Clinical Trials and Quality Assurance Flashcards
What is a clinical trial?
Biomedical or health-related scientific experiment designed to answer specific question(s)
What is the difference between a clinical trial and a clinical study?
Clinical trials are prospective whereas clinical studies can be both prospective and retrospective
What are some study designs?
Experimental (interventional):
Semi-experimental
Observational (non-interventional)
What is an experimental study?
Evaluates efficacy (explanatory) and effectiveness (pragmatic) of a therapeutic or treatment
What is a semi-experimental study?
Trials with historical controls
What is an observational study?
Subjects observed and specific outcomes measured without any active intervention of the subjects’ medical care
No experiment is being performed
What are some types of experimental clinical trials?
Diagnostic
Screening
Quality of Life
What is a diagnostic clinical trial?
Evaluates the ability of a test or procedure to correctly diagnose a disease or medical condition or to measure a specific parameter
What is a screening clinical trial?
Tests the best way to detect certain diseases or health conditions
What is a quality of life clinical trial?
Measure effect on quality of life or changes in behaviors or lifestyle factors
What is the difference between efficacy and effectiveness?
Efficacy = explanatory Effectiveness = pragmatic
What is efficacy?
Measure product’s ability to treat the indicated condition
Tests whether the product produces the desired clinical outcome under research (or optimal) conditions
What is effectiveness?
Measure of how well the drug or device works; includes efficacy as well as the tolerability and ease of use of the product
Focuses on whether an intervention or procedure works under usual conditions or actual practice
Why are interventional clinical trials needed?
Definitive method and provides sounder rationale for determining an intervention’s effect
Helps determine incidence of AE or complications of intervention
Clinical practice influence
What are some types of interventions?
Single/individual treatment/therapy Exposure (i.e. radiotherapy) Medical device Surgical technique Combination treatment Educational or behavioral program Dietary change
What is clinical research? What of the individual subject?
Goal: to test a hypothesis and generate knowledge to improve medical care or public health; serve the common good
Individual subject may or may not benefit from participation
What is clinical practice? What of the individual subject?
Goal: diagnose, provide preventative care, or treat illness or medical condition in a particular individual(s) with reasonable expectation of success
Care provided to enhance individual patient’s well-being
T/F: High quality care and treatment for the patient is the goal of clinical research?
F
When was the concept of blindness introduced and by whom?
1931
Amberson via flip of a coin as a form of random treatment group assignment
When was the importance of controlled experiments emphasized and by whom?
1930
Sollman
When was the Nuremberg Code created and in reaction to which event?
1949
to the Nazi human experimentations
When was the Federal Food, Drug, and Cosmetic Act and what did it entail?
1962
required informed consent and that subjects be told if the drug is investigational
When was the Declaration of Helsinki and what did it entail?
1964
stressed importance of assessing risks vs potential benefits of clinical research
What is IRB and when was it established?
Institutional Review Board: reviews all clinical research performed under Public Health Service grants
1966
What is a benefit to clinical research?
Enables advances in medical practice and healthcare that otherwise would not be possible
What are some limits to clinical research?
Rigorous conduct required to avoid false results could cause harm
Individual subjects may or may not benefit
Opportunity for exploitation when subjects are exposed to potential risks for benefit of others/society
What are some historical violations of human rights?
Nazi War Crimes
Brooklyn Jewish Chronic Disease Hospital (1963)
Hepatitis B study at Willowbrook
Tuskegee syphilis study (1932-1972)
What documents have helped shape the current ethical framework for human research studies conduct?
Nuremberg Code
Declaration of Helsinki
Belmont Report
When was the Declaration of Helsinki established and what did it entail?
1964
Recommendations to be used as an ethical code by all medical doctors conducting biomedical research
When was the Belmont Report established and what did it entail?
1979
Emphasizes need to protect human subjects from exploitation and harm
What are the basic ethical principles that guide the conduct of research?
Respect for persons
Beneficence
Justice
What is respect for persons?
Individuals should be treated as autonomous
Some persons are in need of protection (and may even need to be excluded from potential harm)
What is beneficence?
Study has social/scientific value, scientific validity, and favorable risk/benefit ratio
Do not harm
Maximize potential benefits and minimize potential harms
What is justice?
Recruitment and selection of subjects is fair and inclusion/exclusion criteria are reasonable
Selection should not be based on easy availability, compromised position, manipulability
What elements does informed consent contain?
Information
Comprehension
Voluntariness
What is the ethical framework for clinical research?
Value Validity Fair subject selection Favorable risk-benefit ratio Independent review Informed consent Respect for enrolled participants
Who is the end customer?
Patient
What is the purpose of a clinical trial?
Assess safety and efficacy/effectiveness
Develop package insert or instructions/directions for use
Enable safe and effective use of the product by HCP and/or patient
What is the FDA mission?
