DESIGN DECISIONS

& TRIAL DESIGNS

CLINICAL DEVELOPMENT PLAN

4-JUL-10
7 major design decisions
• Should the study be performed?
• What are the study’s objectives?
• What are the primary and secondary response
variables?
• How will the quality of the information be assured?
• What types of subjects will be included in the study?
• What is the time line of the study?
• How will the study be terminated?
 5 technical design decisions
• What experimental design will be utilized?
• What baseline measurements will be made on
each patient?
• Will it be a single-blind or a double-blind study?
• What sample size is necessary to detect the effect?
• How many examination sites will we need?
1. Should the study be performed?
• Critical decision
• Promising molecule – go ahead with extensive
trials
• However if surgical procedures in
experimental stage of drug-drug interactions
not known – short term trials
WHICH COMES FIRST?

TRIAL DESIGN
OR
TRIAL OBJECTIVE
Trial Design
• Framework by which the trial objectives will be met
• Generally established after the trial objectives have been clearly
elucidated.
• Otherwise, one may be in a position of attempting to fit the
trial objectives to a imposed or fixed trial design
• If a trial design is not acceptable for addressing the
objectives posed, it may be necessary to refine or modify
the trial objectives
• Several reasons why the specific clinical trial design required to
address the trial objectives may be either unsuitable /impossible to
adopt
Clinical trial design & Objectives-
reasons for mismatch
• Design might require:
– Methods that are beyond the state of the art in the field of
medicine involved
– Equipment is too expensive or too difficult to obtain or operate
– Too many patients
– Efforts that are too arduous for patients to meet comfortably
– Too long a period to conduct
– Too much manpower to conduct
• Necessary to revise trial objectives to bring them within the
limitations imposed on trial design by resources, state –of-the-art
considerations, etc
Types of Clinical trials
Primary purpose Example

Safety evaluation How high a dose patients can receive without having
clinically significant adverse reactions, physical signs or
laboratory abnormalities

Pharmacokinetic Investigation of one or more of basic PK concepts like

evaluation absorption, distribution, metabolism and excretion

Efficacy When a medicine is expected to cause a specific change in

evaluation a laboratory parameter in normal volunteers as well as
patients
Contd…
Primary Example
purpose
Mechanism of To elucidate the MOA & drug interactions
action evaluation
General Therapeutic use of a drug-Phase III and IV
Population
Evaluation
Evaluation of Evaluation of new dosage formulations (e.g. tablets
Clinical vs. capsule), new routes of administration, new
Pharmacology dosage regimens (e.g. bid vs. tid dosing), etc.
Post-marketing Varied types of Phase IV studies that are designed to
evaluations identify rare or infrequent adverse reactions as well as
beneficial effects
2. What are objectives?
• If an underlying question is the basis of the proposed
objective, it may then be desirable to modify
objective to reflect underlying consideration
• In case other individuals are assisting in developing
protocol, one should obtain their agreement that
established objectives are appropriate, correctly stated
and will meet the goals or purposes of the clinical
trial
– Goals (purposes) – represent the type of trial to be ducted
– Objectives –Concise statements that will enable the goals
to be achieved
Why are Clinical trial objectives so
critical?
• Objectives are questions the clinical trial asks and tries
to answer
• Asking the right type of question is the most important
part of the research
• The way the research problem is stated, determines the
trial design used, data collected, analyses conducted and
interpretation/conclusions that can be drawn
• Therefore essential that the objective (s) be clearly,
completely and concisely expressed
• If not rest of the enterprise may be irrelevant and
represent a significant waste of efforts.
Trial Objectives
1. To compare a drug with other drugs already in the
market;
2. To monitor a drug's long-term effectiveness and
impact on a patient's quality of life;
3. To determine the cost-effectiveness of a drug
therapy relative to other traditional and new
therapies.
Keep the objectives specific & simple

 To evaluate the effects of To determine the mechanism

daily T dose of medicine M, of action of medicine M
in population P on - Objective is too general,
parameters A & B by vague and merely restates the
continuous or daily recording overall goal of the trial
of results obtained in tests Y
and Z during time period C
as compared to medicine D at
dose E under the same
experimental condition.
Information to include in the statement of a clinical trial’s
objective

