Appendix H: Food and Drug Administration Regulations Requiring Reporting of Adverse Events ( Research Involving Human Participants V1)
The regulations containing provisions related to adverse event reporting include:
- 21 CFR Part 56
- Institutional Review Boards
- 21 CFR Part 56
- Institutional Review Boards
- 21 CFR Part 310
- New Drugs
- 21 CFR Part 312
- Investigational New Drug Application
- 21 CFR Part 314
- Applications for FDA Approval to Market a New Drug
- 21 CFR Part 600
- Biological Products: General
- 21 CFR Part 803
- Medical Device Reporting
- 21 CFR Part 812
- Medical Device Reporting
(b) Safety reports. An investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the effect immediately.
[312.64(b) requires the investigator to report certain adverse effect to the sponsor. Life-threatening adverse drug experience, serious adverse drug experience and unexpected adverse drug experience are defined in 312.32(a), but adverse effect is not defined in Part 312. Therefore, the reporting requirement is open-ended.]
1 Annotations provided by P. Goebel, Office for Human Research Protections.
[The investigator is required to notify the sponsor of only probably drug-caused adverse effects. However, most sponsors require the investigator to report all adverse effects to the sponsor, no matter what the cause. This is probably because 21 CFR 312.32(b) and 21 CFR 812.3(s) appear to require the sponsor to know about all events that happen anywhere in the world both to people on study or just taking the drug. Recent FDA enforcement actions have reinforced this view.]
21 CFR 812.150 - Reports
(a) Investigator reports. An investigator shall prepare and submit he following complete, accurate, and timely reports:
(1) Unanticipated adverse device effects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect 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.
[Investigator informs the sponsor and his/her IRB, not all of the IRBs of a multi-site study. The Part 312 regulations do not include a time limit.]
21 CFR 812.3 - Definitions
(s) Unanticipated adverse device effect means any serious adverse effect on health or safety or 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 investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.
[The unanticipated adverse device effect definition (21 CFR 812.3(s)) requires reporting of certain unexpected effects.]
Back to Top
21 CFR 312.66 - Assurance of IRB review.
An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity [this wording is identical to 21 CFR 56.108(a)(3)] and all unanticipated problems involving risk to human subjects or others, [This wording is identical to 21 CFR 56.108(b)(1), which follows] and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.
21 CFR 56.108 - IRB functions and operations.
In order to fulfill the requirements of these regulations, each IRB shall: (b) Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of:
- any unanticipated problems involving risks to human subjects or others;
- any instance of serious or continuing non-compliance with these regulations or the requirements or determinations of the IRB;
- any suspension or termination of IRB approval.
[Any unanticipated problem is all-inclusive. It includes adverse events that occur at the investigator's study site, and adverse events that occur at all other institutions that are reported to the investigator by the sponsor. This section seems to require the investigator to notify the IRB of all unanticipated problems that occurred anyplace in the world.]
21 CFR 812.150 - Reports.
(a) Investigator reports. An investigator shall prepare and submit the following complete, accurate, and timely reports: (1) Unanticipated adverse device effects. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect 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.
Back to Top
21 CFR 312.32 - IND safety reports.
(b) Review of safety information. The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been previously reported to the agency by the sponsor.
[This review requirement is not limited to 'serious and unexpected' or to 'adverse events that may be caused by the drug,' but includes 'all information relevant to the safety of the drug....' Also, the requirement to review information 'from any source' is interpreted by sponsors to mean they are required to aggressively search worldwide for any event that may remotely be related to use of the drug.]
21 CFR 312.32 - IND safety reports.
d) Followup.
- The sponsor shall promptly investigate all safety information received by it.
- Followup information to a safety report shall be submitted as soon as the relevant information is available.
- If the results of a sponsor's investigation show that an adverse drug experience not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor shall report such experience in a written safety report as soon as possible, but in no event later than 15 calendar days after the determination is made.
- Results of a sponsor's investigation of other safety information shall be submitted, as appropriate, in an information amendment or annual report.
21 CFR 812.46 - Monitoring investigations.
(b) Unanticipated adverse device effects (1) A sponsor shall immediately evaluate any unanticipated adverse device effect.