Protect and promote public health through safety, efficacy, and security of products regulated
What is the FDA’s definition of a drug?
An article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of a disease
An article intended to affect the structure or any function of the body
What is the FDA’s definition of a biologic?
Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or rasphenamine or derivative of arsphenamine, applicable to the prevention, treatment, or cure of a disease or condition of human beings
What is the FDA’s definition of a medical device?
Instrument, apparatus, implement, machine, implant, in vitro reagent which is intended for use in diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or which is intended to affect the structure or function of the body
What is the FDA’s definition of a combination product?
Product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity
Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products
What is CDER?
Center for Drug Evaluation and Research
Regulates new molecular entities (NMEs)/chemically synthesized drugs
What is CDRH?
Center for Devices and Radiological Health
Regulates manufacturing, performance, and safety of medical devices and radiation-emitting products
What are the classes of medical devices?
Class 1, 2, and 3
What is a class 1 device?
Everyday items which are unlikely to cause serious consequence if they fail
What is a class 2 device?
“Medium risk” such as demineralized bone powder
What is a class 3 device?
Products which would cause obvious risk of injury or death if they don’t function properly
Require pre-market approval (PMA)
What is CFR and which pertains to drugs?
Code of Federal Regulations
Title 21
What are guidance documents?
Describe the FDA’s current thinking on, interpretation of, or policy on, a regulatory issue
Intended to help the “public” understand and comply with regulations and laws
T/F: Guidance documents are legally binding.
F
What is 21 CFR 312?
Investigational new drugs regulations
What is 21 CFR 3?
Definition of primary mode of action of a combination product
What is 21 CFR 50?
Protection of human subjects
Informed consent
What is 21 CFR 56?
Institutional review boards
What is 21 CFR 58?
Good laboratory practice (GLP) for non-clinical lab studies
What is 21 CFR 314?
New drug applications
What is 21 CFR 601?
Biologics license applications regulations
What is 21 CFR 54?
Financial disclosures by clinical investigators
What is 21 CFR 25?
Environmental impact considerations
What is 21 CFR 201 and 202?
Labeling and advertising
What is 21 CFR 210 and 211?
Current good manufacturing practices (cGMP)
What is 21 CFR 807?
Establishment, registration, and device listing for manufacturers and initial importers of devices
What is 21 CFR 1270 and 1271?
Human tissues
What is a regulated environment?
Controlled environment where decisions made and operations performed are based a on predefined set of criteria
What are the program building blocks?
Chemistry, manufacturing, and controls (CMC)
Nonclinical/preclinical
Clinical (Protocol)
What is an IND?
Request for authorization from FDA to administer investigational drug or biologic to humans
Exemption to transport product across state lines for clinical investigation
When is an IND required?
When an approved drug/biologic is used in a clinical investigation
Clinical investigation is for approved drug but new indication
When is an IND not required?
Product is approved for medical practice
Investigation does not involve route of administration, dosage level, or use that significantly increases risk and conducted in accordance to IRB and informed consent requirements
What if a study is performed outside of the US with an IND?
Test article can be exported from US
Study must conform to US IND regulations
What if a study is performed outside of the US without an IND?
May be accepted for FDA review in support of a marketing application
Export of the test articl from the US must conform to FDA regulations
What is a pre-IND meeting?
Meeting held with FDA before submission of IND
Intended to help ensure all documents are adequately prepared before submission
Not intended as a data review or negotiation meeting
T/F: having a pre-IND meeting does not guarantee safety from a clinical hold?
T
What is a clinical hold?
Legal order to delay or stop the study
What may lead to a clinical hold?
Exposure of subjects to unreasonable risk
Investigator brochure is misleading, erroneous or materially incomplete
Protocol design is inadequate or problematic
Investigator is not qualified
What are some regulatory filing strategies?
Accelerated approval Fast-track/expedited review Rolling/modular submission Priority review Special protocol assessment
What is accelerated approval?
Specializd program to enable promising therapies for serious or life-threatening conditions and that fill unmet medical need to reach the market faster
Contains “surrogate” endpoints or clinical endpoints that can be measured earlier than an effect on irreversible morbidity or mortality
What is fast track review?
Facilitates development and expedites review of drugs and biologics intended to treat serious or life-threatening conditions and demonstrates potential to address unmet medical needs
What are some special protocols?
Animal carcinogenicity
Final product stability
Phase 3 clinical trials that will form the primary basis for an efficacy claim
What is the biologics equivalent of a NDA?
Biologics license application (BLA)
What is the NDA approved by?
Federal food, drug, and cosmetic act (FDCnA)
What is the BLA approved by?
Public health service act (PHSA) and specific sections of the FDCnA
What is BIMO?
Bioresearch monitoring program
What is GLP and when was it established?
1979
Regulations addressed process not science of preclinical safety studies
Required good recordkeeping and collection of toxicological and pharmacological data
What is GCP?
