes.
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Although hypothesescan be employed to test statistically whether each

componentmakes a contribution to the claimed effects of the combination, the type,
form, and magnitudeof the joint contribution by both components cannot be
quantied.
For example, consider theresults of vascular mortality rates in days 035 reported
by ISIS2, as shown in Table 2.4.2.
The vascular mortality rates of IV placebo active aspirin, IV streptokinase
aspirinplacebo, and IV streptokinase and active aspirin are 10.7%, 10.4%, and
8.0%, respectively.The contribution of IV streptokinase to the combination is
2.7% (10.7% 8.0%) and contributionof activeaspirin to the combination is 2.4%
(10.4% 8.0%). However,without includinga concurrent placebo control,it is not
clear what the joint contribution of both drugs is.
The mortality rate of IV placebo and aspirin placebo is 13.2%. The reduction in
mortality rateof the combination therapy as compared to the concurrent placebo is
5.2% which is approximatelythe sum of the contribution
of each component (2.7% 2.4%). The estimated effectof combination versus
placebo can be expressed as follows:

where S, A,and P stand for mortality rates of IV streptokinase, oral aspirin, and the
placebo.
The last term on the right-hand side of (7.6.4) is the interaction between the two
components,which can be measured by the difference between the difference in
vascular mortalitybetween the streptokinase and placebo for patients taking the
aspirin placebo tablets andthat between the streptokinase and placebo for patients
taking the active aspirin tablets. Inturns out that the reduction in mortality of the
combination as compared to the concurrentplacebo is the sum of the contributions
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to the reduction in mortality by each component plusthe interaction between two

components as demonstrated by the mortality rates from ISIS2.
That is,

It can be seen from the above that the interaction (0.1%) between IV
streptokinase and oralaspirin in the reduction of mortality is negligible. As a
result, the magnitude of the contributionsmade by each component to the
reduction in vascularmortality is quite similar,andtheir joint contribution to
vascular mortality of the combination is additive. In practice, it
isrecommendedthat

complete

2 factorial design, as given in panel A of Table 7.6.3, be

employed to assess the ecacy and safety of the combination with the two
componentseach at a xed dose. One could argue that there is no need for a
concurrent placebo controlin the evaluation of a xed-combination drug
because the clinical benets of monotherapyfor each component have been
established through prospective, randomized, double-blind,

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