LMR Flashcards
If an investigator uses the test article in an emergency use situation, what must happen afterwards and in what time frame?
The investigator must have an independent physician review the reason for use within 5 working days of use. This documentation must be submitted to IRB within 5 working days of use.
How is the prospect of direct benefit to the subject determined?
1) Subject is facing life-threatening situation that necessitates intervention
2) Appropriate animal and other preclinical studies have been conducted, supporting potential for direct benefit
3) Risks associated with investigation are reasonable in relation to what is known about medical condition of potential class of subjects, and risks/benefits of standard therapy, and what is known about risks and benefits of proposed intervention or activity
What are examples of additional protections of rights and welfare provided to subjects?
5 examples
I) consultation with reps of communities in which investigation will be conducted
II) Public disclosure to communities in which investigation will be conducted
III) Public disclosure of sufficient information following completion of trial
IV) Establishment of an independent data monitoring committee
V) If obtaining informed consent is not feasible and a LAR is not reasonably available, the investigator will attempt to contact family member who is not a LAR; the investigator will summarize efforts made to contact family members and make this available to IRB at time of continuing review
Each IRB should have at least how many members?
5
Each IRB shall include:
1 member whose primary concerns are in the scientific area
1 whose primary concerns are in nonscientific areas,
1 who is not otherwise affiliated with the institution.
When must an IRB register/when does registration become effective?
Each IRB must submit an initial registration and must renew every 3 years. IRB registration become effective after review and acceptance by HHS/FDA.
How often does an IRB need to revise its registration information? (if changes are made)
must submit changes concerning main contact within 90 days. 30 days if disbanding, otherwise at time of registration renewal.
May a clinical investigator be an IRB member?
Yes except they can not participate in initial or continuing review of a study in which they have a conflicted interest.
The IRB regulations require an IRB to have a diverse membership. May one member satisfy more than one membership category?
Yes.
May the IRB use alternate members?
Yes, if they are formally appointed, listed on the IRB roster and proper IRB procedures are in place that describe their appointment and function.
Does a non-affiliated member need to attend every IRB meeting?
No.
What are examples of IRB members considered to be non-scientists?
FDA believes the intent of the requirement for diversity of disciplines was to include members who had little or no scientific or medical training or experience. In the past, lawyers, clergy and ethicists have been cited as examples of persons whose primary concerns would be in non-scientific areas.
The FDA regulations [21 CFR 56.104(c)] exempt an emergency use of a test article from prospective IRB review, however, “… any subsequent use of the test article at the institution is subject to IRB review.” What does the phrase “subsequent use” mean?
“Subsequent use” would be a second use with that subject or the use with another subject. FDA regulations allow for one emergency use of a test article in an institution without prospective IRB review, provided that such emergency use is reported to the IRB within five working days after such use.
What is IRB expedited review?
Procedure through which certain kinds of research may be reviewed and approved without convening a meeting of the IRB. The IRB may also use the expedited review procedure to review minor changes in previously approved research.
May informed consent be obtained by telephone from a legally authorized representative? (non-emergency)
No, A verbal approval does not satisfy the 21 CFR 56.109(c) requirement for a signed consent document. However, a consent form can be sent to the LAR and discussion can be conducted over the phone with the LAR signing the form and sending it back.
How long does an IRB retain its records? (And what happens when an IRB refuses to allow an inspection of records)
3 years
FDA may refuse to consider a clinical investigation in support of an application for a research/marketing permit if the institution or IRB that reviewed the investigation refuses inspection
Active Protocol
any protocol for which an IRB conducted an initial review or a continuing review at a convened meeting or under an expedited review procedure during the preceding 12 months
If an IRB changes information that is not contact/chair person or cessation of research, how long does it have to report such information?
Whenever the IRB renews it’s registration
Independent ethics committee (IEC)
a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection.
FDA shall provide a written determination within ____ days after receiving IND application
30
Grounds for clinical holds on Phase I studies:
unreasonable risk
unqualified investigators
IB is misleading, inaccurate or incomplete
or IND doesn’t contain sufficient information to assess risk to subjects
Grounds for clinical holds on Phase II or III studies:
deficient protocol to meet stated objectives
When an ongoing study is on a clinical hold can new subjects be enrolled and what happens to subjects currently enrolled and on IP?
no new subjects,
subjects on IP have to stop unless specifically permitted by the FDA
Who can appeal the FDA’s decision for a clinical hold?
