Principles and Practice of Clinical Research

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NIH Intro Course
George Perros
Flashcards by George Perros, updated more than 1 year ago
George Perros
Created by George Perros over 3 years ago
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Resource summary

Question Answer
What makes research ethical? TBD
Goal of Clinical Research Generate useful knowledge about human health and illness, and ways to prevent, diagnose and treat diseases.
Ethics of Clinical Research 1. Promote benefits to society and future patients; 2. Protect and respect the rights and welfare of participants.
National Research Act 1. created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 2. identify basic ethical principles to be followed when conducting biomedical and behavioral research on human subjects. 3. Developed guidelines
Ethics Codes and Guidelines 1. Nuremberg Code (1949) 2. Declaration of Helsinki (1964....) 3. Belmont Report 4. CIOMS/WHO International Guidelines (1993, 2002) 5. ICH/GCP International Conference on Harmonization - Good Clinical Practice
The Belmont Report Ethical principles underlying the conduct of research: 1. Respect for persons 2. Beneficence 3. Justice
Clinical Research vs Clinical Practice - Goals - Method - Risks
Regulations in the U.S. - The Common Rule (US 45CFR.46) - FDA Regulations (US 21 CFR50 and 56 and others) - NIH Policy and Guidelines
45CFR.46 Protection of Human Subjects Composition and function of a local Institutional Review Board (IRB) Criteria for IRB approval of proposals Requirements regarding informed consent
Existing Guidance Most developed in response to specific problems Some issues incompletely addressed, include divergent recommendations Need for a systematic, coherent, universally applicable framework
7 Principles Ethical Framework Valuable scientific question Valid scientific methodology Fair subject selection Favorable risk-benefit evaluation Independent review Informed consent Respect for enrolled subjects
Valuable Scientific Question One that will generate new knowledge or understanding
Social Value Promote benefit to society Minimize exploitation Justify asking individuals to accept risk or burden Responsible use of resources
Valid scientific methodology Research designed in a methodologically rigorous manner
Scientific validity Choice of Endpoints Choice of design Choice of procedures Statistical methods Feasibility
Fair subject selection Scientific objectives should guide inclusion criteria. recruitment strategies and selection Fairly distribute harms and benefits No exclusion without justification
Favorable risk-benefit Are risks to subjects necessary and minimized? Are risks justified by benefits to individuals subjects and/or the importance of the knowledge to society? Are benefits enhanced?
Risks in research - Probability and magnitude - Types of risk - Uncertainty Minimizing risks Limiting risks
Benefits in research Direct vs secondary benefits Maximizing benefits Balancing risks and benefits
Independent Review To ensure that ethical requirements have been met To check investigator biases and conflicts To assure the public that research is not exploiting individuals or groups
Criteria for IRB review (45CRF.46.111 and 21CFR.56.111) Risks are minimized Risks are justified by anticipated benefits to the subjects of the value of the knowledge to be gained Subjects will be selected and treated fairly Informed consent is adequate
Challenges in Independent Review Volume Conflicts Varied interpretations (Inconsistency) Notice of Proposed Rule making (NPRM) Proposal (Single IRB for multi-site studies)
Informed Consent
Informed Consent (2) Disclosure of information Understanding Voluntary Decision making Authorization
Respect for enrolled subjects
Framework Systematic and sequential Necessary - procedural requirements may be waived Universal - Adapted and implemented according to context Require balancing, specifying
Ethical Framework
Changing Landscape Multisite/Multinational Learning healthcare systems, quality improvement Comparative effectiveness research and usual care research Research using databases or samples Genomic data and sharing
Links to more information
8 Ethical Requirements
Collaborative Partnerships
Collaborative Partnerships (2)
Social Value
Scientific Validity
Informed Consent (3)
Informed Consent (4)
Respect for Human Subjects
Respect for Human Subjects (2)
8 Ethical Requirements
8 Ethical Requirements (2)
Revised Common Rule
Informed Consent Process
Informed Consent Process (2)
Informed Consent Process (3)
Role of FDA 1. Protecting the Public Health 2. Advancing the Public Health 3. Regulating Tobacco Products 4.Counterterrorism capability
FDA Regulations Title 21, Code of Federal Regulations Part 201, 202 - Labeling and Advertising Part 312 - Investigational new drug (IND) Part 314 - New drug application (NDA) Parts 600 - 800 Biologics Parts 800 - 861 Devices and In vitro diagnostics
FDA Regulations Title 21, Code of Federal Regulations (2) Part 25 - Environmental Impact Considerations Part 50 - Protection of Human Subjects Part 54 - Financial Disclosure Part 56 - Investigational Review Boards (IRB) Part 58 - Good Laboratory Practices
21 CFR 312 IND and GCP consolidated guideline (ICH E6) GCP - Unified Standard for designing conducting, recording and reporting clinical trials IND - Content and format of IND and the Investigator's Brochure (IB) Essential reading for Clinical Trial design
Clinical Trials Phases Phase 1 50 or less Focus on safety (tolerability) Preliminary evidence of activity dose escalation
Clinical Trials Phase 2 Phase 2 a few hundred subjects Focus on safety (tolerability) Evidence of activity Dose escalation/finding Activity assessment
Clinical Trials Phase 3 Phase 3 Size is dependent on Several factors Confirm clinical benefit Expand knowledge of safety Evaluate risk-benefit of the product Provide an adequate basis for labeling Data forms basis for marketing application
Clinical Hold in Phase 1 Safety
Clinical Hold in Phase 2 & 3 Safety and Trial design
Quality & safety issues Manufacturing Biological Products Raw materials Production Characterization Process validation Testing Comply with cGMP Comply with FD&C
Clinical Considerations Trial design and Analysis Conduct and monitoring of trial Adverse event reporting Pediatric development Demographic subgroups
Institutional Review Board (IRB) 21 CFR 56 Review and approve all protocols Assure risks are minimized Selection of subject is equitable Informed consent will be sought and documented
Institutional Review Board (2) Have at least 5 members with varying backgrounds Authority to approve or disapprove research activities Informed consent Continuing review at least once/year Compliance with special protections for children Maintain records for at least 3 years
Expanded Access to INDs 21 CFR 312 Subpart H (2009) Serious/life threatening condition and no satisfactory alternative Potential benefit justifies risk Won't interfere with ongoing clinical trials
Expedited Programs Fast Track designation (FT) Breakthrough therapy designation (BT) Accelerated Approval (AA) Priority Review Designation (PR)
The Common Rule current regulations to protect individuals who participate in research as human subjects
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