Professional Documents
Culture Documents
Final protocol (ethical and scientific, signed by a statistician) Evaluation (scientific review, IRB, funding) Implementation Final analysis and publication
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
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
OBrien and Fleming Boundaries Lan & DeMets Spending function Equivalence testing Repeated measures Bayesian methods Nonlinear random effect modeling
To procure funding
7days-6months!!!
4-50 pages long!!!
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Rationale Unpublished work of the investigators Pharmacological and toxicity Any new and non standard methods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
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
Trial Design
Trial Design
Blinding
Mechanism of treatment blinding Single, double, triple, quadruple blinding Assessment of the effectiveness of blinding
Experimental design
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
Randomization
Planned schedule Follow-up visits Early termination
Outcome Measures
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
into the trial Regulatory obligations, including informed consent and reporting of adverse events Plan and action if a SAE be detacted
Laboratories Compliance
How compliance is monitored Methods used to improve compliance
Organization
Roles Responsibilities
CRF Design
Soilker, B. Schoenfelder, J. (1991). Data Collection Forms in Clinical Trials. Racen Press, New York
Consent dates Eligibility checklist Baseline assessments Dosing of study medications ( incl. compliance) Concomitant illness Safety Effectiveness Premature termination of study
Steering Committee
Leadership body of the investigative group
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
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
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
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)
Shipment Receipt Control at study sites Dispensing inventory Compliance with use of study medication Randomization procedures Clinical laboratory samples
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
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.
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
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.
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
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 subjects 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 Universitys 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
Violations of
human subject protection regulations, international recognized ethical standards for
An official journal for the Society for Clinical Trials The first issue was published in the May of 1980. Aim and scope:
Thank you!
Type of Comparison
Trials to show superiority Trials to show Equivalence or Non-
Full Analysis Set Per Protocol Set Roles of the Different Analysis Sets
Data Transformation Estimation, CIs and Hypothesis Testing Adjustment of Significance and Confidence Levels Subgroups, Interactions and Covariates Integrity Data and Computer Software Validity