• An expression describing the overall approach (e.g. to

assess, to compare, to evaluate, to determine)
• Names of all medicines being evaluated
• Specification of the dose (s) or dose range to be
studied (e.g. 200 and 400 mg)
• Identification of the dosage regimen (e.g. once a day
for 3 weeks)
• Disease (s) being evaluated
• Type of patient (s) being evaluated (e.g. pediatric,
renal failure)
• General purpose (e.g. safety , efficacy,
pharmacokinetics)
Contd..

• Specific purpose (e.g. dose-response, superiority to placebo)

• Parameter (s) to be measured
• One or two major objectives are usually all that may be tested
in a single clinical trial – Do not use terms like “To prove”-
since it implies that results are known
• One to three secondary objectives may also be tested
• Each objective should be listed and is usually described in one
or two sentences
• The primary (major) objectives should be clearly delineated
and separated from the secondary objectives so that no
confusion develops
Objectives and End-points
• Objective (or aim)- question (preferably only one) –
the trial is seeking to answer
– Could be either efficacy or safety
• End-point (or outcome measure or variable)
– May be primary or secondary
– Must be actual defined measurement or assessment
– There is a time point of clinical interest
– Clarity of thought is required
– Protocol writer has to justify the choice of primary end-
point
Objectives and End-points -Examples

• Hypertension study:
– Objective – to compare the efficacy of Drug A with that of
Drug B in the treatment of hypertension
– End-points for comparing effect of the two drugs:
• The percentage of subjects who achieve a target
diastolic blood pressure (e.g. 90 mm Hg) at the end of
treatment (e.g. at 12 weeks) or
• The change from baseline in diastolic blood pressure at
the end of the treatment (e.g. at 12 weeks)
Contd..

• Dyslipidemia study
– Objective : To compare the efficacy of drug A with that of
Drug B in the treatment of Dyslipidemia
– End-points for comparing effects of the two drugs:
• The percentage of subjects who achieve a target HDL-
Cholesterol( e.g. 50 mg%) at the end of the treatment
(e.g. at the end of 16 weeks)
• The change from baseline in HDL-cholesterol levels at
the end of the treatment (e.g. at the end of 16 weeks)
3. End-points- types
• May be :
– Hard end-points: objective measurements that are not dependant
on the opinion of the observer- e.g. death, blood pressure,
laboratory values
– Surrogate end-points: Measurements of subjective symptoms of a
disease e.g. pain, discomfort, irritation
• Care needs to be taken to ensure that the surrogate end-point
accurately correlates with disease levels and symptoms and
that it is an accurate predictor of clinical outcome
– Certain diseases –characterized by subjective symptoms (e.g.
itching, pain or irritation)-can only be scored by subject & by
related symptoms (e.g. redness) that can be assessed by the
investigator only
• Score of clinical effectiveness as judged by investigator and
the subject is often included as an additional observation
Desirable characteristics of End-points
• End –points should be
– Feasible to measure - it should be possible to obtain the end-point
measure in all or nearly all the subjects – missing data may
substantially reduce the ability to draw valid inference from a trial
– Should be sensitive to the desired effects of the interventions under
study
– Clinically meaningful- should be a direct measure of an important
benefit to the patients such as longer survival, less pain, improved
physical functioning
• End-points that do not directly measure benefit (e.g. laboratory tests, x-rays)
are of value as primary efficacy measures only when they correlate with and
predict clinical benefit
Contd..
– Readily communicated to those who will receive
the results of the study e.g. % survival at 1 year
than if alternative end-points are used (e.g. an
unfamiliar scoring system)
– Objective – particularly in trials that may be
unblinded or in which the study treatment has
unblinding effects
• Objective endpoints reduce bias
End-points : events and measurements

