Final Flashcards
An IRB must require that info given to subjects as a part of informed consent is in accordance with __
50.25
An IRB must require documentation of ___. Exceptions to this are __ & __
informed consent
minimal risk or emergencies
An IRB must review continuing research based on the degree of risk but not less than how often?
once per year
Applicable ethics and informed consent regulations are __ and ___
- 21 CFR part 50
- ICH guidelines section 4.6
Which founding document created 10 points describing basic principles of ethical behavior in human experimentation? What year?
Nuremberg Code, 1947
What document was passed after thalidomide tragedy? What year?
Kefauver-Harris Bill, 1962
The kefauver-harris bill strengthened __ regulations and required ___
- IND regulations
- proof of efficacy for new drugs
Which document was created by the world health organization? What year?
Declaration of helsinki, 1964
Which document provides a statement of ethical principles and defines therapeutic and non-therapeutic research?
Declaration of helsinki
This document was published as a guide for US research with human subjects. What year?
Belmont report, 1979
3 basic principles of belmont report=
- respect for persons (autonomy)
- beneficence
- justice
This document was written in response to abuse of human subjects and has three primary objectives. What year?
IND rewrite regulations, 1987
What are the three primary objectives of the IND rewrite regulations?
- protecting safety of subjects in clinical trials
- ensure adequate trial designs
- ensure quality, integrity, and validity of data for FDA submissions
Two essential parts of informed consent=
- dialogue
2. documentation
When obtaining consent, the investigator MUST (5):
- explain research and study procedures
- give subject time to digest info & consider all options
- ensure understanding of study and consent process
- give opportunity to ask ?s
- provide consent document in language subject understands
The ICF is written at a __ grade level and does not include any __
6-8th grade reading level
no exculpatory language
What must happen for an ICF to be considered “legally effective”?
must be signed by the subject or his/her legally authorized representative
How many copies are made of an ICF?
1 for investigators study files; 1 for subject
Basic elements of informed consent that are required by law come from:
21 CFR part 50
Additional IC elements are considered __, come from __ and are usually required by __
- guidance, not law
- ICH guidelines section 4.6
- IRBs
How many basic elements of IC exist?
8
Basic element 1 of 8 for IC is a statement that the study involves ___, an explanation of __ and ___, a description of __ and identification of ___
- study involves research
- explanation of purposes of the research
- expected duration of subjects participation
- description of procedures to be followed
- identification of any procedures which are experimental
Element 2 of 8 for IC is a description of:
any reasonably forseeable risks or discomforts to the subject
Element 3 of 8 for IC is a description of:
any benefits to subject or to others which may reasonably be expected from research
payment for participation and/or reimbursement for costs are considered __ and should be described in __
- benefits
- element 3 of IC
if subjects are paid, they should receive some amt of money regardless of __
whether subject completes the study
payment only at study completion is viewed as ___ by ___
coercion by FDA
The amount and schedule of payments must be explained in element __ of __
3; consent form
Element 4 of 8 is:
a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject and their important potential risks/benefits
Element 5 of 8 is a statement describing:
the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that FDA may inspect the records
Element 6 of 8: for research involving more than minimal risk:
an explanation as to whether any compensation or medical treatments are available, if injury occurs, and if so, what they consist of, or whether further info may be obtained
ICF Element 7 of 8 is an explanation of:
whom to contact for answers to pertinent ?s about the research itself and research subjects rights and whom to contact in the event of a research-related injury to the subject
ICF element 8 of 8 is a statement that:
participation is voluntary, that refusal to participate will involve no penalty or loss of benefits and that subject may discontinue at any time
What does the new element of informed consent include/involve?
IC documents for applicable drug and device clinical trials must include a statement that info about the trial will be entered into a databank
What does HIPAA stand for?
health insurance portability and accountability act of 1996
Additional IC elements that may be included are (6):
- treatment/procedure may involve risks to the subject that are currently unforseeable
- anticipated circumstances under which subjects participation may be terminated by PI w/out regard to subjects consent
- additional costs to subject
- consequences of a subjects decision to withdraw from research and procedures for orderly termination of participation by the subject
- significant new findings developed during the course of the research which may relate to the subjects willingness to continue participation will be provided to the subject
- approximate number of subjects and centers involved in the study
What are two primary methods for reducing bias?
randomization and blinding
What is the most commonly used statistical design?
parallel group design
What is considered the blueprint of the study?
protocol
The design of __ can impact data quality
CRF
pertinent site information and investigator responsibilities are found on what form?
statement of investigator (FDA 1572)
who has the ultimate responsibility for subject safety during a clinical trial?
investigator
Assessment of site capacity to conduct a clinical trial effectively is done during __
PSSV
Regulatory and financial documents are collected during __
site startup
___ ensures that there is no potential conflict of interest that could bias the trial
financial disclosure
__ and __ are used to ensure all sites have the same understandin of all protocol and study procedures
SIVs and investigator meetins
What does SDV stand for?
