When can an exception be made for the requirement of informed consent?
n research situations where requirements for exception from informed consent are met for emergency research (21 CFR 50.24)
In treatment situations where an individual has a life-threatening condition and the following requirements are met and documented (21 CFR 50.23):
-The investigator, with the concurrence of another physician not directly involved in the care of the patient, believes the situation necessitates the use of a test article (in other words, an investigational drug, device, or biologic).
-The participant and/or LAR is unable to communicate consent.
-There is insufficient time to obtain consent.
-No alternative exists that will provide an equal or better chance of saving the participant’s life.
When can a PI obtain consent verbally?
In limited circumstances, the FDA regulations at 21 CFR 56.109(c)(1) allow for an investigator to obtain consent verbally without obtaining a signature on the consent form. The IRB/IEC must approve this consent process, which is referred to as a “waiver of documentation of consent.”
When study participation presents minimal risk to the participant and
The research involves no procedures requiring consent outside the context of participation in a research study.
FDA Final Rule for Waving and Altering Informed Consent
On 21 December 2023, the FDA (2023b) issued a final rule (effective 22 January 2024) allowing IRBs/IECs to waive or alter consent for a no more than minimal risk clinical investigation if the IRB/IEC determines that (21 CFR 50.22):
The clinical investigation involves no more than minimal risk (as defined in 21 CFR 50.3[k] or 56.102[i]) to participants;
The research could not practicably be carried out without the requested waiver or alteration;
If the clinical investigation involves using identifiable private information or identifiable biospecimens, the clinical investigation could not practicably be carried out without using such information or biospecimens in an identifiable format;
The waiver or alteration will not adversely affect the rights and welfare of the participants; and
Whenever appropriate, the participants (or LARs) will be provided with additional pertinent information after participation.
When can the IRB waive the requirement of assent?
1.The children are incapable of understanding the research;
2.There is a prospect of direct benefit to the children that is not available outside of the research; or
3.The requirements for a waiver of consent are met.
Consenting children
For research in which LARs are providing consent for participants, the participants should still be included in the consent process “to the extent possible and consistent with their desires and abilities.
H (2025) E6(R3) also requires investigators to obtain assent from children and reminds investigators to obtain consent from children who continue in a trial after reaching the age of majority.
Exemptions from the Requirement for an IND
As stated above, not every study using an approved drug requires an investigator-initiated/sponsor-investigator IND. According to 21 CFR 312.2(b) (Investigational New Drug Application 2014), investigations using a marketed drug or biologic do not require submission of an IND if all six conditions below are met:
1.It is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling for the drug.
2.It is not intended to support a significant change in the advertising for the product.
3.It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug.
4.It is conducted in compliance with the requirements for Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and informed consent.
5.It is conducted in compliance with the requirements concerning the promotion and sale of drugs.
6.It does not intend to invoke 21 CFR 50.24 (exception from informed consent for emergency research).
Humanitarian Device Exemption (HDE)
is an application that is similar to a premarket approval (PMA)(So FDA does have to approve) application, but for which the manufacturer does not need to provide evidence of efficacy. HDEs are subject to restrictions on profitability and can only be used in a facility after an IRB/IEC has approved their use in that facility, except in certain emergencies
ANSI/AAMI/ISO 14155:2020
There are also international guidelines and standards for conduct of clinical investigations of devices, including the “ANSI/AAMI/ISO 14155:2020 -Clinical investigation of medical devices for human subjects - Good clinical practice” commonly referred to as ISO 14155:2020. This international standard differs slightly from FDA regulations,
510(k) Devices
Section 510(k) of the Food, Drug, and Cosmetic Act requires a manufacturer to submit a Premarket Notification (the so-called 510[k]) to the FDA at least ninety (90) days in advance when the manufacturer wishes to market many Class I devices that are not exempt and all Class II devices in the U.S. The 510(k) must show that the device to be marketed is substantially equivalent to a legally marketed similar device by demonstrating that the new device is as safe and effective as the legally marketed device. Occasionally, the FDA will require a clinical investigation to determine the substantial equivalence. The 510(k) premarket notification requirements apply to almost all Class II devices, and Class I devices that are not exempt.
Exemption Criteria where a IDE is not required
A device, other than a transitional device, in commercial distribution immediately before 28 May 1976, when used or investigated in accordance with the indications in labeling in effect at that time.
A device, other than a transitional device, introduced into commercial distribution on or after 28 May 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before 28 May 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under Subpart E of 21 CFR 807 in determining substantial equivalence.