• Some end-points assess events, others provide a measurement of an outcome

• Events :
– Occur at specific point in time
– Assessment is binary- it has occurred or not
– E.g. Death, stroke, cure of infection, progression to AIDS, MI, flare of asthma
• Measurements:
– Have several or many potential values that may change over time
– Can detect a broad range of change in the outcome measure in each patient
– Can detect a broad range of change in the outcome measure in each patient
– E.g. Blood pressure, strength, weight, CD4+ cell count, tumor size, quality of
life scored on standard scale and visual acuity
• Measurement –based end-points will be often be more sensitive and yield
greater power than event-based end-points
– May detect very small changes & may raise more questions about clinical
meaningfulness
Surrogate End-points
• Surrogate end-points:
– Laboratory or other measurements that do not
directly indicate clinical benefit but are expected to
correlate with or predict clinical benefit
– Not clinically meaningful in its own right
– Ability to predict clinical benefit may be
overestimated
– Use often considered when direct measures of
clinical benefit arise only after a lengthy period of
observation
– E.g. in trials with interferons for the treatment of
chronic hepatitis C infection, decrease in the levels
of circulating liver enzymes, improvements in liver
histopathology and loss of detectable virus in
plasma have been used as surrogate end-points
• Indicate a likelihood of serious, long-term
clinical sequelae
Surrogate endpoints – benefits
• Can be of substantial value as secondary or supportive end-
points in Phase III trials
• Likely to be useful as efficacy end-points earlier in clinical
development (Phase II trials)
• Reliance on clinical benefit end-points in all trials of a drug
could be extremely costly, time-consuming & may prevent
primary development
• Trials with surrogates may help to determine if an agent is
sufficiently promising to warrant investment of the time, effort
and money to conduct a trial measuring clinical benefit , and
may also be used to determine the optimal dose, regimen,
target population or concomitant medications for such a trial
• Use of a surrogate marker in earlier clinical trials will not lead
to an incorrect final determination that an ineffective treatment
is effective
Safety objectives
• If objectives of clinical trial relate to evaluation of drug safety,
then trial design chosen will depend on which aspects of safety
are of particular interest for evaluation
– Safety considerations may focus on doses used, laboratory
results, physical examinations, adverse reactions or other areas
• If purpose of trial is focused on determination of safe doses for –
– Dose ascension
– Loading the patient
– Determining the maximally tolerated maintenance dose
– Defining a safe rate of dose taper
– Safety of sudden withdrawal of medicine
Other Objectives:
• Trial goals & objectives may be developed that relate
to comparative claims with other medicines, labeling
of the medicine, new dosage strengths or
formulations and establishment of various parameters
related to pharmacokinetics
• Although trials primary objective (s) may be focused
on efficacy or pharmacokinetics, evaluation of safety
or medicine toxicity is virtually always performed at
the same time even if not a stated objective and is
conducted in a non-rigorous manner
4. How will the quality of the information be
assured?
• The secret of successful clinical trials lies in maintaining the quality of
the data you collect. The most frequent sources of error are the
following:
• Protocol deviations that result when the intervention is not
performed/administered as specified
• Noncompliance of patients with the treatment regimen
• Improperly labeled formulations
• Improperly made observations
– Inaccurate measuring devices
– Inconsistent methods of observation, the result of
• Ambiguous directions
• Site-to-site variation
• Time-period to time-period variation
– Fraud (sometimes laziness, sometimes a misguided desire toplease)
• Improperly entered data
• Improperly stored data
Preventive measures
• Keep the intervention simple
• Keep the experimental design simple
• Keep the data collected to a minimum.
• Pretest all questionnaires to detect ambiguities.
• Use computer-assisted data entry to catch and correct data entry errors as
they are made
• Ensure the integrity and security of the stored data
• Prepare a highly detailed procedures manual for the investigators and
investigational laboratories to ensure uniformity in treatment and in
measurement. Provide a training program for the investigators with the
same end in mind.
– This manual should include precise written instructions for measuring
each primary and secondary end point. It should also specify how the
data are to be collected. For example, are data on current symptoms
to be recorded by a member of the investigator’s staff, or by the self-
administering patient?
• Monitor the data and the data collection process. Perform frequent on-site
audits. In one series of exceptionally poorly done studies Weiss et al.
(2000) uncovered the following flaws:
– Disparity between the reviewed records and the data presented at two
international meetings
– No signed informed consent
– No record of approval for the investigational therapy
– Control regimen not as described in the protocol
• Inspect the site where the drugs or devices are packaged; specify the
allowable tolerances; repackage or relabel drugs at the pharmacy so that
both the patient’s name and the code number appear on the label; draw
random samples from the delivered formulations and have these samples
tested for potency at intervals by an independent laboratory.
• Write and rewrite a patient manual to be given to each patient by their
physician. Encourage and pay investigators to spend quality time with each
patient.
5. What types of subjects will be included in the
study?
• What group of patients and for what disease condition? –
Decision to be taken during the design stage itself.
• Be sure to have in hand a list of potential contra-indications
based on the drug’s mechanism of action as well as a list of
common medications with which yours might interact. For
example, many lipid lowering therapies are known to act via
the liver, and individuals with active liver disease are
specifically excluded from using them.
• Eligibility requirements should be as loose as possible to
ensure that an adequate number of individuals will be
available during the proposed study period. Nonetheless, your
requirements should exclude all individuals
– Who might be harmed by the drug/device
– Who are not likely to comply with the protocol
– For whom the risks outweigh any possible benefits
Contd..

