Protocol DesignProtocol Design

Shirley XuSenior Director QA

Shanghai Clinical Research Centre (SCRC)CME Training Course 22 Oct. 2009

Development of a Clinical TrialDevelopment of a Clinical Trial Idea

Reviews from the experts(Sponsor or CRO)

First planning meeting (basic design features)

Second planning meeting (draft protocol)

Final protocol (ethical and scientific, signed by a statistician)

Evaluation (scientific review, IRB, funding)

Implementation

Final analysis and publication

Evolution of Trial StructureEvolution of Trial Structure

Large cooperative trials (multicenter trials) High scientific level protocol Well-defined administrative structure Control of performance at all levels (SOPs) Competent biometric advice (ICH

E9) Careful ethical considerations

Why Multicenter Trials?Why Multicenter Trials?

Small but important effect Enhance generalizability of the resultsBring new treatment to the community

Clinical Trial ProtocolClinical Trial Protocol

Clinical Trial ProtocolClinical Trial Protocol

A detailed plan giving instructions to the study investigators(doctors) about the way to conduct the study.– Contributors to the protocol development

investigators, medical personnel from the Sponsor or

delegated CRO representatives from the study monitoring team project statistician

Crucial Roles of StatisticiansCrucial Roles of Statisticians

Design (very important!!!)MonitoringAnalysisReportingNew statistical methodology

Sophisticated Statistical TechniquesSophisticated Statistical Techniques

O’Brien and Fleming Boundaries Lan & DeMets “Spending function” Equivalence testing Repeated measures Bayesian methods Nonlinear random effect modeling

Functions of Clinical Trial ProtocolFunctions of Clinical Trial Protocol

Guideline for the conduct of the trialQuality control for all aspects of a

clinical trialTo provide guidelines to the monitoring

groups such as: IEC / IDMC.

Functions of Clinical Trial ProtocolFunctions of Clinical Trial Protocol

Written agreement between:– the investigator– the participant, – and the scientific community

Legal documents for – FDA and other regulatory bodies

To procure funding

Duration of Protocol DevelopmentDuration of Protocol Development

7days-6months!!!

4-50 pages long!!!

Three Fundamental AspectsThree Fundamental Aspects

Which patients are eligibleWhich treatment are to be evaluateHow each patient’s response is to be

assessed

Background Background Rationale Unpublished work of the investigatorsPharmacological and toxicityAny new and non standard methods

Specific ObjectivesSpecific Objectives

New treatmentNew indicationDetermine the best of a number of

standard treatmentsTo provide additional data on safety or

efficacy

MethodsMethods

– Hypothesis– Patient population (operational definition)

Inclusion Criteria Exclusion Criteria

More homogeneous less generalizable!!

Treatment RegimensTreatment Regimens

Required procedures for treatment administration, including precise rules for does determinations

Trial DesignTrial DesignControl groups

Define and justify the control group Safety consideration of the placebo group

Trial DesignTrial Design

Randomization (verifiable method)–Method used to generate the

allocation schedule–Method of allocation concealment

• Packing number• Telephone• Remote data entry

–Timing of assignment

Trial DesignTrial Design

Balance on Prognostic Factors–Stratification–Minimization

Trial DesignTrial DesignBlinding

Mechanism of treatment blinding Single, double, triple, quadruple blinding Assessment of the effectiveness of blinding

Experimental design Parallel designs Cross-over designs Factorial designs Sequential designs

Treatment PhaseTreatment Phase

Patient management guidelines, including specifications for does reductions, treatment delays and treatment terminations

Schedules of required clinical tests and assessments

Follow-up phaseFollow-up phase

Schedule of submission of required materials and data, including long-term follow-up

Data and materials submission procedures

TerminationTermination

Procedures for ending patients’ participation in the trial

Study Flow DiagramStudy Flow Diagram

A flowchart describe how patients progress through the trial– Initial screening– Randomization– Planned schedule– Follow-up visits– Early termination

