FDA CFRs and ICH GCP regulations
21 CFR 56.108(c)
Disapproval of a research can only be done with the non-expedited review procedure
21 CFR 312.62
FDA form 1572 also requires that the protocol be reviewed and approved by a complied IRB.
21 CFR 56.115(c)
FDA may refuse to consider a clinical investigation in support of an application for a research or marketing permit if the institution or the IRB that reviewed the investigation refuses to allow an inspection
21 CFR 312.53(d)
FDA regulations require that the monitor be qualified to monitor the progress of the trial through training and experience
21 CFR 312.60 and 21 CFR 812.110(b)
Failure to follow the investigational plan and signed investigator statement/agreement (e.g., failure to conduct or supervise the study in accordance with the relevant, current protocol(s)).
21 CFR 812.150(a)(1)
For device studies, this regulation requires that investigator reports any unanticipated adverse device effects to the sponsor and to the reviewing IRB as soon as possible, but no later than 10 working days after discovery.
21 CFR 312.69
For investigational product that also falls under Controlled Substances Act, this regulation requires that investigational product be kept in secure location with control access.
21 CFR 56.113
Terminate any research that is not being conducted following regulations or research that caused unexpected serious harm to subjects
21 CFR 312.55(a)
Before the investigation begins, a sponsor (other than a sponsor-investigator) shall give each participating clinical investigator an investigator brochure
21 CFR 312.53(c)
lists specific information from investigator prior to clinical trial participation
21 CFR 50.25
lists the basic elements of informed consent:
21 CFR 812
Investigational Device Exemptions (IDE) regulation
21 CFR 56.109(a)
Review, approve, or disapprove all research activities under its jurisdiction based on benefits and risks evaluation
Three primary responsibilities of an investigator:
1. Oversee conduct of the trial under appropriate regulation 2. Protect the rights, safety, and welfare of subjects 3. Control the use of investigational product
FDA Form 3454
A certification that no financial interests exists
21 CFR 812.5(c)
A device shipped solely for research on or with laboratory animals and labeled in accordance to this regulation
subpart E of part 21 CFR 807
A device that FDA deemed substantially equivalent to a device in criteria 1 above, and that is used following indications in the labeling FDA reviewed determining substantial equivalence.
21 CFR 312.59
A sponsor who discovers that an investigator is not in compliance should either secure compliance or discontinue shipments and end the investigator's participation. If the investigator's participation is ended, the sponsor should require that the investigator destroy or return the investigational drug and should notify FDA
21 CFR 50.25(b)(2)
Allows for an investigator to discontinue / withdraw the subject's participation in clinical trial
21 CFR 312.62(b) and 21 CFR 812.140(3) regarding source data:
Although FDA regulation does not specifically define source data and source document, it uses the term medical records in these regulations
21 CFR 56.110
An "expedited review" procedure can be used in IRB approval.
21 CFR 812.2(c)
An IDE exempt study
FDA Form 3455
Complete disclosure statement
21 CFR 56.109(f)
Conduct continuing review of research activities at least once per year
21 CFR 56.109(c)
Determine when and at what level of informed consent is required or waived
21 CFR 56
Covers IRB related topics
21 CFR 56.111(a)
Criteria that an IRB committee must find when approving a study
21 CFR 812.3(m)
Defines significant risk (SR) device as an investigational device
21 CFR 56.102(i)
Definition of Minimal risk research requirements
21 CFR 312.62(c)
Describes record retention requirement for an investigator
45 CFR 46 Subpart B
Describes regulations for participation of pregnant women in clinical trials.
45 CFR 46 Subpart D
Describes regulations to protect children participating in clinical research. For children who are pregnant, assent and permission are obtained
21 CFR 312.23(a)(5)
Describes the content that should be in the investigator's brochure (IB)
21 CFR 312.61
Describes the responsibility of an investigator for investigational product use and access in drug trials
21 CFR 812.140(3)(i)
Document informed consent
21 CFR 812.140(3)(iii)
Document treatment given to subjects
21 CFR 50.27(a)
Documentation of informed consent
21 CFR 50.27
Documentation of informed consent is required
21 CFR 50.20
Enrollment responsibilities for the investigator
21 CFR 50.24
Emergency research requirements
21 CFR 812.3(b)
Exemptions for a custom device as defined in this regulation, unless the device is being used to determine safety or effectiveness for commercial distribution.
21 CFR 809.10(c)
Exemptions for a diagnostic device, if the sponsor complies with applicable requirements
21 CFR 812.3
For medical device clinical trials, an unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects
21 CFR 812.140(b)(5)
For medical device trials, the sponsor is required to maintain records of adverse device effects (whether anticipated or unanticipated) and complaints
21 CFR 50, subpart D
For study involving children, an IRB must determine that the research study is in compliance with this regulation
21 CFR 812.40
General responsibilities for medical device clinical trial
21 CFR 312.53(c)(3)
Gives a list of items that a clinical protocol should contain
45 CFR 46.116(d)
If a child reaches the legal age of consent while enrolled in a study, unless the IRB determines that the requirements for obtaining informed consent can be waived, the child, who is now an adult should be re-consent for ongoing continuation in research.
21 CFR 54.4(a)
If there are financial interests involved, steps taken to minimize the potential for bias should be given to FDA
21 CFR 312.62(a)
In addition to secure storage, tracking usage and accounting for investigational product is also required by the regulations.
21 CFR 312.62(a) and 21 CFR 812.140(a)(2)
Inadequate accountability for the investigational product
21 CFR 312.62 and 21 CFR 812.140(a)
Inadequate record keeping
21 CFR part 50, 21 CFR 312.60, and 21 CFR 812.100
Inadequate subject protection, including informed consent issues.