• Define the inclusion/exclusion criteria carefully.

• Criteria that are more restrictive will yield a homogeneous
sample of patients, so that variability will be lower. This will
require a smaller target sample size, but recruitment will be
difficult. Another drawback is that the results of the study
may not be generalizable to other types of patients with the
disease (lack of external validity).
• Criteria that are less restrictive will yield a heterogeneous
sample of patients, so that variability will be higher. This will
require a larger target sample size, but recruitment will be
easier. More importantly, the results of the study should have
some external validity.
6. What is the timeline of the study?
Time lines to be decided between:
•Determination of eligibility
• Baseline measurement
• Treatment assignment
• Beginning of intervention
• (If applicable) Release from hospital
• First and subsequent follow-ups
• Termination.
7. How will the study be terminated?
• Will you follow each participant for a fixed period?
• Or will you terminate the follow-up of all participants
on a single fixed date?
• What if midway through the trials, you realize your
drug/device poses an unexpected risk to the patient?
• Or that your drug/device offers such advantages over
the standard treatment that it would be unethical to
continue to deny control patients the same
advantages.
• Planned closure:

• Unplanned Closure:
– SAEs, Unblinding of the code
Comparative Trials
• Most common, used for registration purposes
• Compare the new drug with a standard drug
(or placebo)
• Blinding preferred, eliminates bias
• Simultaneous analysis of efficacy and safety
Long term efficacy
• Generally on marketed drugs
• Seek to establish safety and efficacy
• Blinding not essential
• Measure both objective and subjective changes
in patient.
Pharmacoeconomic studies
• Should be comparative
• Estimate relevance of particular therapy for a
population
• Used to calculate the disease burden
• Results may vary from country to country
hence studies should be site specific
Types of Trials
• Protocol based
Fixed dose, or duration trials

• Intent to treat
Dose or duration continued till end points are
achieved
Clinical trials can be controlled or uncontrolled.
A clinical trial without a control group is somewhat
akin to a cases-series study in that it is hypothesis
generating but not confirmatory.
The optimal design for a clinical trial is to include a
concurrent control group because the intervention
group and the control group are subject to the same
conditions and eligibility criteria for the study.
Open Label
– Both patients and investigators know who is
receiving what
– No blinding, no randomization
– Could be per protocol or intent to treat.
– Patients do not like to be in the placebo arm of the
trial
– Surgical or devices trials are generally open
Blinded
• Closed label (Blinded)
– Either one or both the patient and investigators are blind to
the identity of treatment
– Single Blind
– Double Blind
– Triple Blind
• Establish efficacy and safety
• Placebo or comparator to be used
• Most commonly used in Phase III
• More acceptable to regulatory authorities
Factorial Trials
• Drugs to be used in combination
• Use a number of groups eg.,
– Group A
– Group B
– Group A+B
– Control
• Difficult to interpret
Parallel
• 2 or more arms
• Runs in parallel
• Simplest design & most widely used

Arm A

Arm B
Crossover Trials
• All patients receive both drugs.
• Group A receive X, and Group B receives Y
• After a fixed duration both drugs are stopped
and the patients remain drug free for a short
time
• Then Group A receives Y and Group B
receives X
• Carry over effects make such trials difficult
Contd….