source document verification
What is source document verification?
verifying that the data in a patients source document matches the data recorded in the case report form
SDV is considered the first place that data for any patient is recorded/captured and includes (5):
- medical records (paper or electronic)
- lab reports
- paper towels
- sheets
- scrubs
Data to be verified is specified in:
Clinical monitoring plan
If 100% SDV is specified, the CRAs are responsible for reviewing ___
EVERYTHING
Are handwritten notes considered source data?
yes
Are electronic medical records where physicians record data directly into the system source data?
yes
Is a napkin with BP measurements considered source data?
yes
Is notes in a study-specific source document template abstracted from a hospital chart considered source data?
no
Are electronic medical records where physicians make handwritten notes which are typed into the electronic medical records by data technicians considered source data?
no
Are notes in a study specific source document template handwritten by site staff during the patient visit considered source data?
yes
Are lab reports from a hospital or central laboratory considered source data?
yes
Sponsors are responsible for
ensuring proper monitoring of
investigations= 21 CFR ___
312.50
Sponsors are responsible for
selecting a monitor qualified by training
and experience= 21 CFR __
312.53
Monitoring AEs during clinical trials is important for (3):
- safety of subjects
- providing accurate info for NDA & package insert
- proper use of drug after marketing (What patients should not receive the drug; Treatment decisions – risk/benefit;
Expected adverse events; Dose reductions, other actions)
Managing the safety of patients enrolled in a clinical trial and reporting AEs are key responsibilities of ___.
Investigator
Monitoring the safety of patients enrolled in a
clinical trial is one of the most important
responsibilities of a ___
CRA
An AE is any _____ in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a ___ with this treatment
- untoward medical occurrence
- causal relationship
An AE can be any ___ and ___ sign, __, or __ with the use of a medicinal product whether or not related to the product
-any unfavorable or unintended sign, symptom or disease temporally associated
A serious AE is defined as Any drug experience occurring at any dose
that results in any of the following
outcomes (6):
- death
- life-threatening adverse drug experience
- inpatient hospitalization or prolonged existing hospitalization
- persistant or significant disability/inability
- birth defect/ congenital anomaly
- important medical events
An important medical event that may not result in death, be life-threatening or require hospitalization may be considered a serious AE when based upon appropriate medical judgement including __ and __. Examples = (3).
- may jeopardize patient
- may require medical or surgical intervention to prevent one of outcomes listed
Examples: allergic bronchospasm, blood dyscrasias, convulsions
A Severe AE is defined as __ or __ and is not always ___.
- grave or critical
- “serious”
An unexpected AE is defined as:
any AE in which the specificity or severity is not consistent with the current investigators brochure
Life-threatening AE is defined as:
any AE that places the patient or subject in the view of the investigator, at immediate risk of death from the reaction as it occurred
“Associated with the use of the drug” means:
there is a reasonable possibility that the AE may have been caused by the drug
Where are non-serious AEs documented?
In source data and transcribed into the AE page of a case report form
What data must be documented for non-serious AEs?
- disease or description of symptoms
- start and stop dates
- severity
- causality/relationship to drug
- treatment
Non-serious AEs are summarized in the __ and __and are usually reported to the FDA when ___
- final study report and NDA
- NDA is submitted
Serious AEs are documented in __ and are transcribed into __ and ___
- documented in source data
- transcribed into AE page of case report form AND into a serious adverse event (SAE) form
When is an SAE form sent to the sponsor or CRO?
within 24 hrs after the investigator learns of the SAE (regardless of relationship to study drug)
If SAE is judged “not related” to study drug, the data is listed in:
the sponsors annual report to FDA
For serious and unexpected drug related AEs, ___ is sent to FDA and all participating investigators for the drug within:
FDA form 3500A (aka Medwatch)
-within 15 calendar days
Life-threatening, unexpected drug-related AEs should be reported using __ to FDA and all investigators within:
FDA form 3500A (aka Medwatch)
-within 7 calendar days
Only suspected AEs should be reported as :
an IND safety report
Is pregnancy during a study regarded as an AE?
no
Most studies have ___ to capture information for women who become pregnant during study
“pregnancy forms”
If a woman stops treatment due to pregnancy during a study, they must be followed until:
followed to end of pregnancy or birth
“Drug accountability” is defined as verification or documentation of the amount of study drug (3):
- received at the study site (retail pharmacy)
- dispensed to and returned from patients in the clinical study (patients who purchase the drug)
- returned to sponsor or destroyed on site at the end of the study (on hand at the end of the shift)
What is the formula for patient dosing compliance?
