Transcript 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)

Final protocol (ethical and scientific, signed by a statistician)

Evaluation (scientific review, IRB, funding)

Implementation

Final analysis and publication
Evolution 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?
Small but important effect
 Enhance generalizability of the results
 Bring new treatment to the community

Clinical Trial Protocol
Clinical 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 Statisticians
Design (very important!!!)
 Monitoring
 Analysis
 Reporting
 New statistical methodology

Sophisticated 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 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.

Functions 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 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

Background
Rationale
 Unpublished work of the investigators
 Pharmacological and toxicity
 Any new and non standard methods

Specific Objectives
New treatment
 New indication
 Determine the best of a number of
standard treatments
 To provide additional data on safety or
efficacy

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


Define and justify the control group
Safety consideration of the placebo group
Trial 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 Design

Balance on Prognostic Factors
–Stratification
–Minimization
Trial Design
Blinding



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 Phase
Patient management guidelines,
including specifications for does
reductions, treatment delays and
treatment terminations
 Schedules of required clinical tests and
assessments

Follow-up phase
Schedule of submission of required
materials and data, including long-term
follow-up
 Data and materials submission
procedures

Termination

Procedures for ending patients’
participation in the trial
Study Flow Diagram

A flowchart describe how patients
progress through the trial
– Initial screening
– Randomization
– Planned schedule
– Follow-up visits
– Early termination
Outcome Measures

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

Ethics 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 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 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 CRF








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

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.

Coordinating Centre
– Training
– Registration
– Randomization
– Supplying
– Collecting and processing CRFs
– Coordination of accrual sites
– Auditing study sites
– Regulatory reporting
Statistical Centre
–
–
–
–
–
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










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/

– Participants accrual
– Intervention
– Primary data collection
– Follow-up
Standard Operating Procedures
(SOPs)

To ensure that the specific tasks in the
trial are carried out in a consistent
manner.

Topics for SOPs for Investigators:
General Topics





General quality assurance
Quality control procedures
Research personnel qualifications
Clinical audit
Regulatory authority inspections
Ethics

Initial and continuing review by ethics
committees
 Informed consent
 Consent forms and information sheets
Study Setup

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

Management of Study Medications
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 Reporting
Definitions
 Recording and reporting AEs
 Recording and reporting AEs to ethics
committees;

Closing The Study
Review of clinical study reports
 Premature termination or suspension
 Archiving

Some 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
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
Research Study (MV)- Oklahoma 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:

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:

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:

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

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

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

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
A 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 Journals
Applied Clinical Trials
 Statistical Methods in Medical Research
 Statistics in Medicine
 Biometrics

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

Scope of Trials (ICH E9)
Population
 Primary and Secondary Variables
 Composite variables
 Global Assessment variables
 Multiple Primary Variables
 Surrogate Variables
 Categorized Variables

Design Techniques to Avoid Bias
(ICH E9)
Blinding
 Randomization

Trial Design Considerations (ICH E9)
Design Configuration
 Parallel Group Design
 Cross-over Design
 Factorial Design
 Mulitcentre Trials

Trial Design Considerations (ICH E9)

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

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

Data Analysis Considerations
(ICH E9)
Prespecification of the Analysis
 Analysis Sets

– Full Analysis Set
– Per Protocol Set
– Roles of the Different Analysis Sets

Missing Values and Outliers
Data Analysis Considerations
(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