Planning, Development of Clinical Trials

Planning of Clinical Trials
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
* A detailed plan giving instructions to the study investigators(doctors) about the way

to conduct the study.
o 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.
* Written agreement between:
o the investigator
o the participant,
o and the scientific community
* Legal documents for
o 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* Unpublished work of the investigators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
o Hypothesis
o 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
+ Randomization (verifiable method)
# Method used to generate the allocation schedule
# Method of allocation concealment
* Packing number
* Telephone
* Remote data entry
# Timing of assignment
+ Balance on Prognostic Factors
# Stratification
# Minimization
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

* 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
o Initial screening
o Randomization
o Planned schedule
o Follow-up visits
o 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
o How the patient is approached for entry into the trial
o Regulatory obligations, including informed consent and reporting of adverse

events
o Plan and action if a SAE be detacted

Other Topics in a Study Protocol
* Laboratories
* Compliance
o How compliance is monitored
o Methods used to improve compliance
* Organization
o Roles
o Responsibilities
* Budget
* Study Forms (CRFs) and data handling
* Administrative responsibilities

CRF Design
* Identification data
* Research data
* Administrative data
* Regulatory data

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
o Leadership body of the investigative group
* Data and Safety Monitoring Committee
o Assess the progress, safety and efficacy
o 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
o Training
o Registration
o Randomization
o Supplying
o Collecting and processing CRFs
o Coordination of accrual sites
o Auditing study sites
o Regulatory reporting

Statistical Centre
o Data entry and processing
o Ongoing monitoring of toxicity data
o Periodical interim analysis of study endpoints
o Final data analyses
o 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/
o Participants accrual
o Intervention
o Primary data collection
o 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:
o investigator brochures
o Protocols
o Protocol amendments
o CRFs
o 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)
o ICH home page: http://www.ifpma.org/ich1.html
o 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
o the purpose of the study
o Procedures
o Foreseeable risks and discomforts
o Any expected benefit from study participation
o 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.
* 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.
* Federal lawsuit against
o study’s PI,
o its corporate co-sponsor
o and its IRB members,
* Violations of
o human subject protection regulations,
o international recognized ethical standards for research conduct
o 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:
o Basic Design
o Operating features
o Organization
o Analysis

Other Useful Journals
* Applied Clinical Trials
* Statistical Methods in Medical Research
* Statistics in Medicine
* Biometrics

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
o Trials to show superiority
o Trials to show Equivalence or Non-inferiority
o 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
o Full Analysis Set
o Per Protocol Set
o 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

Planning, Development of Clinical Trials.ppt