amount of study drug dispensed- amount of study drug returned/100
Control of drug: A sponsor shall ship investigational new drugs only to investigators participating in the investigation= 21 CFR __
312.53
A sponsor shall maintain adequate
records showing the receipt, shipment or other disposition of the investigational drug. These records are required to include, asappropriate, the name of the investigator to whom the drug is shipped, and the date, quantity and batch code mark
of each such
shipment= 21 CFR ___
312.57
The sponsor shall assure the return
of all unused supplies of the investigational drug from each individual
investigator whose participation in the investigation is discontinued or terminated. The sponsor may authorize alternative disposition of unused supplies of the investigational drug provided this alternative disposition does not expose humans to risks from the drug. The sponsor shall maintain written records
of any disposition of the drug in accordance with 21 CFR 312.57= 21 CFR __
312.59
Who is responsible for supplying the investigators with the investigational drug?
sponsor
Who is responsible for obtaining required documentation before shipment?
sponsor
Who is responsible for ensuring timely delivery of drug to the study sites?
sponsor
Who is responsible for providing written instructions for handling and storageof drug including procedures for receipt, handling, storage, dispensing, retrieval of unused drug from subjects, return of unused drug to sponsor?
sponsor
Who is responsible for maintaining records of shipment, receipt, disposition, return and destruction of the investigational drug?
sponsor
Who is responsible for maintaining a system for retrieving drug in the event of recalls, expiration, etc
sponsor
Who is responsible for maintaining a system for the disposition of unused investigational drug and documentation?
sponsor
Who is responsible for taking steps to ensure that the investigational drug is stable over the period of use?
sponsor
Who is responsible for maintaining sufficient quantities of the investigational drug used in trials to reconfirm specifications, if necessary?
sponsor
Who is responsible for investigational drug accountability?
investigator
Who is responsible for maintaining records of drug delivery, drug inventory at the site, the use by each subject and return of unused drug?
investigator
Who is responsible for maintaining records that include dates, quantities, batch/serial numbers, expiration dates and any study-specific codes or numbers?
investigator
Who is responsible for maintaining records that show that subjects were provided the doses specified by the protocol?
investigator
What required records must the sponsor maintain? (2)
- product shipment to investigator
2. disposition of unused drug
The __ is responsible for recording product receipt at investigational site
investigator
The __ is responsible for recording inventory at the site- overall for each study
investigator
The monitor is responsible for ensuring (3), training __ and documenting __
- ensuring the site complies with applicable regulations
- ensuring data accuracy and quality
- ensuring compliance with the protocol
- training and communicating with the PI and other site staff
- documenting activities during site visits and any findings
Generally, __% compliance with a drug regimen is considered excellent on a study
80%
Drug compliance decreases with (4):
- duration of therapy
- frequency of dosing
- side effects and 4. symptoms of disease being treated
Relationship with the __ is key for good patient compliance
site staff
Fraud is considered deliberate __ and is practiced to secure:
deception
unfair or unlawful gain
Behavior not in conformity with prevailing standards or laws is called:
scientific misconduct
Dishonest or bad management, especially by persons entrusted or engaged to act on behalf of another is called:
scientific misconduct
Falsification of data in proposing, designing, performing, recording, supervising or reviewing research, or in reporting research results is called:
fraud (FDA definition)
Fraud does not include __ or ___
honest error or honest differences in opinion
Deliberate or repeated noncompliance with the protocol and GCP can be considered __ but is considered secondary to falsification of data
fraud
Who is usually blamed for fraud?
study coordinator
With study closeout, the ___ is responsible for submitting a final study report to the IRB
PI
The most common targets for site audits by sponsors are (2):
high enrolling sites and sites with compliance issues
FDA can audit both __ and __ files
site and study (trial master file) files
Best practice for audit preparation is to maintain:
audit-ready status throughout study
What are the types of FDA audit findings? (3)
- no action indicated (NAI)
- voluntary action indicated (VAI)
- official action indicated (OAI)
Misconduct is commonly associated with __; fraud is commonly linked to __
hurriedness; personal gain
A written description of a study of any
therapeutic, prophylactic, or diagnostic
agent conducted in human subjects, in
which the clinical & statistical description,
presentations & analyses are fully
integrated into a single report is called:
clinical study report
The clinical study report is integrated into the __ with data from other studies conducted with the investigational new drug
new drug application (NDA)
Regarding study monitoring, drug accountability should be done when?
at every site visit
The site visit report should summarize __ and document __
summarize all activities that took place and document any issues with actions needed
Proper training on safety event management is part of every ___ activity
site initiation
Typical timeframe for reporting an event to the sponsor is :
24-48 hours
In most studies, what is the biggest enrollment limitation?
inclusion/exclusion criteria
Advertising is allowed but must be approved by:
IRB before use
Proactive assessment of ___ is key to subject retention
potential issues
What are the four areas of primary focus for the study closeout visit?
- CRFs, Informed consents complete and retrievable
- study drug accounted for and returned to sponsor or destroyed
- study file reconciliation
- discussion with PI and SC
