protocol design
DESCRIPTION
Protocol Design. Shirley Xu Senior Director QA Shanghai Clinical Research Centre (SCRC) CME Training Course 22 Oct. 2009. Development of a Clinical Trial. Idea Reviews from the experts(Sponsor or CRO) First planning meeting (basic design features) - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/1.jpg)
Protocol DesignProtocol Design
Shirley XuSenior Director QA
Shanghai Clinical Research Centre (SCRC)CME Training Course 22 Oct. 2009
![Page 2: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/2.jpg)
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
![Page 3: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/3.jpg)
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
![Page 4: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/4.jpg)
Why Multicenter Trials?Why Multicenter Trials?
Small but important effect Enhance generalizability of the resultsBring new treatment to the community
![Page 5: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/5.jpg)
Clinical Trial ProtocolClinical Trial Protocol
![Page 6: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/6.jpg)
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
![Page 7: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/7.jpg)
Crucial Roles of StatisticiansCrucial Roles of Statisticians
Design (very important!!!)MonitoringAnalysisReportingNew statistical methodology
![Page 8: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/8.jpg)
Sophisticated Statistical TechniquesSophisticated Statistical Techniques
O’Brien and Fleming Boundaries Lan & DeMets “Spending function” Equivalence testing Repeated measures Bayesian methods Nonlinear random effect modeling
![Page 9: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/9.jpg)
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.
![Page 10: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/10.jpg)
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
![Page 11: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/11.jpg)
Duration of Protocol DevelopmentDuration of Protocol Development
7days-6months!!!
4-50 pages long!!!
![Page 12: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/12.jpg)
Three Fundamental AspectsThree Fundamental Aspects
Which patients are eligibleWhich treatment are to be evaluateHow each patient’s response is to be
assessed
![Page 13: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/13.jpg)
Background Background Rationale Unpublished work of the investigatorsPharmacological and toxicityAny new and non standard methods
![Page 14: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/14.jpg)
Specific ObjectivesSpecific Objectives
New treatmentNew indicationDetermine the best of a number of
standard treatmentsTo provide additional data on safety or
efficacy
![Page 15: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/15.jpg)
MethodsMethods
– Hypothesis– Patient population (operational definition)
Inclusion Criteria Exclusion Criteria
More homogeneous less generalizable!!
![Page 16: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/16.jpg)
Treatment RegimensTreatment Regimens
Required procedures for treatment administration, including precise rules for does determinations
![Page 17: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/17.jpg)
Trial DesignTrial DesignControl groups
Define and justify the control group Safety consideration of the placebo group
![Page 18: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/18.jpg)
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
![Page 19: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/19.jpg)
Trial DesignTrial Design
Balance on Prognostic Factors–Stratification–Minimization
![Page 20: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/20.jpg)
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
![Page 21: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/21.jpg)
Treatment PhaseTreatment Phase
Patient management guidelines, including specifications for does reductions, treatment delays and treatment terminations
Schedules of required clinical tests and assessments
![Page 22: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/22.jpg)
Follow-up phaseFollow-up phase
Schedule of submission of required materials and data, including long-term follow-up
Data and materials submission procedures
![Page 23: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/23.jpg)
TerminationTermination
Procedures for ending patients’ participation in the trial
![Page 24: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/24.jpg)
Study Flow DiagramStudy Flow Diagram
A flowchart describe how patients progress through the trial– Initial screening– Randomization– Planned schedule– Follow-up visits– Early termination
![Page 25: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/25.jpg)
Outcome MeasuresOutcome Measures
Primary end pointsSecondary end points
![Page 26: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/26.jpg)
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
![Page 27: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/27.jpg)
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
![Page 28: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/28.jpg)
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
![Page 29: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/29.jpg)
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
![Page 30: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/30.jpg)
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
![Page 31: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/31.jpg)
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.
![Page 32: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/32.jpg)
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.
![Page 33: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/33.jpg)
Coordinating CentreCoordinating Centre
– Training– Registration– Randomization– Supplying– Collecting and processing CRFs– Coordination of accrual sites– Auditing study sites– Regulatory reporting
![Page 34: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/34.jpg)
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
![Page 35: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/35.jpg)
Central LaboratoryCentral Laboratory
![Page 36: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/36.jpg)
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
![Page 37: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/37.jpg)
Field Site PersonnelField Site Personnel
Investigator/Study coordinatorResearch Nurse/
– Participants accrual– Intervention– Primary data collection– Follow-up
![Page 38: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/38.jpg)
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:
![Page 39: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/39.jpg)
General TopicsGeneral Topics
General quality assurance Quality control procedures Research personnel qualifications Clinical audit Regulatory authority inspections
![Page 40: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/40.jpg)
Ethics Ethics
Initial and continuing review by ethics committees
Informed consent Consent forms and information sheets
![Page 41: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/41.jpg)
Study SetupStudy Setup
Review of:– investigator brochures– Protocols – Protocol amendments– CRFs– agreements (e.g. responsibility, financial,
confidential, insurance/indemnity agreement)
![Page 42: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/42.jpg)
Monitoring and Initial Data Review:Monitoring and Initial Data Review:
Monitoring visitsSource data verification Data query
![Page 43: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/43.jpg)
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
![Page 44: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/44.jpg)
Safety Event ReportingSafety Event Reporting
Definitions Recording and reporting AEs Recording and reporting AEs to ethics
committees;
![Page 45: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/45.jpg)
Closing The StudyClosing The Study
Review of clinical study reportsPremature termination or suspensionArchiving
![Page 46: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/46.jpg)
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
![Page 47: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/47.jpg)
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.
![Page 48: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/48.jpg)
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
![Page 49: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/49.jpg)
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.
![Page 50: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/50.jpg)
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.
![Page 51: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/51.jpg)
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.
![Page 52: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/52.jpg)
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
![Page 53: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/53.jpg)
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.
![Page 54: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/54.jpg)
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.
![Page 55: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/55.jpg)
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
![Page 56: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/56.jpg)
Other Useful JournalsOther Useful Journals
Applied Clinical TrialsStatistical Methods in Medical ResearchStatistics in MedicineBiometrics
![Page 57: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/57.jpg)
Thank you!
![Page 58: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/58.jpg)
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
![Page 59: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/59.jpg)
Scope of Trials (ICH E9)Scope of Trials (ICH E9)
PopulationPrimary and Secondary VariablesComposite variablesGlobal Assessment variablesMultiple Primary VariablesSurrogate VariablesCategorized Variables
![Page 60: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/60.jpg)
Design Techniques to Avoid Bias Design Techniques to Avoid Bias ((ICH E9)ICH E9)
BlindingRandomization
![Page 61: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/61.jpg)
Trial Design Considerations Trial Design Considerations ((ICH E9)ICH E9)
Design ConfigurationParallel Group DesignCross-over DesignFactorial DesignMulitcentre Trials
![Page 62: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/62.jpg)
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
![Page 63: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/63.jpg)
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
![Page 64: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/64.jpg)
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
![Page 65: Protocol Design](https://reader036.vdocument.in/reader036/viewer/2022070502/56814d10550346895dba4c45/html5/thumbnails/65.jpg)
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