Good clinical practice
International ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects
What are the GCP objectives?
Protect safety, well-being and privacy of human subjects
Data integrity
What is 21 CFR 11?
Electronic records and signatures
What is 21 CFR 812?
Investigational device exemptions
What is 21 CFR 814?
Premarket approval of medical devices
What is the medical device equivalent of IND?
Investigational device exemptions (IDE)
What is ICH?
International conference on harmonization
What is the ICH guideline for GCP?
Provide unified standard for EU, Japan, and US to facilitate mutual acceptance of clinical data
What are the GCP practice tenets?
Rights, safety, and well-being of trial subjects should prevail over interest of science and society
Clinical RnD activities must be conducted within the context of an established plan
Clinical RnD tasks must be conducted according to written standardized procedures
Clinical RnD systems and procedures must be tested by conducting planned reviews and audits to ensure validity of data and compliance with applicable requirements
What is SOPs?
Standard operating procedures
Standardization of terms and definitions, documentation, and research activities
What is quality control?
Operational techniques and activities within quality assurance system to verify that requirements for quality of trial-related activities have been fulfilled
What is quality assurance?
Planned and systematic actions established to ensure that the trial is performed and data is generated, documented, and reported in compliance with GCP and applicable regulatory requirements
What main categories make up ICH-GCP principles?
Ethics Protocol and science Responsibilities Informed Consent Data quality and integrity Investigational products Quality control and assurance
What does an investigator’s brochure contain?
Description of investigational product Rationale for research Physical, chemical, and pharmaceutical properties and formulation Non-clinical studies Effects in humans
What is a clinical protocol?
Detailed step by step description of how the study must be conducted
What are the key components of a protocol?
Synopsis
Background info
Objectives
Subject selection and conditions for withdrawal
Treatment of subjects
method of subject assignment to treatment groups
Efficacy (drugs) or effectiveness (devices) and/or safety statements
What is an open trial design?
Investigator(s) and subjects are aware of the treatment assignment
What is a single-blinded trial design?
Only the investigator is aware of the treatment assignment
What is a double-blinded trial design?
Investigator(s) and subjects are unaware of treatment assignment
When is a “masked evaluator” used?
Device trials when it is not possible to mask treatment assignment from the subject and investigator(s)
Why is randomization used?
To minimize potential for bias
What is a parallel trial design?
Subjects are randomly assigned to participate in one arm of the study (i.e. treatment or control group)
What is a cross-over trial design?
Subjects are randomly assigned to participate in one arm of the study and then switched over to the other arm after a specified period.
What is a stratified trial design?
Subjects are statistically allocated to treatment arms based on characteristics that may affect the outcome of the study
What is a matching trial design?
Subjects are paired according to characteristics and then one is assigned to treatment and the other to control
What is a CRF?
Case report form or data collection form
Anything that needs to be entered into the database and analyzed to determine the study’s endpoints and evaluation of safety
What is a PI?
Principal investigator
Lead investigator at the site who takes full responsibility for conduct of the trial and activities of his/her designated staff
What is a sub-investigator?
Qualified individuals who assume various for the medical/scientific conduct of the study as designated by the PI
What are some PI specific responsibilities?
Determining subject eligibility
AE, SAE/SADE, and UADrE/UADE assessment(s) and reporting
Keeping sponsor informed of IRB approvals
CRF sign-off
What is documentation?
All records that describe or record the methods, conduct, results, and factors affecting a trial, and the actions taken
What are source documents?
First hard copies on which clinical observations are recorded
Legally valid raw data that support a study’s findings
What is a study coordinator?
Individual at the study site who is designated by the PI to assume various responsibilities for the daily conduct of the study
What are some study coordinator responsibilities?
Subject ID Screening and enrollment CRF completion Maintenance of regulatory (essential) documents Reporting AEs and deviations Communicating with the IRB
How can an investigator get disqualified?
Beginning study without prior FDA/IRB approval
Ignoring dictates of IRB
Falsifying data
Failure to get informed consent and deceiving the patient
Deviating from the protocol or established procedures
Refusal of file audits
What is a sponsor?
Individual/company/governmental agency/academic institution/private organization who funds a study
What are some sponsor responsibilities?
Select qualified investigators Monitor progress of trial and safety Ensure protocol compliance Drug disposition and reconciliation Maintain required records and reports Transfer of obligations to a CRO
What is study management?
Clinical/project manager responsible for the overall development, implementation, and management of the clinical trial to ensure compliance with Sponsor’s responsibilities
What is a medical monitor?
Medical doctor responsible for assessment of AE and relationship to investigational product and interpretation of clinical study results
What is the purpose of monitoring?
Verify that rights and well beings of human subjects are protected, data integrity, and trial is conducted in accordance to currently approved protocol, GCP, applicable regulatory requirements and SOPs
