Miscellaneous Flashcards
By signing the 1572 the PI agrees to
1) Personally conduct or supervise the study
2) Protect the health and welfare of the subjects per 21 CFR 50
3) Report AEs to the sponsor
4) Ensure all staff on the study understand their obligations and commitments
5) Maintain adequate and accurate records and make them available for inspection
6) Ensure that an IRB compliant with 21 CFR 56 reviews the trial
7) Comply w/ requirements in 21 CFR 312 (Investigational new drug application)
What do sponsors do with completed 1572s?
Submit them to the FDA
What is 21 CFR 54 about?
Financial Disclosure
Per 21 CFR 54, what information must be reported by investigators to a company submitting a new drug application?
1) Compensation to the investigator in which the value of the compensation could affect the outcome of the study
2) A proprietary interest in the test product
3) Any equity interest in the sponsor of a covered study
4) Any equity interest in a publicly held company exceed $50K in value
What is the dollar limit for payments made to an investigator/institution a companies must disclose to the FDA when submitting a NDA?
$25,000 +
What is the time frame in which a sponsor is required to obtain financial disclosures from an investigator?
Before an investigator can participate in a trial until 1 year following completion of the trial
What is form FDA 3455 used for?
Disclosing financial interests
What is form FDA 3454 used for?
Certifying that there are no reportable financial interests
What is 21 CFR Part 11 about?
Electronic records - specifies processes that must be in place to ensure that electronic documents and signatures are equivalent to paper documents & handwritten signatures.
What are the requirements for a computer system to comply with 21 CFR Part 11?
- Computer systems with electronic records and signatures must ensure accuracy, reliability, and consistent performance
- Must use and maintain secure, computer-generated, time-stamped audit trails
- Include system checks so only authorized individuals have access to the system, can alter records, and perform operations
- Procedures must be established to ensure that records are retained for a period of time, in an appropriate format, and meet FDA requirements.
Required elements of a DOA?
- Names of study staff members and the responsibilities assigned to them
- Staff signatures w/ date
- PI initials and date
Form FDA 1572 is legally binding between the investigator and whom?
FDA
Which two CFRs cover informed consent?
21 CFR 50 and 45 CFR 46
Which CFR discusses broad consent?
45 CFR 46 (not included in 21 CFR 50)
Required elements for informed consent per 21 CFR 50 & ICH E6
1) The study involves research (purpose, duration, procedures, which procedures are experimental, group assignment)
2) Foreseeable risks, inconveniences and discomforts
3) Potential benefits
4) Alternatives procedures or treatments that may be advantageous (ICH E6 requires important risks/ benefits of the alternatives)
5) Confidentiality of records
6) Compensation for injury and access to medical treatments
7) Who to contact & contact details for more info
8) Voluntariness
9) ICH E6 (only; not FDA or HHS) requires outline of subject responsibilities
10) Subject payment
11) 21 CFR 50 (only) requires posting on clinicaltrials.gov
12) 45 CFR 46 (only) requires research collecting private health information or identifiable biospecimens to include either:
- statement that identifiers might be removed and data/samples used for future studies without further consent
- The samples, even with identifiers removed, will not be used or distributed for future research.
Additional required elements of consent if relevant
1) There may be risks that are unforeseeable
2) When participation may be terminated by the investigator
3) Additional costs to subject from participation
4) Consequences for withdrawal
5) Statement that significant new findings that may influence subject’s willingness to continue participation will be shared
6) Approximate number of subjects involved
For studies subject to HHS 45 CFR 46:
7) Biospecimens may be used for commercial profit and whether subject will share the profit
8) Statement re: whether clinically relevant research results will be shared and when
9) If study involves biospecimens, whether the research will or might include whole genome sequencing
Which regulatory body requires that the person obtaining consent sign and date the consent form?
ICH E6 (as opposed to HHS or FDA)
Which regulatory body/bodies require the subject/subject’s LAR receive a copy of the consent?
FDA requires they receive a copy. ICH E6 requires they be given a signed and dated copy.
If a consent is signed electronically which CFR should be considered?
The investigator must ensure the subject’s electronic signature fulfills the requirements of 21 CFR 11
The HHS and FDA issued joint guidance on the use of electronic systems for obtaining informed consent. What is one of the major topics made clear in this guidance?
That obtaining the subject’s informed consent ultimately lies with the investigator and cannot be delegated to an electronic system.
What is Form FDA 1571?
IND application
What form is used to apply for an IND?
Form FDA 1571
Which CFR/regulation/regulatory body requires a copy of a clinical trial’s consent form be posted publicly?
45 CFR 46. It is not required by the FDA or ICH E6
Which regulation requires the submission of a Form FDA 1572?
21 CFR 312. ICH does not require a document of this type.
Which regulation or regulatory body uses ALCOA-C?
ICH E6. It also requires that changes to source data be traceable, not obscure original entry, and should be explained if necessary.
What does ICH E6 require with regards to quality management?
ICH E6 requires that sponsors implement quality management system that uses a risk-based approach.
Which regulatory body addresses the role of a sponsor-investigator?
The FDA. ICH E6 does not directly address it.
What is the minimum primary information required by the FDA when labeling an investigational drug?
