Assessing Study Design for Institutional Review Committees/Boards

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Assessing Study Design for Institutional Review
Committees/Boards
Monica Brown, PhD Alternate Member The Sutter
Health Central Area Institutional Review Committee
September 21, 2010
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Presentation Objectives

• Identify the 2 basic study designs.

• What 2 elements drive clinical study design?

• Name the 1 reason why C.R.A.P. detection in
  clinical study design is so important?

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Presentation Outline

• Study Design Basics
• Selecting the Appropriate Design to Meet the
  Studys Goal
• Experimental Studies Clinical Study Design
• Issues in Poor Clinical Study Design
• Conclusion

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Introduction

• Why must IRC/IRB members understand study design?

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Ethical codes and federal regulations require
that the IRB evaluate study design and
scientific quality

• Section 18 of the Declaration of Helsinki (2000)
• Medical research involving human subjects should
  only be conducted if the importance of the
  objective outweighs the inherent risks and
  burdens to subjects.
• Federal Regulation 45 CFR 46.111 (a)
• Criteria for IRB approval of research Risks to
  subjects are minimized by using procedures which
  are consistent with sound research design, and
  which not, unnecessarily, expose subjects to risk.

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Study Design Basics

1. definition
2. purpose
3. types

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Study Design
A study design is a specific plan or protocol for
conducting a study, which allows the investigator
to translate the conceptual hypothesis into an
operational one.
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Basic Study Design Types
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Categories of Quantitative Study Designs
Studies where there is no manipulation of the
study factor or subjects
Studies that entail manipulation of the study
factor (exposure) and randomization of subjects
to exposure (treatment or intervention)
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Experimental studies are superior to
Observational studies

• Provide stronger evidence of the effect (outcome)
  compared to observational designs
• Yield more valid results, as variation is
  minimized and bias controlled
• Determine whether experimental treatments are
  safe and effective under controlled
  environments (as opposed to natural settings
  in observational designs), especially when the
  margin of expected benefit is narrow (10 - 30)

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Clinical Efficacy
The primary purpose of a clinical trial is to
compare the clinical efficacy, as measured by
clinical endpoints, of those receiving
experimental treatment, over those receiving
standard treatment or placebo
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Clinical Trial Design
Clinical trial design is driven by endpoints and
the sponsors labeling goals for the
therapeutic agent
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Clinical Endpoints

• Ultimate clinical endpoint survival
• Proximal Clinical Endpoints
• symptom benefit
• progression-free survival
• biomarkers
• response rates

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Clinical Trial Design Complexity
Clinical endpoints define the complexity of a
trial - to recruit and enroll participants
perform the study gather and analyze the data.
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Basic Elements of a Clinical Study Design

• Patient Population
• Sample size
• Patient selection (diversity)
• Clinical endpoint
• Survival
• Proxy
• Desirable Treatment Differences
• How large is acceptable?
• Control Treatment
• Standard treatment vs. Placebo

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Design Options

• Controls Use of a comparison or control group.
• Randomization the random (by chance) assignment
  of participants into exposure groups.
• Blinding

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Basic Clinical Design Strategy
Clinical Endpoint
outcome
Recruit / Enroll / Consent
Experimental Treatment
Randomization
no outcome
Patient Population
outcome
Control (Std Tx or Placebo)
no outcome
baseline
future
T i m e
Study begins here
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Classic Drug Development Process

• Phase I Dose-finding Safety
• Phase II Initial Efficacy Data
• Phase III Pivotal FDA Approval
• Phase IV Post-marketing Surveillance (a.k.a.,
  registries)

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Comparison of Drug Development Phases
Source Research Coordinator Orientation,
University of Pittsburgh, 2002
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Issues in Clinical Study Design
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Attributes of Well Designed Studies
The Protocol has

• a clear concise research question/statement of
  purpose/goal /hypothesis
• measurable aims or objectives that directly
  build to answer the research question
• appropriate (validated) clinical endpoints
• the participants steps, clinical measures, data
  analysis, etc., laid out in an easy to follow
  manner

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Attributes of Well Designed Studies
The Investigator has