21 CFR 312.3
Investigator means an individual who actually conducts a clinical investigation (i.e. , under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team.
21 CFR 50.25(a)(8)
Item 8 of the basic elements of informed consent allows a subject to discontinue / withdraw participation in clinical trial at any time without penalty or loss of benefits.
21 CFR 56.101
Maintain IRB compliance in term of its policies and standard of practice with the requirements of all relevant regulatory agencies
21 CFR 812.2(b)
NSR studies need to meet the abbreviated IDE requirements in this regulation. NSR studies do not required an IDE during initial IRB application submission.
21 CFR 50.20
No person can participate in clinical research without the person's or the person's legally authorized representative (LAR) consent
FDA Form 3500A
One way that an IND Safety Report can be submitted
1.46 and 1.47 of the ICH GCP guideline:
One way to prevent or reduce these errors is to develop quality assurance and quality control system for clinical trial conduct at site. -guideline definition of Quality Assurance and Quality Control
21 CFR 56.109(b)
Oversee informed consent process and all documents to be used to present to subjects (advertisement, fact sheets, etc.)
21 CFR 312.62(b), 21 CFR 812.140(a)
Prepare and maintain adequate and accurate case histories (e.g. case report forms, informed consent forms, source documents or medical records)
21 CFR 50
Protection of Human Subjets/Informed Consent
21 CFR 312.66 and 21 CFR 812.150(a)(4)
Protocol deviations (e.g., failure to appropriately document and report any medically necessary protocol deviations).
21 CFR 312.62(b), 21 CFR 812.140(3)(ii)
Record all observations and other relevant data (e.g. adverse events, previous medical history, test results)
21 CFR 312.62(b), 21 CFR 812.140(3)(i)
Record in case histories (e.g. source documents or medical records) that informed consent was obtained prior to participation in the study
21 CFR 56.115
Requires IRB to prepare and maintain documentation of IRB activities
21 CFR 56.108(a)
Requires IRBs to follow written procedures. This requirement includes the preparation, maintenance, and implementation of written procedures
21 CFR 812.140(a)(4)
Requires an investigator to keep records on study protocol with documents showing the dates of and reasons for each deviation from the protocol.
21 CFR 56.115(b)
Requires that IRB records be retained for at least three years after completion of the research.
21 CFR 312.64
Requires that an investigator immediately reports to the sponsor any serious adverse event (SAE), whether or not considered drug related, and must include an assessment of whether there is a reasonable possibility that the drug caused the event.
21 CFR 812.150
Requires that an investigator submits to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect (UADE) occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect.
21 CFR 312.64(b)
Requires that investigator reports any serious adverse events (SAEs), whether or not considered drug related, to sponsor immediately after discovery. This includes known SAEs that are listed in the Investigator Brochure or protocol
21 CFR 312.56
Requires that the sponsor review ongoing investigations
21 CFR 312.32
Requires that the sponsor then must notify FDA and all participating investigators of potential serious risks, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting
45 CFR 46.404
Research not involving greater than minimal risk
45 CFR 46.407
Research that is not otherwise approvable, but which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. The overseeing IRB must finds that the research presents an opportunity to further the understanding, prevention, or alleviation of a significant problem affecting the health and welfare of children. The research must also be done with sound ethical principles
21 CFR 312.32(b)
Sponsor is required to review all relevant safety information for the investigational drug that is available
FDA form 1572
Statement of Investigator: -required for the investigator to complete and sign prior to the start of the study. FDA form 1572 is a signed declaration of the investigator that he or she will comply with FDA regulations on clinical trial conduct.
45 CFR 46 Subpart A
The consent is obtained in accord with the required informed consent provisions
45 CFR 46.406
The intervention or procedure is likely to yield generalizable knowledge for the understanding or treatment of the subject's disorder or condition
21 CFR 812.110(c)
The regulations require that an investigator administer the investigational product or supervise appropriate staff who will be administering.
45 CFR 46.405
The relationship of risk to benefit is at least as favorable as any available alternative approach
21 CFR 312.55(b)
The sponsor should also update the IB and give the updated IB to investigator
21 CFR 312.33
The sponsor should make annual reports on the progress of the investigation
21 CFR 312.68
Time required to keep clinical trial records at site is: -2 years after FDA approval -2 years after study ended
45 CFR 46.409
When research involves greater than minimal risk with no direct benefit to subjects, the research must be either related to the children status as wards or be conducted in settings where majority of children involved are not wards,
21 CFR 56.108 (a) and (b)
Written procedures for the IRB
21 CFR 50.27(b) (2)
allow the use of a short form consent document.
45 CFR 46.117(b) (2)
allow the use of a short form consent document.
21 CFR 56.102(g)
defines IRB as: The Institutional Review Board (IRB) means any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects. The term has the same meaning as the phrase institutional review committee as used in section 520(g) of the act.
21 CFR 56.109
describes an approach for IRB review of research
21 CFR 54
describes financial disclosure required by clinical investigators
21 CFR 312.50
describes general responsibilities of sponsors
Section 4.9 of the ICH GCP guideline:
describes how an investigator should approach case report forms (CRFs) completion and maintenance of essential study related documents.
21 CFR 312.60
describes responsibilities of investigators
21 CFR 312.53(a)
describes specific requirements that sponsors should follow when selecting an investigator / clinical trial site
21 CFR 312.53 (c)
regulation lists clinical protocol as one of the items that the sponsor need to obtain from investigator prior to the start of the clinical trial, but it is generally the responsibility of the sponsor to generate and provide a protocol to investigator.
21 CFR 56.109
requirement that continuing review and re-approval of a research study is needed
21 CFR 312.33 and 21 CFR 812.150(b)(5)
sponsor is required under these regulations to submit annual reports to FDA on the progress of the clinical study (continuous review).