A diagnostic device, if the sponsor complies with applicable requirements in 21 CFR 809.10(c) and if the testing:
Is non-invasive;
Does not require an invasive sampling procedure that presents significant risk;
Does not by design or intention introduce energy into a subject; and
Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.
A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk.
A device intended solely for veterinary use.
A device shipped solely for research on or with laboratory animals and labeled in accordance with 21 CFR 812.5(c).
A custom device as defined in 21 CFR 812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.
How to qualify for an abbreviated IDE?
In order to qualify for an abbreviated IDE (21 CFR 812.2[b]), the study must fall under one of the following categories (unless the FDA has notified the sponsor that approval of an application is required):
An investigation of a device other than a significant risk device, if the device is not a banned device and the sponsor:
Labels the device in accordance with 21 CFR 812.5
Obtains IRB/IEC approval of the investigation after presenting the reviewing IRB/IEC with a brief explanation of why the device is not a significant risk device, and maintains such approval
Ensures that each investigator participating in an investigation of the device obtains from each subject under the investigator’s care, informed consent under part 21 CFR 50 and documents it, unless documentation is waived by an IRB/IEC under 21 CFR 56.109(c)
Complies with the requirements of 21 CFR 812.46 with respect to monitoring investigations
Maintains the records required under 21 CFR 812.140(b)(4) and (5) and makes the reports required under 21 CFR 812.150(b)(1) through (3) and (5) through (10)
Ensures that participating investigators maintain the records required by 21 CFR 812.140(a)
Complies with the prohibitions in 21 CFR 812.7 against promotion and other practices
An investigation of a device other than one subject to paragraph (e) of this section, if the investigation was begun on or before 16 July 1980, and to be completed, and is completed, on or before 19 January 1981.
Bioavailability (BA) and Bioequivalence (BE) Studies AE reporting
For BA and BE studies, the FDA and all participating investigators must be notified within fifteen (15) calendar days of any SAE observed during the conduct of the study, regardless of whether the event is considered drug-related (21 CFR 320.31[d][3] [Bioavailability and Bioequivalence Requirements 2014]).
FDA Bioresearch Monitoring Program
The Bioresearch Monitoring Program, a program of the FDA’s Office of Regulatory Affairs (ORA), was established to routinely inspect clinical investigators; investigative sites; Institutional Review Boards/Independent Ethics Committees (IRBs/IECs); sponsors, CROs, and monitors (also known as clinical research associates [CRAs]); and nonclinical laboratories.
These inspections help assess adherence to regulations and the protection of human research participants. Clinical investigator inspections usually take place after the New Drug Application (NDA) or Premarket Approval (PMA) has been submitted to FDA for marketing approval.
In the context of ICH GCP, what is the ‘investigator’s’ responsibility regarding a ‘Non-Therapeutic Trial’ involving subjects who can only be enrolled with the consent of a legally acceptable representative?
The investigator should be satisfied that the trial objectives cannot be met by means of a trial in subjects who can give informed consent personally. ICH GCP states that for non-therapeutic trials on subjects with LARs, the goals must be unattainable using subjects capable of consent.
21 CFR 312.53 (A)
Selection of investigators and monitors
21 CFR 312.60
PI Responsibilities
21 CFR 803
AE reporting for devices
21 CFR 820 Subpart C
Design controls
42 CFR 11
CT.gov
How long do IRB have to maintain study records after termination of research?
3 years
A ‘Serious Adverse Event’ (SAE) must be reported by the investigator to the sponsor within what timeframe according to ICH GCP?
Immediately.
Essential documents are defined by:
ICH GCP
Which action is considered noncompliance, not a deviation?
A. Missed visit window
B. Intentional enrollment of ineligible subject
C. Late lab collection
D. Missed signature
❌ Question 3
Your answer: D (Missed signature)
Correct answer: B (Intentional enrollment of ineligible subject)
Why this is a trap:
Deviation = unintentional or minor departure
Noncompliance = knowing/intentional violation
👉 Intentionally enrolling an ineligible subject = serious noncompliance
A missed signature = usually:
Documentation error
Possibly deviation
NOT inherently noncompliance unless systemic/intentional
During a monitoring visit, the monitor discovers subjects were re-consented using an outdated IRB-approved form, even though a newer version addressed added risks.
What is the MOST appropriate FIRST action?
A. Notify sponsor immediately
B. Re-consent subjects with correct version
C. Report to IRB
D. Stop enrollment
B.
Patient safety comes first! Also, the sponsor and IRB would both likely need to be updated.