Outcome MeasuresOutcome Measures

Primary end pointsSecondary end points

Statistical IssuesStatistical Issues

Power analysis justifying sample size requirements

Interim monitoring and analysis plansPlanned time and methodology of final

analyses e.g. ITT, PP, NNT, CIMethods on secondary aims, compare

toxicities

Ethics and SafetyEthics and Safety

Protection of the trial patient’s right and safety– How the patient is approached for entry

into the trial– Regulatory obligations, including informed

consent and reporting of adverse events– Plan and action if a SAE be detacted

Other Topics in a Study ProtocolOther Topics in a Study Protocol Laboratories Compliance

– How compliance is monitored– Methods used to improve compliance

Organization– Roles – Responsibilities

Budget Study Forms (CRFs) and data handling Administrative responsibilities

CRF DesignCRF Design

Identification data Research data Administrative data Regulatory data

Soilker, B. Schoenfelder, J. (1991). Data Collection Forms in Clinical Trials.

Racen Press, New York

Basic Information in CRFBasic Information in CRF

Consent dates Eligibility checklist Baseline assessments Dosing of study medications ( incl. compliance) Concomitant illness Safety Effectiveness Premature termination of study

Administrative Structure of Administrative Structure of Multicentre TrialsMulticentre Trials

Steering Committee– Leadership body of the investigative group

Data and Safety Monitoring Committee– Assess the progress, safety and efficacy – Recommendations about continue, modify

or terminate.

Study ChairmanStudy Chairman

Chair steering committeeResponsible for the overall projectOverseeing the design and conduct of

the trialImplementation of SOPs and good

clinical practicesCompliance with international and local

regulations.

Coordinating CentreCoordinating Centre

– Training– Registration– Randomization– Supplying– Collecting and processing CRFs– Coordination of accrual sites– Auditing study sites– Regulatory reporting

Statistical CentreStatistical Centre

– Data entry and processing– Ongoing monitoring of toxicity data– Periodical interim analysis of study

endpoints– Final data analyses– Preparation abstract and manuscripts

Central LaboratoryCentral Laboratory

Other Major PersonnelOther Major Personnel Trial statistician Clinical research associate Data manager Randomization specialist Quality assurance officer Computer support personnel Resource Centre Directors Training directors Field site personnel Independent Data Monitoring Committee

Field Site PersonnelField Site Personnel

Investigator/Study coordinatorResearch Nurse/

– Participants accrual– Intervention– Primary data collection– Follow-up

Standard Operating Procedures Standard Operating Procedures (SOPs)(SOPs)

To ensure that the specific tasks in the trial are carried out in a consistent manner.

Topics for SOPs for Investigators:

General TopicsGeneral Topics

General quality assurance Quality control procedures Research personnel qualifications Clinical audit Regulatory authority inspections

Ethics Ethics

Initial and continuing review by ethics committees

Informed consent Consent forms and information sheets

Study SetupStudy Setup

Review of:– investigator brochures– Protocols – Protocol amendments– CRFs– agreements (e.g. responsibility, financial,

confidential, insurance/indemnity agreement)

Monitoring and Initial Data Review:Monitoring and Initial Data Review:

Monitoring visitsSource data verification Data query

Management of Study Medications Management of Study Medications and Clinical Laboratory Samples:and Clinical Laboratory Samples:

Shipment Receipt Control at study sites Dispensing inventory Compliance with use of study medication Randomization procedures Clinical laboratory samples

Safety Event ReportingSafety Event Reporting

Definitions Recording and reporting AEs Recording and reporting AEs to ethics

committees;

Closing The StudyClosing The Study

Review of clinical study reportsPremature termination or suspensionArchiving

Some Important ICH GuidelinesSome Important ICH Guidelines

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

E3 Structure and Content of Clinical Study Report (1995) E6 Good Clinical Practice (1996) E7 Clinical Trials in Special Populations: Geriatrics (1993) E8 General Consideration for Clinical Trials (1997) E9 Statistical Principles for Clinical Trials (1998) E10 Choice of Control Group in Clinical Trials (TBI)

– ICH home page: http://www.ifpma.org/ich1.html– FDA guidelines: http://www.fda.gov/cder/regulatory/default.htm

Federal Office for Human Research Federal Office for Human Research Protections (OHRP)Protections (OHRP)

OHRP is responsible for monitoring subject protections at more than 4,000 HHS (Department of Health and Human Services) funded universities, hospitals and other research institutions.