Sponsor
Under an IND, if no subjects are entered into a study for 2+ years or if all studies under an IND remain on clinical hold for 1 year+, the IND may be placed on “_____”
Inactive status
INDs that are “Inactive” for ___+ years may be terminated
5
For an IND, how soon should the sponsor report serious unexpected life-threatening safety events to FDA?
7 calendar days.
For an IND, how soon should the sponsor report serious unexpected safety events to FDA when not life-threatening?
15 calendar days.
For an IND, what form is used for the sponsor reporting serious unexpected safety events?
Form FDA 3500A
What does SUSAR stand for?
Suspected unexpected serious adverse reaction
For an IND, when do investigators report serious events to sponsors?
As soon as possible (typically stated in protocol). (15 Days)
For an IND, when is the annual report provided to the FDA by the sponsor?
60 calendar days from the anniversary of the IND becoming active.
True or False: Reactions which are serious but expected are subject to expedited reporting requirements
False. Reactions that are serious but unexpected are subject to expedited reporting.
For an IND, when do Investigator’s provide annual report to sponsor?
No time criteria, give to sponsor to submit to FDA.
For an IND, when does the Investigator need to submit the final report to the sponsor?
When the study site is finished with the investigation (no specified time constraints).
For emergency use of a drug, where immediate use of the product was required and the patient was not able to be consented, how long does the sponsor have to notify the FDA of the use of the product?
5 working days
Fatal or life-threatening unexpected adverse drug reactions are required to be reported no later than how many days after first knowledge? What about non-life-threatening unexpected ADRs?
Fatal unexpected ADRs: 7 calendar days after first knowledge
Non-fatal serious unexpected ADRs: 15 calendar days after first knowledge
When is unblinding inappropriate in the case of a fatal or serious adverse event?
If a fatal or serious outcome is the primary efficacy endpoint, the integrity of the clinical investigation may be compromised if the blind is broken. It may be advantageous to reach an agreement with regulatory authority not to unblind and expedite reporting.
What key data elements should be included in expedited reports for serious adverse drug reactions?
Patient details
Suspected medicinal product
Other treatments patient was receiving
Details of Suspected ADR
Reporter of the event
Sponsor details
Key aspects of Phase II studies:
o Initial demonstration of efficacy in patients, short-term safety information
o Conducted in a relatively limited number (100-300) patients who have the disease
o Often involve hospitalized patients who can be closely monitored
o Many focus on dose-response, dosing schedule, or other issues related to preliminary safety and efficacy
o Takes about 1 to 3 years to complete
Key aspects of Phase 1 studies:
o Small trials with healthy subjects, purpose is to determine pharmacokinetics and maximum tolerated dose
o Conducted to determine the appropriate dose range with regard to safety and toxicity (not to evaluate efficacy)
o Conducted in a limited number (20-80) of health volunteers or patients (cancer, AIDS)
o Many compounds are abandoned in this phase because of safety/toxicity problems
Key aspects of Phase III studies:
o Use in large numbers of patients, long-term safety data
o Conducted in larger (several hundred to several thousand) and more diverse groups for whom the drug is ultimately intended
o Make comparisons between new treatment and standard therapy or placebo
o Study drug used by practicing physicians in the same manner as it would be used after marketing
o Takes about 2 to 5 years to complete
Key aspects of Phase IV studies:
o Post-marketing, continue assessing therapeutic value and monitor less common adverse events
What does CAPA stand for?
Corrective and Preventative Action Plans
What is a significant risk device? (4)
A device that:
1) is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject.
3) is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject
4) Otherwise presented a potential for serious risk to the health safety, or welfare of a subject.
When a sponsor intends to conduct a clinical investigation with an exception from informed consent for emergency research, what must be done?
Sponsor shall submit a separate IND for such investigation.
The sponsors request for a regulatory hearing must be made within ___ of the sponsors receipt of FDA’s notification of nonacceptance
10 days
What are the responsibilities of Sponsors as outlined in 21CFR Part 812?
1) Gaining FDA and IRB approval before beginning the investigation
2) Selecting investigators and monitors
3) Informing investigators
4) monitoring investigations
5) Emergency Research
Can a sponsor make certain changes without prior approval of a supplemental application? If so what is the timeline? (812)
Yes – but the sponsor must notified the FDA within 5 days of the changes going in to effect.
Responsibilities of Investigators as outlined in 21 CFR Part 812
1) Awaiting approval.
2) Compliance.
3) Supervising device use.
4) Financial disclosure.
5) Disposing of device.
For IDE, when does a sponsor need to report an unexpected adverse device event?
10 working days.