Back to Top
21 CFR 312.32 - IND safety reports.
(c) IND safety reports. (1) Written reports - (i) The sponsor shall notify FDA and all participating investigators in a written IND safety report of: (A) Any adverse experience associated with the use of the drug that is both serious and unexpected; or (B) Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification shall be made as soon as possible and in no event later than 15 calendar days after the sponsor's initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a narrative format (foreign events may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological studies shall be submitted in a narrative format) and shall bear prominent identification of its contents, i.e., 'IND Safety Report.' Each written notification to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND. If FDA determines that additional data are needed, the agency may require further data to be submitted.
[The regulations require the sponsor to notify all investigators within 15 days. This may not allow time for the sponsor to analyze the significance of the adverse event. The adverse event report would be of greater value to the clinical investigator and the IRB if it included a judgement as to whether a change in the protocol or the informed consent should be made.]
(ii) In each written IND safety report, the sponsor shall identify all safety reports previously filed with the IND concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of the previous, similar reports.
[The adverse event reports that sponsors presently send to investigators and IRBs do not include an evaluation or if they do, the evaluation is so general as to be of little use to the IRBs in attempting to determine whether changes in the study or consent should be made.]
21 CFR 312.55 - Informing Investigators.
(b) The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means. Important safety information is required to be relayed to investigators in accordance with Sec. 312.32.
[This section requires sponsors to notify all investigators in a multi-site study of all adverse events or 'new observations.' New observations is a very general all-inclusive term.]
21 CFR 812.150 - Reports
(b) Sponsor reports.
(1) Unanticipated adverse device effects. A sponsor who conducts an evaluation of a unanticipated adverse device effect under 21 CFR 812.46(b) shall report the results to FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests.
21 CFR 812.150 - Reports
(b) Sponsor reports.
(1) Unanticipated adverse device effects. A sponsor who conducts an evaluation of a unanticipated adverse device effect under 21 CFR 812.46(b) shall report the results to FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests.
21 CFR 312.32 - IND safety reports
(c) IND safety reports. (1) Written reports - (i) The sponsor shall notify FDA and all participating investigators in a written IND safety report of:
- Any adverse experience associated with the use of the drug that is both serious and unexpected; or
- Any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Each notification shall be made as soon as possible and in no event later than 15 calendar days after the sponsor's initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a narrative format (foreign events may be submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological studies shall be submitted in a narrative format) and shall bear prominent identification of its contents, i.e., 'IND Safety Report.' Each written notification to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND. If FDA determines that additional data are needed, the agency may require further data to be submitted.
[The regulations require the sponsor to notify all investigators within 15 days. This may not allow time for the sponsor to analyze the significance of the adverse event. The adverse event report would be of greater value to the clinical investigator and the IRB if it included a judgement as to whether a change in the protocol or the informed consent should be made.]
(ii) In each written IND safety report, the sponsor shall identify all safety reports previously filed with the IND concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of the previous, similar reports.
[The adverse event reports that sponsors presently send to investigators and IRBs do not include an evaluation or if they do, the evaluation is so general as to be of little use to the IRBs in attempting to determine whether changes in the study or consent should be made.]
21 CFR 312.32 - IND safety reports
(c) IND safety reports.
(2) Telephone and facsimile transmission safety reports. The sponsor shall also notify FDA by telephone or by facsimile transmission of any unexpected fatal or
life-threatening experience associated with the use of the drug as soon as possible but in no event later than 7 calendar days after the sponsor's initial receipt of the information. Each telephone call or facsimile transmission to FDA shall be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND.
[Inconsistency: No requirement to notify each investigator of the 7 day reports, but each investigator must get a copy of the 15 day report. The 7 day report is for reporting more alarming situations.]
21 CFR 312.33 - Annual reports.
(b) Summary information. Information obtained during the previous year's clinical and nonclinical investigations, including:
- A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.
- A summary of all IND safety reports submitted during the past year.
- A list of subjects who died during participation in the investigation, with the cause of death for each subject.
- A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related.
21 CFR 812.150 - Reports
(b) Sponsor reports.
(1) Unanticipated adverse device effects. A sponsor who conducts an evaluation of a unanticipated adverse device effect under 21 CFR 812.46(b) shall report the results to FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests.
[Sponsors are required to send unanticipated adverse device effects directly to the IRBs, and to the investigators. The 10 working day time frame is inconsistent with the IND requirement of 15 calendar days.]