Investigational Melanoma Vaccine Investigational Melanoma Vaccine Research Study (MV)- Research Study (MV)- Oklahoma CaseOklahoma Case

OHRP Halts Human Research at University of Oklahoma for Subject Protection Violations

Suspension Date: June 29 2000 Suspension of 75 federally funded clinical

trials performed though the Tulsa campus

Major OHRP Findings:Major OHRP Findings:

MV failure to meet GMP allowed for potential subject exposure to

bacterial and viral infections. 26 of 96 subjects (vaccine arm) died. Investigators failed to ensure that risks to

subjects were minimized.

Major OHRP Findings:Major OHRP Findings:

Incomplete informed consent documents – the purpose of the study– Procedures– Foreseeable risks and discomforts– Any expected benefit from study participation– Overstated the benefits of the study as capable of

preventing the recurrence of melanoma or reducing existing tumor mass

IRB failure to meet its federal regulatory obligations.

Major OHRP Findings:Major OHRP Findings:

Implemented substantive changes to the study without obtaining IRB approval.

Failure to adhere to the protocol inclusion/exclusion criteria.

Recruited 96 patients with IRB approved size <=40.

Directly ship study vaccine to some subject’s homes for self-administration.

Actions TakenActions Taken

Independent accreditation of a newly formed Tulsa IRB

Require that sponsor use DSMB as a condition for approval;

Mandatory certification in human subject protection for those involved in the conduct of clinical studies

Educational program specially for clinical investigators, research staffs and IRB members

ConsequencesConsequences

Director of the Office of Research resigned Chair of IRB retired PI (Former Vice Chairman of the University’s

dept. of Surgery) has been relieved of all his administrative duty at the University, which in process of terminating his appointment as a tenured faculty member.

ConsequencesConsequences

Federal lawsuit against– study’s PI, – its corporate co-sponsor – and its IRB members,

Violations of – human subject protection regulations, – international recognized ethical standards for

research conduct – and civil rights laws.

Controlled Clinical Trial Controlled Clinical Trial A JournalA Journal

An official journal for the Society for Clinical Trials

The first issue was published in the May of 1980.

Aim and scope:– Basic Design – Operating features– Organization– Analysis

Current editor (1999-) James D. Neaton

Other Useful JournalsOther Useful Journals

Applied Clinical TrialsStatistical Methods in Medical ResearchStatistics in MedicineBiometrics

Thank you!

Statistical Principles for Clinical Trials Statistical Principles for Clinical Trials ICH E9ICH E9

Considerations for overall clinical development

Trial design considerationsTrial conduct considerationsData analysis considerationsEvaluation of safety and TolerabilityReporting

Scope of Trials (ICH E9)Scope of Trials (ICH E9)

PopulationPrimary and Secondary VariablesComposite variablesGlobal Assessment variablesMultiple Primary VariablesSurrogate VariablesCategorized Variables

Design Techniques to Avoid Bias Design Techniques to Avoid Bias ((ICH E9)ICH E9)

BlindingRandomization

Trial Design Considerations Trial Design Considerations ((ICH E9)ICH E9)

Design ConfigurationParallel Group DesignCross-over DesignFactorial DesignMulitcentre Trials

Trial Design Considerations Trial Design Considerations ((ICH E9)ICH E9)

Type of Comparison– Trials to show superiority– Trials to show Equivalence or Non-

inferiority– Trials to show Does-response Relationship

Group sequential designsSample SizeData capture and Processing

Trial Conduct ConsiderationsTrial Conduct Considerations ((ICH E9)ICH E9)

Trial Monitoring and Interim AnalysisChanges in Inclusion and Exclusion

CriteriaAccrual RatesSample Size AdjustmentInterim Analysis and Early stoppingRole of IDMC

Data Analysis ConsiderationsData Analysis Considerations ((ICH E9)ICH E9)

Prespecification of the AnalysisAnalysis Sets

– Full Analysis Set– Per Protocol Set– Roles of the Different Analysis Sets

Missing Values and Outliers

Data Analysis Considerations Data Analysis Considerations ((ICH E9)ICH E9)

Data Transformation Estimation, CIs and Hypothesis Testing Adjustment of Significance and Confidence

Levels Subgroups, Interactions and Covariates Integrity Data and Computer Software Validity