Transcript Writing Clinical Trial Protocol

Tips on clinical trials
Maha Al-Farhan
B.Sc, M.Phil., M.B.A., D.I.C
Accredited Member of the Association of Clinical Research Professionals, USA
In this session
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Essential clinical trials documents and
materials
Definition of the protocol
How to write a clinical study protocol
Ethical Considerations: The declaration of
Helsinki
Informed consent
Case record forms.
Current Compliance Concerns (FDA)
Basic Documents and materials
of clinical trials
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Clinical Trial Protocol
Informed Consent form
Trial Case Record Forms (CRF)
Investigational Product
Study Materials
Definition Of the Protocol
(according to
ICH Good Clinical Practice Guideline)
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A
document
that
describes
the
objective(s),
design,
methodology,
statistical considerations, and organisation
of the trial.
Usually, the protocol also gives
background and rational for the trial.
the
How to write a protocol
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How detailed should a protocol be:
– This is a matter of judgement
– Rule of thumb: Include the right
amount of detail necessary for the
reader of each section to be able to
understand exactly what is required
to conduct the study.
Start by mapping out a study
schedule
Visit 1
Baseline
(day 0)
Informed Consent
X
Inclusion/ Exclusion
X
Medical History
X
Primary diagnosis
X
Clinical assessment
X
Visit 2
Randomization
(day10)
X
Randomisation
X
Adverse Events
X
Assessment of relapse
Visit 3
(day 20)
Follow-up
Visit
(after end of
treatment)
X
X
X
X
X
Objectives and end-points
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Get the primary objective right
The primary objective will dictate
the primary end-point.
Primary end point measurement will
be used to calculate sample size.
Get the primary objective right
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Could be either efficacy or safety
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Well defined
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Well founded
The primary end-point.
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Defined measurement or assessment.
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Implies a time point of clinical interest.
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If possible, end-points need to be
objective measurements rather than
subjective outcomes
Primary end point measurement
will be used to calculate sample
size.
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Statisticians should be consulted.
Many different ways of calculation depending on
whether:
– Trial is designed to show superiority against
placebo or another treatment.
– Trial is designed to show equivalence or noninferiority against standard treatment
Allowance for subjects drop out.
Choice of study design
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Two main types:
– Non-Comparative: usually used to
assess a treatment’s safety and
tolerability.
– Comparative design
comparing treatments:
Cross-over
used
when
Parallel-group
Choice of comparative study
design
Cross-over
Parallel group
Variability
Minimal
Variability must be
taken into account
Number of subjects
needed
Smaller
Larger
Wash out period
between treatments
Must be adequate to
ensure baseline status
No need
Disease
characteristic
Ethically, must be stable
during wash out period.
No restrictions
Primary end-point
Subjective
No restriction
Bias
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Selection/
Allocation
bias
Observer bias
How to avoid it
Randomisation
Blinding
Subject Selection criteria
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Define the population to be studied.
Inclusion criteria/Exclusion criteria should reflect
the wider population of patients.
Balance the scientific integrity and final
application of the treatment in question.
Methodology/ assessments
Details of this section ensure that:
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all observations are performed in a standard
manner.
Sample collection procedure and laboratory tests
are performed in a standard manner
Ethical considerations:
General issues
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Has every possible precaution been taken to ensure
the safety of the subject?
Are the assessments really necessary, especially
those that involve some risk to the subject (e.g.
invasive measurements)?
Is the comparator (especially if it is placebo) ethical
to use or is the subject being deprived of current
proven effective treatment?
Ethical Considerations:
The Declaration of Helsinki
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It is a statement of clinical principles to provide
guidance to physicians and other participants in
medical research involving human subjects.
It confirm the role of the physician above that of
the investigator
It is a set of principles defining the standards that
should apply to biomedical research worldwide.
Ethical Considerations:
Informed consent.
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Often come in two parts:
– Written information describing the clinical
trial
– A form which the subject signs to
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document that he/she has given
consent to take part in the study
Closely reviewed by ethics committees.
Consent is valid when freely given.
Ethical Considerations:
Informed consent content.
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Should include up to date information
That the trial involves research.
The purpose of the trial (experimental aspects).
Trial treatments and probability for random
assignment to each treatment.
Trial procedures to be followed and Subject’s
responsibilities.
Risks, inconveniences, and benefits to the
subject.
Ethical Considerations:
Informed consent content.
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Compensation and/or treatment available to
subject in the event of trial-related injury.
That subject’s participation is voluntary and that
he/she may refuse to participate or withdraw
from the trial at any time.
Monitor(s), Auditor(s), Ethics committee, and
regulatory authority(ies) will be granted access
to subjects medical records.
Confidentiality of subject’s records.
Expected duration of the trial.
Approximate number of trial subjects
Ethical Considerations:
Informed consent process.
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Alternative treatments available.
Subject’s should not be unduly influenced to
participate
Subjects should be fully informed of all pertinent
aspects of the study.
Written information should be as non-technical as
possible.
Ethical Considerations:
Informed consent process.
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Subjects must be given ample time to ask
questions.
Should be signed and personally dated by the
subject (or his/her legally acceptable
representative) and by the person who
conducted the informed consent discussion.
Case Record Forms
Document used to record data on which:
 Reporting
of the clinical trial
 Analysis
Will be based
Case Record Forms
Purpose of the information collected in the
CRF:
– To answer the hypothesis formulated in
the study protocol
– To provide relevant safety data relating to
the study drug.
Case Record Forms Design
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The CRF should:
– Request the precise information required by
the protocol.
– Request Only the information required by the
protocol
– Request the information in a way that
completion is simple, relatively quick, and as
unambiguous as possible, and that all
assessment are straight forward to complete
– Presents information clearly to enable the
investigator to review the subjects continuing
eligibility
Summary
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Study Protocol
Scientific consideration
Practical Considerations
Ethical Issues
Collection of Data (Case Record Forms)
GCP COMPLIANCE:
Emerging Issues in Worldwide
Clinical Trials
David A. Lepay, M.D., Ph.D.
Director, Division of Scientific
Investigations, CDER
June 29, 1999
Current Compliance
Concerns
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Most commonly observed deficiencies
– Failure to follow the protocol
 Violation of inclusion/exclusion criteria
 Failure to perform required tests
– Failure to maintain adequate and accurate
records
 absence of supporting source documents
 inaccurate or incomplete source
documents
Clinical Investigator Deficiency
Categories
25
25%
21
20
20%
13
15%
10%
5%
0%
5
YOU ARE AN INVESTIGATOR FULLY
COMMITTED TO:
– Personally conduct or supervise the investigation*
– Ensure that all associates, colleagues, and employees
assisting in study conduct are informed about their
obligations*
– Conduct the study in accordance with the protocol
– Comply with all requirements regarding obligations of
clinical investigators*
– Inform subjects drugs are being used for investigational
purposes and ensure informed consent and IRB
requirements are met
– Report Adverse Events to the sponsor
*Delegation high risk