Assessing Study Design for Institutional

Review Committees/Boards

Monica Brown, PhDAlternate Member

The Sutter Health Central AreaInstitutional Review Committee

September 21, 2010

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?

Study Design Basics

Selecting the Appropriate Design to Meet

the Study’s Goal

Experimental Studies: Clinical Study Design

Issues in Poor Clinical Study Design

Conclusion

Presentation Outline

Why must IRC/IRB members understand study design?

Introduction

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.

Ethical codes and federal regulations require that the IRB

evaluate study design and scientific

quality

1. DEFINITION

2. PURPOSE3. TYPES

Study Design Basics

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.

Basic Study Design Types

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)

Experimental studies are superior to Observational studies

1. Provide stronger evidence of the effect (outcome) compared to observational designs

2. Yield more valid results, as variation is minimized and bias controlled

3. 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%)

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

CLINICAL EFFICACY

CLINICAL TRIAL DESIGN

Clinical trial design is driven by endpoints and the sponsor’s “labeling” goals for the therapeutic agent

“Ultimate” clinical endpoint – survival

Proximal Clinical Endpoints symptom benefit

progression-free survival

biomarkers

response rates

Clinical Endpoints

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.

Patient Population Sample size Patient selection (diversity)

Clinical endpoint Survival Proxy

Desirable Treatment Differences How large is acceptable?

Control Treatment Standard treatment vs. Placebo

Basic Elements of a Clinical Study Design

Controls: Use of a comparison or control group.Randomization: the random (by chance)

assignment of participants into exposure groups. Blinding:

Design Options

Sponsor's Clinician /

Analysis Team Investigator PatientNo No No open/unblindedNo No Yes single blindedNo Yes Yes double blindedYes Yes Yes triple blinded

T I M EStudy begins here

PatientPopulation

Experimental Treatment

Control(Std Tx or Placebo)

outcome

no outcome

outcome

no outcome

baselinefuture

Basic Clinical Design Strategy

CLINICAL ENDPOINT

Phase I: Dose-finding & Safety

Phase II: Initial Efficacy Data

Phase III: Pivotal FDA Approval

Phase IV: Post-marketing

Surveillance (a.k.a., registries)

Classic Drug Development Process

Comparison of Drug Development Phases

PHASE I PHASE II PHASE III PHASE IV

OBJECTIVES: Determine the metabolic & pharmacological actions

Maximally tolerated dose

Evaluate effectiveness Determine short-term side

effects Identify common risks

Obtain additional information about effectiveness on clinical outcomes

Evaluate overall risk-benefit ratio

Monitor ongoing safety in large populations

Identify additional uses of agent that might be approved by the FDA

FACTORS TO BE IDENTIFIED:

Bioavailability Bioequivalence Dose proportionality Metabolism Pharmacodynamics Pharmacokinetics

Bioavailability Drug-disease interactions Drug-drug interactions Efficacy at various doses Pharmacodynamics Pharmacokinetics Patient safety

Drug-disease interactions Drug-drug interactions Dosage intervals Risk-benefit information Efficacy & safety for

subgroups

Epidemiological data Efficacy & safety within

large, diverse populations Pharmacoeconomics

DATA FOCUS: Vital signs Plasma /serum levels Adverse events

Dose response & tolerance Adverse events Efficacy

Laboratory data Efficacy Adverse events

Efficacy Pharmacoeconomics Epidemiology Adverse events

DESIGN FEATURES:

Single, ascending dose tiers

Unblinded Uncontrolled

Placebo controlled comparisons

Active controlled comparisons

Well-defined entry criteria

Randomized Controlled 2-3 treatment arms Broader eligibility criteria

Uncontrolled Observational

DURATION: Up to 1 month Several months Several years Ongoing (following FDA approval)

POPULATION: Healthy volunteers or individuals with the target disease (i.e., cancer or HIV)

Individuals with target disease Individuals with target disease , demographically diverse sample

Individuals with target disease, as well as new age groups, genders, etc.

SAMPLE SIZE: 20 to 80 200 to 300 Hundreds to thousands Thousands EXAMPLE: Study of a single dose of

Drug X in normal subjects Double-blind study evaluating safety & efficacy of Drug X vs. placebo in patients with hypertension

Drug X vs. standard treatment for hypertension

Economic benefit of newly-approved Drug X vs. standard treatment for hypertension

Source: Research Coordinator Orientation, University of Pittsburgh, 2002

Issues in Clinical Study Design

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 endpointsthe participant’s steps, clinical measures,

data analysis, etc., laid out in an easy to follow manner

Attributes of Well Designed Studies

The Protocol 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

Attributes of Well Designed Studies

The Investigator has …

Can be replicatedBias is minimizedValid – design & its elements can meet

endpointsFeasible

Low patient burden Time commitment Resources

Well Designed Studies

Affect recruitment & enrollmentToo difficult for participant to understand, which results in poor treatment/intervention compliance

Do not get publishedReflects poorly on the Investigator, Institution & IRC/IRB

Poorly Designed Studies

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

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

Issues in Clinical Study Design

CONVOLUTED REASONING OR ANTI-INTELLECTUAL POMPOSITY

Study Design C.R.A.P.*

* Streiner/Norm/Monroe Blum, “PDQ Epidemiology”

1989

1. Patient Safety

2. Inability to meet clinical endpoints

3. Waste of resources

4. Reflects poorly on investigator &

institution

Detecting C.R.A.P. is Important!

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?

How I find C.R.A.P.

Participants/Patients

Data

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

FOR RESEARCHERS

FOR IRC/IRB MEMBERS

Recommendations

Name the type of study i.e., “data-only, retrospective, case-control study”

State the research question/purpose/goal/hypothesis CONCISELY

Aims & objectives should be QUANTIFIABLEClinical endpoints should be DEFINED (not

just named) – give rationale for its/their useSHOW THAT THE CLINICAL TRIAL

EXPERIENCE OF THE PATIENT HAS BEEN CONSIDERED (NOT JUST THAT IT IS SAFE)

Recommendations for Researchers: In Your Protocol

List study design limitations & respond with your solution – don’t 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

Recommendations for Researchers: …

Assign protocols to reviewers who have the appropriate expertise to evaluate study design

Encourage informal discussion of design issues between members & investigators

Unless you’ve been trained in study design, don’t 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

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

In Conclusion

WHY THE FOCUS ON STUDY DESIGN?

Well-designed protocols are important for conducting research studies safely & in a cost-effective manner.

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/documents/eval_study_designGUI03017.pdf Evaluating Sound Study Design

Resources

Thank you