• Local control
• Over protocol implementation
• Consenting participants
• How treatments are administered
• Manner in which clinical measures are taken,
  assessed recorded
• Data control How data will be
• Gathered
• Who will have access
• Where how data will be stored
• Analyses to be conducted
• When destroyed

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Well Designed Studies

• Can be replicated
• Bias is minimized
• Valid design its elements can meet endpoints
• Feasible
• Low patient burden
• Time commitment
• Resources

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Poorly Designed Studies

• Affect recruitment enrollment
• Too difficult for participant to understand,
  which results in poor treatment/intervention
  compliance
• Do not get published
• Reflects poorly on the Investigator, Institution
  IRC/IRB

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Issues in Clinical Study Design

• Patient Selection
• Representative of the patient population
• Patient must be able to tolerate being in a trial
• Sample Size
• Influences size of benefit anticipated
• Influences the amount of certainty we wish to
  have with which to capture that treatment benefit
  (power)
• Can be dependant on resources rather than science
  
• Negative trial results could be due to small
  sample size or insufficient power

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Issues in Clinical Study Design

• Blinding
• Randomization can minimize the influence of bias
  by balancing groups for various characteristics
• Bias can still occur if personnel and/or patients
  know the identity of the treatment knowledge of
  treatment can lead to preconceptions subjective
  judgment in reporting, evaluating and even
  data/statistical analysis

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Study Design C.R.A.P.

• Convoluted Reasoning or Anti-Intellectual
  Pomposity

Streiner/Norm/Monroe Blum, PDQ Epidemiology
1989
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Detecting C.R.A.P. is Important!

• Patient Safety
• Inability to meet clinical endpoints
• Waste of resources
• Reflects poorly on investigator institution

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How I find C.R.A.P.

• Can this methodology be used to answer the
  research question?
• Is there adequate time during the study period to
  reach the clinical endpoints?
• Can study aims/objectives (which should be
  measurable) be measured using this design?
• Is more data being requested/gathered than are
  needed?
• What are the actual steps of the participants?
• When/where does he/she start the process?
• How long does each step take? Where will he/she
  wait for the next step?
• Would I want the same done to me or a loved one?

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Examples of Study Design C.R.A.P.

• Participants/Patients
• Data

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Recommendations

• For Researchers
• For IRC/IRB Members

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Recommendations for Researchers In Your Protocol

• Name the type of study
• i.e., data-only, retrospective, case-control
  study
• State the research question/purpose/goal/hypothesi
  s concisely
• Aims objectives should be quantifiable
• Clinical endpoints should be defined (not just
  named) give rationale for its/their use
• Show that the clinical trial experience of the
  patient has been considered (not just that it is
  safe)

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Recommendations for Researchers

• List study design limitations respond with your
  solution dont wait for the IRC/IRB to point it
  out
• Not sure what will fly with your IRC/IRB? Ask for
  an informal review by their member with the
  greatest study design expertise

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Recommendations for IRC/IRB Members Assessing
Study Design for Patient Safety

• Assign protocols to reviewers who have the
  appropriate expertise to evaluate study design
• Encourage informal discussion of design issues
  between members investigators
• Unless youve been trained in study design, dont
  second guess an investigator ask the
  investigator to explain why a study has been
  designed a certain way
• i.e., multiple control groups, run-in phase

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In Conclusion
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Why the focus on study design?
Well-designed protocols are important for
conducting research studies safely in a
cost-effective manner.
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Resources

• www.ICH.org Efficacy Guidelines
• E8 General Considerations for Clinical Trials
• E9 Statistical Principals for Clinical Trials
• E10 Choice of Control Group and Related Issues
  in Clinical Trials
• http//clinicaltrials.gov/ct2/info/understand
  Understanding Clinical Trials
• http//www.hhs.gov/ohrp/irb/irb_chapter4.htm
  Institutional Review Board Guidebook, CHAPTER IV,
  CONSIDERATIONS OF RESEARCH DESIGN
• http//humansubjects.stanford.edu/research/documen
  ts/eval_study_designGUI03017.pdf Evaluating Sound
  Study Design

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Thank you