For emergency use of a device, where immediate use of the product was required and the patient was not able to be consented, how long does the sponsor have to notify the FDA of the use of the product?
5 working days
For an Significant Risk IDE, how long after the date of finishing the clinical trail does a sponsor have to notify the FDA that they finished the clinical trial?
30 working days.
For non-significant risk IDEs, does the sponsor need to send a final report to FDA? How long after finishing a trial?
No, only to the IRB and within 6 months of finishing the trial.
For significant risk IDE, how long after finishing the clinical trial does the sponsor have to submit their final report?
Within 6 months of finishing the trial.
How often does the investigator need to provide an annual report to the sponsor for an IDE?
At least yearly (this is typically the same as the continuing review provided to the IRB).
For IDE, when and to who does the investigator have to submit a final report after finishing a clinical trial?
Investigator submits a final report to the Sponsor AND to the IRB within 3 months of finishing the trial.
For a significant risk or non-significant risk IDE, how often does a sponsor need to submit an annual report and to who?
For all IDE’s: At least yearly progress reports to IRB.
For SR IDE’s: At least yearly to IRB AND to FDA.
True or False. FDA Form 1572 is required for all trials.
False. Form 1572 is required for IND studies but not required for IDE. A generic doctor agreement is all that is required for IDE.
What is treatment use of an investigational device?
The sponsor can apply for a treatment IDE where the device can be used in treatment of patients who aren’t in the clinical trial. This is typically done in serious or life-threatening diseases/conditions where no other alternatives are available to benefit these patients.
When an unanticipated adverse device effect occurs, what needs to be done by the investigator?
Submit a report to the sponsor and IRB within 10 working days.
True or False. If the investigator uses the device without informed consent, they have 10 working days to report it to the sponsor and IRB.
False. They have 5 working days to report it to the sponsor and IRB.
how often must an IRB renew its registration?
Every 3 years.
How often should Registration info for an IRB be updated when a contact or chair person’s information changes?
Within 90 days after changes occur regarding the contact person who provided the IRB registration information or the IRB chairperson.
How long after an update is accepted by the OHRP does an IRB renew its registration?
Any renewal or update that is submitted to, and accepted by, OHRP begins a new 3 year effective period.
How soon should an IRB report to OHRP that it intends to disband?
An institution’s decision to disband a registered IRB which it is operating also must be reported to OHRP in writing within 30 days after permanent cessation of the IRB’s review of HHS conducted or supported research.
True or False. If an IRB gives a decision of disapproval, the investigator has an opportunity to respond in person or in writing?
True (Within 15 days)
An IRB consists of all institution professionals and the daughter of one of the institution’s deans as its non-institution member. Is this appropriate?
No. All IRBs must have a non-institutional member who can not be an immediate family member of a person affiliated with the university.
Who is required at IRB meeting for research approval?
A majority of members, including at least one non-scientific member.
How often does IRB continuing review occur?
No less than once a year.
What are the general characteristics of IRB submissions that qualify for expedited review?
They are no more than minimal risk or contain minor changes in previously approved research (of one year or less)
Under expedited review, how many IRB members are required in order to approve the research? What about disapprove the research?
Only one member is required to approve the research. However, if the member disapproves it must go through full IRB review in order to be disapproved or require changes.
If an IRB terminates or suspends the approval of research, who is notified?
Investigator, institutional officials and department/agency head.
In the IRB meeting minutes, if a vote was taken what must be recorded?
Action taken,
number of members voting for, against and abstaining,
the basis for requiring changes or disapproving research,
and a written summary of the discussion.
The written informed consent form should be signed AND personally dated by the ______ (or ________ if applicable) and the ________.
Subject (or LAR if applicable) and the person who conducted the informed consent discussion.
What happens during the informed consent process if a subject or LAR is unable to read?
An impartial witness needs to be present during the entire informed consent discussion. When the subject/LAR are orally consented, they sign and personally date the consent form and the witness signs and personally dates the consent form to attest that the information was accurately explained.
What are two publicized examples of ethical abuses in research?
Willowbrook studies (1956-1970) & Jewish Chronic Disease Hospital Study (1963).
What was the atrocity of the Willowbrook Studies?
Children with intellectual disabilities were deliberately infected with the hepatitis virus.
What was the atrocity of the Jewish Chronic Disease Hospital Study?
live cancer cells were injected into 22 cognitively impaired patients.
What was the problem with the Tuskegee Syphillis Study?
Black American men were unknowing subjects in the study; they were not told that they had syphillis, nor were they offered effective treatment when it became available in the late 1940s (penicillin)
What is the Investigator’s Brochure (IB) and what is its purpose?