- Study name
- Name of study drug
- Subject study number
- How supplied (e.g. # of tabs per container)
- Dose per unit
- Lot number
- Batch number
- Federal statement limiting use to experimental studies
Minimum requirements for drug storage areas
- Sponsor-directed storage requirements are met
- Area is monitored w/ evidence of appropriate storage conditions (temp monitoring logs)
- Access is limited at all times
- Product is supplied only to subjects in the trial
- Accountability records are maintained
- Space is adequate
Humanitarian Device Exemption (HDE)
An application similar to a premarket approval (PMA) application, but for which the manufacturer does not need to provide evidence of efficacy. They are subject to restrictions on profitability.
Humanitarian Use Device (HUD)
Device intended to benefits patients with a diagnosed disease affecting fewer than 8,000 individuals in the US per year.
Investigational Device Exemption (IDE)
Submission that must be made to the FDA before conducting a clinical trial with certain types of devices.
Institutional Review Board (IRB)
A committee defined by the FDA regulations in, and subject to the requirements of, 21 CFR 56
Medical Devices
Intended to affect the structure or function of the body of man or other animals, and which does not achieve its primary intended purpose through chemical action within or on the body and which is not dependent upon being metabolized for the achievement of its primary intended purpose.
How does the FDA decide which center has jurisdiction for review and regulation of a combination drug-device product?
It considers the primary mode of action. It established the FDA Office of Combination Products (OCP) to assist with assigning an FDA center for products where jurisdiction is unclear.
What are the three FDA centers for review and and regulation of drugs and/or devices?
- CBER - Center for Biologics Evaluation and Research
- CDER - Center for Drug Evaluation and Research
- CDRH - Center for Devices and Radiological Health
When submitting applications to the FDA related to Device investigations the sponsor/investigator must state whether the investigation complied with what?
For studies w/in the US: 21 CFR 50, 56, and 812
For studies outside the US: GCP
Does the FDA require submission of IND Safety Reports for investigations of marketed drugs where an IND isn’t being used?
No - the sponsor would follow relevant post marketing safety reporting requirements
When does an investigator need to complete and sign a new 1572?
1) When an investigator is participating in a new protocol that has been added to the IND
2) When a new investigator is added to the study
For other changes to the info on a 1572, investigator should document in study records, and inform sponsor so they can update the IND. The 1572 itself doesn’t need to be revised, nor a new one completed and signed. (Per 2010 FDA Info Sheet re: 1572s)
What are the types of FDA inspections of a clinical investigator?
1) Study-oriented inspections - Sometimes called a “routine” inspection. Directed towards review of study data supporting a pending marketing application. The FDA picks the top enrolling sites and 10% of the remaining sites for inspection.
2) Investigator-oriented inspections - Sometimes called a “for cause” inspection. Directed at a specific clinical investigator conducting the trial. Typically they occur when there are complaints of known or suspected misconduct.
When is form 482 used?
The FDA provides form 482 (Notice of Inspection) to a site they are going to be inspecting.
What is form 483 for and when is it used?
The FDA may provide form 483 (Inspectional Observations) at the conclusion of an inspection. It is a list of deficiencies that they think need to be remediated.
When are FDA follow-up inspections normally completed?
If completed, they usually occur about 2 years after the initial inspection.
What is the timeline for responding to an FDA form 483?
15 business days. Response must be in writing.
What types of letters may the FDA sent after an inspection?
- A letter stating the FDA observed basic compliance with no violations (not always sent)
- An information or untitled letter - identifies deviations that do not meet the threshold for a warning letter
- Warning letter - identifies serious deviations that require correction and a written response. Warning letters are posted publicly on the FDA website.
Which regulatory groups support a risk-based monitoring approach?
Both the FDA and ICH
Types of federally-funded research that may be done using prisoners as subjects
- possible causes, effects, and processes of incarceration and criminal behavior
- prisons as institutional structures or prisoners as incarcerated persons
- conditions particularly affecting prisoners
- practices aimed at improving the health or well-being of prisoners
3 regulatory agency sponsors of ICH
European Union, Japan, United States
What 5 classes of products do the informed consent regulations apply? (test articles)
- drugs
- medical devices
- biological products
- electronic products
- food (including dietary supplements and infant formulas)
- color additives
Topic of 21 CFR 312
INDs
Topic of 21 CFR 812
IDEs
When does an SAE have to be reported to the FDA within 15 calendar days?
When it fits all SAE criteria but is not life-threatening and does not result in death.
Topic of 21 CFR 50
Protection of Human Subjects / Informed Consent
Topic of 21 CFR 11
Electronic Records / Signatures
Where would you look to find official government information regarding GCP?
US Code of Federal Regulations
How many calendar days does a sponsor have to report a fatal or life-threatening unexpected adverse drug reaction?
7 Calendar Days
According to ICH guidelines, IRB must retain records for…
3 years
Topic of 21 CFR 56
IRBs
45 CFR 46 Part A
The Common Rule
Are devices intended solely for veterinary use exempt form IDE regulations?
Yes
Year of publication of FDA regulations
1980
Year HHS and FDA revised the regulations
1981
Year the common rule was published
1991
Year of GCP and HIPAA
1993
Year of OHRP
2000
Topic of 21 CFR 50 Subpart A
General provisions
Topic of 21 CFR 50 Subpart B
Informed Consent
Topic of 21 CFR 50 Subpart D
Additional Safeguards for Children in Clinical Investigations