• Some trials may invoke a crossover design in which patients

serve as their own controls. For example, subjects may
undergo an experimental therapy for six weeks and then “cross
over” to the control therapy for another six weeks (or vice
versa).
• Crossover designs are appealing because the patients serve as
their own controls. A crossover design typically will require a
much smaller sample size than a “parallel” design.
• A disadvantage of a crossover design is the potential for
“carryover” effects, i.e., the treatment administered during the
first period may carry over into the second treatment period.
Sequential Trials
• In sequential design, data are monitored throughout
the collection, and the data may be analyzed after a
block of data is accrued. This is especially beneficial
if electronic data capture (EDC) methods are used for
data collection.
• Subjects are recruited sequentially over a time
interval called accrual period (weeks, months, years0
• Subjects receive assigned treatment for prespecified
duration to be evaluated over a follow-up period
• Allows interim analysis
• PEST 4 & S+Seq Trial Softwares for trials
Orphan Drug Trials
• For drugs to treat diseases affecting less than
200,000 people in the US.
• Trials need not be large, controlled or
randomized
• Design cannot be used for all drugs
• Specific rules may be relaxed by authorities
Titration designs
• Dose ranging / dose escalating
• Generally in phase II – when we need to
decide the dose.
• Parallel group – dose titrations (single /
multiple) – common
• Cross-over titrations – less frequently used
Run-in periods
• Acts as washout period
• Obtain baseline data and fullfillment of
recruitment criteria
• Training period for patient ,investigator and
staff
• Help identify placebo responders
• Patient compliance
Randomization
• Investigator may have a bias towards New or old
treatments
• All treatment groups should have
Older patients, Younger patients, Poorer patients,
(malnourished), Male patients, (different physiology),
Serious patients, Mild patients, Complicated patients,
(with other diseases) Older patients, Younger patients,
Poorer patients, (malnourished), Male patients, (different
physiology), Serious patients, Mild patients, Complicated
patients,(with other diseases)
ONLY RANDOMIZATION CAN ACHIEVE THIS!!
History of Randomisation

• A patient can improve by his own defence

mechanisms, and the effect can get wrongly attributed
to a drug was recognised in 1930s

• Randomisation was earlier employed in agriculture to

reduce bias by confounding factors, -sun, soil,
moisture, wind (RA Fisher,1920*)

• Sir Austin Bradford in 1930 adopted Randomisation

designs in Clinical trials
• Randomisation is a process based on Chance allocation of
subjects to different treatments planned in a Clinical trial.
• Randomisation decides which patient will Receive which
treatment.
• Assurance that subject populations are similar in test and
control groups is best attained by randomly dividing a single
sample population into groups that receive the test or control
treatments.
• Randomization avoids systematic differences between groups
with respect to known or unknown baseline variables that
could affect outcome.
• Randomization also provides a sound basis for statistical
inference.
 How is Randomisation done ?

