Tips on clinical trials

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Tips on clinical trials

• Maha Al-Farhan
• B.Sc, M.Phil., M.B.A., D.I.C

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In this session

• 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)

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Basic Documents and materials of clinical trials

• Clinical Trial Protocol
• Informed Consent form
• Trial Case Record Forms (CRF)
• Investigational Product
• Study Materials

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Definition Of the Protocol (according to ICH Good
Clinical Practice Guideline)

• A document that describes the objective(s),
  design, methodology, statistical considerations,
  and organisation of the trial.
• Usually, the protocol also gives the background
  and rational for the trial.

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How to write a protocol

• 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.

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Start by mapping out a study schedule
Visit 1 Baseline (day 0) Visit 2 Randomization (day10) Visit 3 (day 20) Follow-up Visit (after end of treatment)
Informed Consent X
Inclusion/ Exclusion X
Medical History X
Primary diagnosis X
Clinical assessment X X X X
Randomisation X
Adverse Events X X X
Assessment of relapse X
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Objectives and end-points

• 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.

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Get the primary objective right

• Could be either efficacy or safety
• Well defined
• Well founded

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The primary end-point.

• Defined measurement or assessment.
• Implies a time point of clinical interest.
• If possible, end-points need to be objective
  measurements rather than subjective outcomes

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Primary end point measurement will be used to
calculate sample size.

• 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
  non-inferiority against standard treatment
• Allowance for subjects drop out.

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Choice of study design

• Two main types
• Non-Comparative usually used to assess a
  treatments safety and tolerability.
• Comparative design used when comparing
  treatments
• Cross-over Parallel-group

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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
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Bias

• Selection/ Allocation bias
• Observer bias

How to avoid it

• Randomisation
• Blinding

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Subject Selection criteria

• 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.

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Methodology/ assessments

• Details of this section ensure that
• all observations are performed in a standard
  manner.
• Sample collection procedure and laboratory tests
  are performed in a standard manner

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Ethical considerationsGeneral issues

• 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?

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Ethical ConsiderationsThe Declaration of
Helsinki

• 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.

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Ethical ConsiderationsInformed consent.

• Often come in two parts
• Written information describing the clinical trial
• A form which the subject signs to document that
  he/she has given consent to take part in the
  study
• Closely reviewed by ethics committees.
• Consent is valid when freely given.

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Ethical ConsiderationsInformed consent content.

• 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 Subjects
  responsibilities.
• Risks, inconveniences, and benefits to the
  subject.

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Ethical ConsiderationsInformed consent content.

• Compensation and/or treatment available to
  subject in the event of trial-related injury.
• That subjects 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 subjects records.
• Expected duration of the trial.
• Approximate number of trial subjects

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Ethical ConsiderationsInformed consent process.

• Alternative treatments available.
• Subjects 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.

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Ethical ConsiderationsInformed consent process.

• 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.

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Case Record Forms

• Document used to record data on which
• Reporting of the clinical trial
• Analysis
• Will be based

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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.

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Case Record Forms Design

• 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

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Summary

• Study Protocol
• Scientific consideration
• Practical Considerations
• Ethical Issues
• Collection of Data (Case Record Forms)

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GCP COMPLIANCEEmerging Issues in Worldwide
Clinical Trials
David A. Lepay, M.D., Ph.D. Director, Division of
Scientific Investigations, CDER June 29, 1999
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Current Compliance Concerns

• 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

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Clinical Investigator Deficiency Categories
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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