The IB is a collection of clinical and nonclinical data on the investigational product relevant to the study. Its purpose is to provide investigators and other in the trial information necessary to comply with the protocol and understand the purpose for the trial.
According to ICH GCP, how often should the IB be reviewed?
At least annually and revised as necessary with compliance to sponsor’s written procedures.
Who is responsible for keeping an up-to-date IB?
The sponsor.
According to ICH GCP, what constitutes a Serious Adverse Event (SAE) or a Serious Adverse Drug Reaction (Serious ADR)?
Any untoward medical occurrence that:
Results in death
Is life threatening
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
According to ICH GCP, what is an Unexpected Adverse Drug Reaction?
Adverse reaction the nature or severity of which is not consistent with the applicable product information (Not in investigator’s brochure)
Adverse Event/Experience
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment
Adverse Drug Reaction (pre-approval)
all noxious and unintended responses to a medicinal product related to any dose should be considered an ADR
Adverse Drug Reaction (marketed medicinal product)
a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function
According to ICH GCP, whom are generally considered vulnerable populations?
Individuals whose willingness to volunteer may be or have a higher chance of being unduly influenced by their expected benefits of participating or perceived retaliation of not participating.
Severity
used to describe the intensity of a specific event (as in mild, moderate, or severe mycoardial infarction); the event iteself, however, may be or relatively minor medical significance (such as a severe headache).
Reporting time frame for ADRs (not fatal or life-threatening)
15 days after first knowledge by sponsor that case meets minimum criteria for expedited reporting
Who is responsible for documenting and explaining any deviation from the approved protocol.
The investigator or person designated by the investigator.
Reporting time frame for ADRs (fatal or life-threatening)
7 days after first knowledge by sponsor that case qualified, followed by complete as possible report within 8 additional calendar days
What is required for an investigator to implement a deviation from the protocol?
Approval of the change from the sponsor and IRB/IEC.
If immediate hazard to trial subjects is possible or the change is logistical/administrative, approval is not required.
What records should be maintained by the investigator or designated pharmacist in regards to use of the investigational product?
1) Delivery of the product to the trial site
2) Product inventory at the site
3) Use of what product by each subject
4) Return or disposition of unused product at the end of trial
5) ID’s, dates, quantities, batch/serial numbers, etc.
An investigator implements a deviation from the protocol to eliminate an immediate hazard to a trial subject without prior IRB/IEC approval. What must happen next?
-ASAP the change, reasons for the change and, if relevant, proposed protocol changes should be submitted to the:
A) IRB/IEC for review and opinion
B) Sponsor for agreement
C) Regulatory authorities (only if required)
True or False: The sponsor is responsible for investigational product(s) accountability at the trial site(s)
False. The investigator/institution is responsible.
If the trial is blinded, the _______ should promptly document and explain to the ________ any premature unblinding of the investigational product(s).
Investigator
Sponsor
Investigational product(s) should be stored as specified by the __________.
Sponsor.
When should an investigator revise a written informed consent form?
Whenever important new information becomes available that may be relevant to the subject’s consent. This should be approved by the IRB/IEC ahead of use.
How long should essential documents be retained by the investigator after marketing approval or discontinuation of the trial?
2 years.
According to ICH GCP, serious expected adverse events should be reported when and to who by the investigator?
Investigator should immediately report SAEs to the Sponsor. Detailed written reports should be submitted following the immediate report.
According to ICH GCP, the investigator should submit summaries of the trial’s status to the IRB/IEC how frequently?
At least annually or more often if the IRB/IEC requires it.
According to ICH GCP, the investigator terminates or suspends a previously active trial without prior agreement of the sponsor, who(m) should the investigator inform of this decision?
The sponsor and the IRB/IEC with a written explanation.
According to ICH GCP, the sponsor terminates or suspends a previously active trial, who(m) should the sponsor inform of this decision?
The sponsor informs the investigator, who in turn informs the IRB/IEC of the decision.
According to ICH GCP, an IRB/IEC terminates or suspends a previously active trial, who(m) should be informed of this decision?
IRB/IEC informs the investigator of this decision and the investigator, in turn informs the sponsor.
According to ICH GCP, what are the investigator’s responsibilities following the completion of a trial?
Investigator should provide the IRB/IEC and any relevant regulatory authorities with a final report.
What is considered significant equity interest?
If the PI gets interest/stock options or any other financial and equity interest during the time of the study and 1 year following completion of the study.