1.Unrestricted 3.Stratified
Randomisation Randomisation

2.Blocked 4.Dynamic
Randomisation Randomisation

Griffin and O’Grady (2006),The Textbook of Pharmaceutical Medicine,Blackwell Publishing,p 294-297

Unrestricted Randomisation
• Take Random No.table (Cambell and Machin)
• Choose randomly 21st row…4th block…
• Nos read as 316427816281
• Give even nos. to Treatment A, odd to B
• Treatment Schedule will read as
• BBAAABABAAAB (7 As abd 5 Bs)
• Disadvantage - Random No. tables may not give
equal nos in 2 treatment arms
 How does a Random no. table look ?
42505 29928 18850 17063 70236 35432 61247
75849 20194 28561 20957 35260 77382 23109
98372 78293 76093 15972 28152 18204 25153
29928 18550 17260 70236 35432 61657 20947
20194 28561 20957 35260 87982 24108 38295
78293 76293 15263 28352 19204 28153 28163
17263 50746 35432 61247 20940 63729 29583
21957 35260 77382 23159 38295 39675 18352
15272 28252 19206 28153 28763 84936 37251

-Muth James E.De (1999), Basic Statistics and Pharmaceutical Statistical Applications, Marcel Dekker Inc,50,572
2.Blocked Randomisation
-Take blocks of 4/6/8 treatments
Block 1 Block 2 Block 3
AABB ABBA BABA

Block 1 Block 2 Block 3 Block 4

AABBAA BAABBA BABAAB ABABAB

-Blocks are allotted to different centres

-There are all treatments in every block
-There are equal treatments in every group
Griffin and O’Grady (2006),The Textbook of Pharmaceutical Medicine,Blackwell Publishing,p 294-297
Advantages

• Protects against “Time effect” i.e. If characteristics of

patients recruited change over time, it has no effect
on outcome

• Helps to keep Same no. of patients in different groups

in Multicentre trials
 Blocked Randomisation
Disdvantages
Block 1 Block 3
ABBA BABA

The last treatment may reveal itself due to

a particular drug effect…e.g.,a drug which
colours urine, or causes loose stools etc

Overcome this by making

the Investigator blind to block length
Griffin and O’Grady (2006),The Textbook of Pharmaceutical Medicine,Blackwell Publishing,p 294-297
3.Stratified Randomisation
ICH E9 recommends that
-Do Centrally,
-Allocate several blocks to each centre
If Sex and Age are known to affect the outcome,
Stratification Blocks
Sex Age Block 1 Block 2 Block 3
F 40-60 ABAB BBAA AABB
F > 60 BAAB ABBA BBAA
M 40-60 BAAB ABBA BBAA
M > 60 AABB BAAB BABA
Griffin and O’Grady (2006),The Textbook of Pharmaceutical Medicine,Blackwell Publishing,p 294-297
• Advantages:
– Minimises bias with known factors
– Increases the power to detect differences
• Disadvantages:
– Delays randomisation reaching different centres
– ‘Misclassification’ of patients to strata may be
revealed at the completion of the study!!
Dynamic Randomisation

• When factors requiring stratification are too many,

some groups may in the end have less patients.
• Hence, Minimisation undertaken to bring back the
balance and increase the efficiency of the study
Suppose, the picture at 50/100 patients is as below
Factor Level
No.on each treatment
A B
Disease Moderate 30 31
50
Severity Severe 20 19
Age < 55 18 17
> 55 32 33
Centre 1 19 21
2 8 7
3 23 22
If the next patient is Severe,<55 years at Centre 2,
Add nos opposite these characteristics…..
Griffin and O’Grady (2006),The Textbook of Pharmaceutical Medicine,Blackwell Publishing,p 294-297
 How is Dynamic Randomisation or
Minimisation done ?
Factor Level
No.on each treatment
A B
Disease Moderate 30 31
Severity Severe 20 19
Age < 55 18 17 Hence
> 55 32 33 Called
Centre 1 19 21 Minimi
2 8 7 sation
3 23 22
Treatment A=20 +18+8=46 As 43 is lesser than 46,
Treatment B=19+17+7= 43 Patient receives B
Griffin and O’Grady (2006),The Textbook of Pharmaceutical Medicine,Blackwell Publishing,p 294-297
• Advantages:
– Provides good balance of prognostic factor and
increases efficiency of trial
• Disadvantages:
– ‘Future’ treatments decided by ‘earlier’
treatments….not ideal randomisation
– Earlier patient may be at another centre ! Hence
communication by Fax/Net /Telephone becomes
necessary with associated difficulties