Clinical Trial

Planning of Clinical Trials

13, July 2001 CCTER CUHK

Development of a Clinical Trial
Idea  Reviews from the experts(Sponsor or CRO)  First planning meeting (basic design features)  Second planning meeting (draft protocol)

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Final protocol (ethical and scientific, signed by a statistician)  Evaluation (scientific review, IRB, funding)  Implementation  Final analysis and publication

Evolution of Trial Structure
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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?
Small but important effect  Enhance generalizability of the results  Bring new treatment to the community
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Clinical Trial Protocol

Clinical Trial Protocol
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A detailed plan giving instructions to the study investigators(doctors) about the way to conduct the study.
– Contributors to the protocol development
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investigators, medical personnel from the Sponsor or delegated CRO representatives from the study monitoring team project statistician

Crucial Roles of Statisticians
Design (very important!!!)  Monitoring  Analysis  Reporting  New statistical methodology
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Sophisticated Statistical Techniques
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O’Brien and Fleming Boundaries Lan & DeMets “Spending function” Equivalence testing Repeated measures Bayesian methods Nonlinear random effect modeling

Functions of Clinical Trial Protocol
Guideline for the conduct of the trial  Quality control for all aspects of a clinical trial  To provide guidelines to the monitoring groups such as: IEC / IDMC.
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Functions of Clinical Trial Protocol
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Written agreement between:
– the investigator – the participant,

– and the scientific community

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Legal documents for
– FDA and other regulatory bodies

To procure funding

Duration of Protocol Development

7days-6months!!!
4-50 pages long!!!

Three Fundamental Aspects
Which patients are eligible  Which treatment are to be evaluate  How each patient’s response is to be assessed
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Background
Rationale  Unpublished work of the investigators  Pharmacological and toxicity  Any new and non standard methods
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Specific Objectives
New treatment  New indication  Determine the best of a number of standard treatments  To provide additional data on safety or efficacy
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Methods
– Hypothesis
– Patient population (operational definition)  Inclusion Criteria  Exclusion Criteria

More homogeneous less generalizable!!

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

Trial Design
Control groups
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Define and justify the control group Safety consideration of the placebo group

Trial Design
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Randomization (verifiable method)
–Method used to generate the allocation schedule –Method of allocation concealment • Packing number • Telephone • Remote data entry –Timing of assignment

Trial Design
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Balance on Prognostic Factors –Stratification –Minimization

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

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

Treatment Phase
Patient management guidelines, including specifications for does reductions, treatment delays and treatment terminations  Schedules of required clinical tests and assessments
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Follow-up phase
Schedule of submission of required materials and data, including long-term follow-up  Data and materials submission procedures
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Termination
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Procedures for ending patients’ participation in the trial

Study Flow Diagram
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A flowchart describe how patients progress through the trial
– Initial screening

– Randomization
– Planned schedule – Follow-up visits – Early termination

Outcome Measures
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Primary end points Secondary end points

Statistical Issues
Power analysis justifying sample size requirements  Interim monitoring and analysis plans  Planned time and methodology of final analyses e.g. ITT, PP, NNT, CI  Methods on secondary aims, compare toxicities
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Ethics and Safety
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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 Protocol
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Laboratories  Compliance
– How compliance is monitored – Methods used to improve compliance

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Organization
– Roles – Responsibilities

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Budget  Study Forms (CRFs) and data handling  Administrative responsibilities

CRF Design
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Identification data  Research data  Administrative data  Regulatory data
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Soilker, B. Schoenfelder, J. (1991). Data Collection Forms in Clinical Trials. Racen Press, New York

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

Administrative Structure of Multicentre Trials
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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 Chairman
Chair steering committee  Responsible for the overall project  Overseeing the design and conduct of the trial  Implementation of SOPs and good clinical practices  Compliance with international and local regulations.
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Coordinating Centre
– Training
– Registration – Randomization

– Supplying
– Collecting and processing CRFs – Coordination of accrual sites

– Auditing study sites
– Regulatory reporting

Statistical Centre
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Data entry and processing Ongoing monitoring of toxicity data Periodical interim analysis of study endpoints Final data analyses Preparation abstract and manuscripts

Central Laboratory

Other Major Personnel
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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 Personnel
Investigator/Study coordinator  Research Nurse/
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– Participants accrual – Intervention – Primary data collection – Follow-up

Standard Operating Procedures (SOPs)
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To ensure that the specific tasks in the trial are carried out in a consistent manner. Topics for SOPs for Investigators:

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

Ethics
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Initial and continuing review by ethics committees  Informed consent  Consent forms and information sheets

Study Setup
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Review of: – investigator brochures – Protocols – Protocol amendments – CRFs – agreements (e.g. responsibility, financial, confidential, insurance/indemnity agreement)

Monitoring and Initial Data Review:
Monitoring visits  Source data verification  Data query
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Management of Study Medications and Clinical Laboratory Samples:
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Shipment Receipt Control at study sites Dispensing inventory Compliance with use of study medication Randomization procedures Clinical laboratory samples

Safety Event Reporting
Definitions  Recording and reporting AEs  Recording and reporting AEs to ethics committees;
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Closing The Study
Review of clinical study reports  Premature termination or suspension  Archiving
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Some Important ICH Guidelines
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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 Protections (OHRP)
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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 Research Study (MV)- Oklahoma Case
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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:
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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:
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Incomplete informed consent documents
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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

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IRB failure to meet its federal regulatory obligations.

Major OHRP Findings:
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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 Taken
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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

Consequences
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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.

Consequences
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Federal lawsuit against
– study’s PI, – its corporate co-sponsor

– and its IRB members,

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

research conduct – and civil rights laws.

Controlled Clinical Trial A Journal
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An official journal for the Society for Clinical Trials  The first issue was published in the May of 1980.  Aim and scope:
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Basic Design Operating features Organization Analysis

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Current editor (1999-) James D. Neaton

Other Useful Journals
Applied Clinical Trials  Statistical Methods in Medical Research  Statistics in Medicine  Biometrics
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Thank you!

Statistical Principles for Clinical Trials ICH E9
Considerations for overall clinical development  Trial design considerations  Trial conduct considerations  Data analysis considerations  Evaluation of safety and Tolerability  Reporting
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Scope of Trials (ICH E9)
Population  Primary and Secondary Variables  Composite variables  Global Assessment variables  Multiple Primary Variables  Surrogate Variables  Categorized Variables
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Design Techniques to Avoid Bias (ICH E9)
Blinding  Randomization
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Trial Design Considerations (ICH E9)
Design Configuration  Parallel Group Design  Cross-over Design  Factorial Design  Mulitcentre Trials
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Trial Design Considerations (ICH E9)
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Type of Comparison
– Trials to show superiority – Trials to show Equivalence or Non-

inferiority – Trials to show Does-response Relationship

Group sequential designs  Sample Size  Data capture and Processing
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Trial Conduct Considerations (ICH E9)
Trial Monitoring and Interim Analysis  Changes in Inclusion and Exclusion Criteria  Accrual Rates  Sample Size Adjustment  Interim Analysis and Early stopping  Role of IDMC
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Data Analysis Considerations (ICH E9)
Prespecification of the Analysis  Analysis Sets
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– Full Analysis Set – Per Protocol Set – Roles of the Different Analysis Sets

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Missing Values and Outliers

Data Analysis Considerations (ICH E9)
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Data Transformation Estimation, CIs and Hypothesis Testing Adjustment of Significance and Confidence Levels Subgroups, Interactions and Covariates Integrity Data and Computer Software Validity