For a publicly traded company, this means more than $50k to PI, spouse or children.
What is considered a significant payment to an investigator in a covered clinical trial?
Payments to the investigator that have a monetary value over $25k (excluding research related payments) during trial or up to 1 year after completion.
If sponsor obligations are assumed by a contract research organization (CRO), is that CRO subject to the same regulatory action as a sponsor for failure to comply with any regulations?
Yes. In this case, all references to “sponsor” apply to the CRO to the extent of which the sponsor has given them one or more obligations.
What is considered a covered clinical trial?
A covered clinical trial is any submitted in a marketing application for the FDA proving the effectiveness of the drug/device or significantly contributes to product safety.
Before permitting an investigator to begin, the sponsor shall obtain the following from them:
1) Form FDA-1572: Investigator statement and commitment
2) Investigator CV
3) Clinical protocol (More extensive for Phase 2/3)
4) Financial disclosure information
What are the important components of Form FDA-1572?
IND numbers to be conducted by the investigator
Name and address of IRB responsible for review/approval of studies
Place where investigation will occur
Commitment by investigator to conduct the investigation according to relevant regulations
According to the ICH GCP, the sponsor should provide the investigator with what before entering into an agreement to conduct a trial?
The clinical trial protocol and an up to date investigator’s brochure. Should provide investigator with sufficient time to review these materials.
Does the sponsor or investigator submit the investigator’s brochure to the IRB? (And who keeps the IB up to date)
The Investigator. The sponsor is required to keep the IB up to date.
Who is responsible for selecting the investigator(s)/institution(s) for the investigation?
Sponsor
Who determines the proper storage temperature, condition, time and procedures for the investigational product?
Sponsor
The _____ is responsible for ongoing safety evaluation of the investigational product(s).
Sponsor
What should a sponsor monitor verify in an onsite visit in regards to the investigational product?
Storage times and conditions of investigational product (IP)
IP delivered to appropriate subjects
Subjects provided necessary instruction on use, storage, handling, etc. for IP
Receipt, use and return of IP is controlled and documented
Disposition of unused IP at trial sites is acceptable
Monitors are appointed by the _____.
Sponsor
True or False: According to the ICH GCP, The investigator should develop a systematic, prioritized, risk-based approach to monitoring clinical trials.
False. The sponsor should do this, not the investigator.
What is the purpose of trial monitoring? (3)
1) Ensure the rights and well-being of human subjects.
2) Ensure reported trial data are accurate, complete and verifiable from source docs.
3) Trial is conducted in compliance with trial protocol, GCP and regulatory requirements.
What is it called when a sponsor provides remote monitoring of the clinical trial site using a team of trained persons (e.g., data managers, biostatisticians)
Centralized monitoring
What should the monitor verify in relation to clinical report forms (CRFs)?
Data is reported accurately and consistent with source docs
Any dose/therapy modifications are documented
Adverse events, concomitant meds, and intercurrent illnesses are reported according to protocol
Missed visits, tests not conducted and exams not performed are clearly reported in CRF
Withdrawals and dropouts of enrolled subjects are reported and explained
What is a monitoring plan?
Plan created by the sponsor tailored to subject protection and data integrity risks of the trial. This includes a monitoring strategy, responsibilities of the party, methods to be used, and rationale for their use.
What is included in a monitoring report?
Date, site, monitor, investigator’s name
Summary of what was reviewed and any significant findings
Actions to be taken or actions recommended to secure compliance
Monitoring report should be reviewed and documented by sponsor’s designated representative
According to ICH GCP, how long after discontinuing clinical development of an investigational product does the sponsor maintain sponsor-specific essential documents?
2 years.
According to ICH GCP, what information should be in the investigator agreement obtained by the sponsor?
1) Assurance that the investigator will comply with GCP, FDA, OHRP, etc. requirements
2) The investigator will comply with data recording / reporting policies
3) Investigator allows monitoring, auditing and inspection
4) Retention of essential documents by the investigator
According to ICH GCP, if an sponsor discontinues clinical development of an investigational product, who does the sponsor notify?
All investigators/institutions and regulatory bodies (FDA).
True or False: The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
True. Sponsor ultimately responsible for updating IB and notifying everyone with new safety information.
Generally, what is the responsibility of the sponsor in performing a clinical investigation?
Selecting qualified investigators and providing them with everything required to perform the investigation
Monitoring the trial and ensuring the trial is conducted correctly (protocol, GCP, FDA regs, etc.)
Maintaining the IND ensuring FDA is informed of any new risks
