Source: https://www.fdalawblog.net/2011/03/effective-march-28-2011-new-safety-reporting-requirements-for-certain-drug-and-biological-products/
Timestamp: 2019-04-25 20:14:07+00:00

Document:
Effective March 28, 2011, sponsors and investigators of human drug and biological products subject to either an investigational new drug application ("IND") or bioavailability ("BA") or bioequivalence ("BE") studies exempt from IND requirements will have revised safety reporting requirements under the FDA regulations. FDA issued its final rule on September 29, 2010, which amends the IND safety reporting requirements under 21 CFR Part 312 and adds safety reporting requirements for persons conducting BA or BE studies under 21 CFR Part 320. 75 Fed. Reg. 59935 (Sept. 29, 2010).
FDA had published a proposed rule to revise its premarketing and postmarketing safety reporting regulations on March 14, 2003. The agency decided to bifurcate the premarketing and postmarketing safety reporting requirements in separate rulemakings, and this final rule focuses only on the premarketing safety reporting regulations. Simultaneous to finalizing the regulations, FDA issued draft guidance on the topic, “Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies,” and published a Q&A on the agency’s website. The revised requirements are designed to clarify and improve the quality of safety information reported to FDA, harmonize international reporting standards and definitions, and improve safety monitoring by sponsors and investigators. However, the regulations appear to impose a greater burden on sponsors to determine when an adverse event is reportable.
An adverse event or suspected adverse reaction is considered a “life-threatening adverse event or life-threatening suspected adverse reaction” if, in the view of the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.
Prompt Review of Safety Information: Similar to the former regulations, a sponsor must continue to “promptly” review all safety information obtained from foreign or domestic sources. However, the sources of information listed in the regulation has expanded to include “any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.” Revised 21 C.F.R. § 312.32(b). The guidance recommends that the sponsor also conduct literature searches at least annually to find new safety information for reporting purposes.
Serious and unexpected suspected adverse reaction (Revised 21 C.F.R. § 312.32(c)(1)(i): the event must be serious, unexpected, and suspected adverse reaction. Under the revised reporting requirements, the definition of “suspected adverse reaction” imposes a greater burden on sponsors to determine whether the drug caused the event.
Findings from other sources (Revised 21 C.F.R. § 312.32(c)(1)(ii)): the event must suggest a significant risk in humans exposed to the drug. Other sources may include epidemiological studies, pooled analysis of multiple studies, and clinical studies other than those conducted under the present IND.
Findings from animal or in vitro testing (Revised 21 C.F.R. § 312.32(c)(1)(iii)): the event must suggest a significant risk to humans exposed to the drug. This requirement expands a sponsor’s reporting obligations to include findings from in vitro studies. Findings from carcinogenicity, mutagenicity, teratogenicity, and other organ toxicity studies are types of studies that could reveal a significant risk. The guidance advises sponsors to determine whether the finding suggests a significant risk to humans or is too early to interpret without further investigation.
Increased occurrence of serious suspected adverse reactions (Revised 21 C.F.R. § 312.32(c)(1)(iv)): any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The decision about whether to report depends on several factors, including study population and the nature and seriousness of the event.
Submission of Unexpected Fatal or Life-Threatening Risks: Similar to the former regulations, a sponsor must continue to notify FDA of any unexpected fatal or life-threatening suspected adverse reaction within 7 calendar days after the sponsor’s receives the information. Revised 21 C.F.R. § 312.32(c)(2).
Reporting of Certain Study Endpoints: FDA clarified that study endpoints must not be reported as IND safety reports for trials that are designed to evaluate the effect of the drug on disease-related mortality or morbidity. Revised 21 C.F.R. § 312.32(c)(5). The sponsor must report study endpoints to FDA as described in the protocol. However, if a serious and unexpected adverse event occurs for which a causal relationship between the drug and the event is suggested, the event must be reported under § 312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction even if it is a component of the study endpoint.
Unblinding: FDA acknowledged that breaking the blind may be necessary to determine the reportability of serious, unexpected, suspected adverse reactions. Knowledge of the treatment may provide important safety information and could impact the ongoing conduct of a clinical trial. If the sponsor believes that breaking the blind may compromise study integrity, the sponsor can propose an alternative reporting format to maintain the blind.
Investigator Reporting Requirements: FDA’s revised regulations imposes additional investigator reporting requirements. Under the final regulations, investigators must report immediately to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and the report must include a causality assessment. Revised 21 C.F.R. § 312.64(b). Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, investigators are required to report the event immediately to the sponsor.
Bioavailability and Bioequivalence Studies: Under the former regulations, certain in vivo BA/BE studies in humans were exempt from the IND safety reporting requirements. The final rule contains safety reporting requirements for such BA/BE studies that are conducted in the United States. The person conducting the study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event that is observed in a BA/BE study. This requirement does not apply to human BA and BE studies exempt from the IND requirements that are conducted outside of the United States.
Timing of Safety Reports Submission: The timing of the safety reports remains unchanged. Safety reports must be submitted to FDA and all participating investigators no later than 15 calendar days after the sponsor or person conducting the study becomes aware of the event, except for fatal and life-threatening adverse events which must be submitted no later than 7 calendar days.
Format of Safety Reports: The format for IND safety reports is based on the type of expedited report; for individual case reports, a sponsor would use FDA Form 3500A, though FDA will accept foreign suspected adverse reaction reports on a CIOMS I Form. Revised 21 C.F.R. § 312.32(c)(1)(v). For reports of overall findings or pooled analyses, a narrative format must be used. FDA may require a sponsor or a sponsor may request to submit IND safety reports in a different format or frequency than that prescribed in the regulations. Revised 21 C.F.R. § 312.32(c)(3). For BA/BE studies, each report must be submitted on FDA Form 3500A or in an electronic format that FDA can process. Revised 21 C.F.R.§ 320.31(d)(3).

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