Name of GuidanceGuidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies
Status of Guidance Draft
Release DateSeptember 2010
Link to the Guidancehttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf
Target AudienceSponsors and investigators conducting investigational new drug application (IND) studies or bioavailability/bioequivalence (BA/BE) studies.
Laws and Regulations Referenced (and what each Law states in relevant part)• 21 CFR 312.32(c)(1)(i)(A) and (B)—requires sponsors investigating a drug under an IND to submit a written safety report notifying the FDA and all participating investigators of any adverse event (AE) that is serious, unexpected, and “associated with the use of the drug,” and any finding from animal testing that suggests a significant risk for humans.
• 21 CFR 312.32(a)—defines the phrase “associated with the use of the drug” as meaning “there is a reasonable possibility that the experience may have been caused by the drug.”
• 21 CFR 312.53(c)(1)(vii), 312.66, and 56.108(b)(1)—require investigators to report to the investigational review board (IRB) all unanticipated problems involving risk to subjects.
• 21 CFR 312.32(b)—requires sponsors to review all information relevant to the safety of the drug.
Other Guidances Referenced• Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs—Improving Human Subject Protection (http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm079753.pdf)
• ICH E2A Guideline for Industry, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm073087.pdf)
SummaryThis guidance provides FDA recommendations regarding when and how to submit a safety report, defines terms used in safety reports, and provides clarification regarding other safety reporting issues.
RationaleOn September 29, 2010, FDA published a final rule changing IND safety reporting requirements (21 CFR part 312) and adding safety reporting requirements for BA and BE studies (21 CFR part 320).
The changes for IND safety reports were implemented because sponsors too frequently submitted safety reports for serious AEs that were unlikely to be related to the investigational drug. Although such reports consume resources of FDA, investigators, and IRBs, they provide no meaningful information about a drug’s safety. The final rule revises definitions for safety reporting and clarifies when and how to submit IND safety reports.
Certain in vivo BA and BE studies were previously exempted from IND safety report requirements. However, because the FDA has received important safety information from such studies, the final rule contains new safety reporting requirements for previously-exempt BA and BE studies.
Resulting RecommendationsThe final rule provides definitions for terms that are meant to be clear, consistent, and harmonious with international terms. The definitions are as follows:
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Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
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Adverse reaction means any adverse event caused by a drug.
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Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction.
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Unexpected refers to an adverse event, adverse reaction, or suspected adverse reaction that is not listed in the investigator brochure or is not listed at the observed specificity or severity; or, if an investigator brochure is not available, is not consistent with the risk information described in the investigational plan or the current application.
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Serious refers to an adverse event, adverse reaction, or suspected adverse reaction that, in the view of either the investigator or sponsor, results in any of the following: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or a congenital anomaly/birth defect.
Events that require medical or surgical intervention to prevent an outcome listed above may also be considered serious.
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Life-threatening refers to an adverse event, adverse reaction, or suspected adverse reaction that, in the view of either the investigator or sponsor, places the subject at immediate risk of death.
According to the final rule, it is the responsibility of the sponsor to review all new safety information relevant to the drug, whether from clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, unpublished scientific papers, foreign regulatory authorities, or foreign commercial marketing experience. Literature searches should be conducted at least annually.
If an IND safety report is required, the sponsor must submit it to FDA and all participating investigators no later than 15 calendar days after receiving the safety information. (Fatal or life-threatening adverse events must be reported no later than 7 calendar days after becoming aware of the occurrence.) In each IND safety report, the sponsor must analyze the significance of the suspected adverse reaction in light of any previously-submitted safety reports. Sponsors should periodically review their entire safety database, not only for IND safety reporting, but also to update investigator brochures.
An IND safety report is required when any of the following occurs:
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Serious and unexpected suspected adverse reaction. The event must be a suspected adverse reaction (as defined above) that is both serious and unexpected. Otherwise, it should not be submitted as an IND safety report.
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Findings from other sources. This includes findings from other studies, or any findings from animal or in vitro testing, that suggest a significant risk to humans. A finding that suggests a significant risk requires a protocol amendment to be submitted as well as an IND safety report.
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Increased occurrence of serious suspected adverse reactions. A clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure must be reported.
Other IND safety reporting issues include alternative reporting arrangements (must be agreed to in advance of the investigational study), investigator brochures (a serious suspected adverse reaction is considered unexpected if not listed in the investigator brochure; until the investigator brochure is updated, all subsequent, similar, serious suspected adverse reactions must be submitted as IND safety reports), and unblinding (if the blind was broken and the subject was receiving placebo, the event should not be reported in an IND safety report), investigator reporting (except for study endpoints, the investigator must immediately report all serious adverse events, drug-related or not, to the sponsor), and investigations of marketed drugs (the only reports that must be submitted as IND safety reports for a US-marketed or US-approved drug are those arising from a study conducted under the IND; all others should be reported per the relevant postmarket safety reporting requirements).
For IND safety reports for individual cases, a sponsor should use FDA Form 3500A. Foreign suspected adverse reaction reports may be submitted on a CIOMS I Form instead. A narrative format must be used for reports of overall findings or pooled analyses. The report must be submitted to the CDER (or CBER) review division responsible for review of the IND.
Persons conducting a BA or BE study must notify FDA and all participating investigators of any serious adverse event, drug-related or not, observed during conduct of the study, no later than 15 calendar days after becoming aware of its occurrence. This includes BA and BE studies exempt from the IND requirements under part 312 that are conducted in the US, but not those conducted outside the US. Serious adverse events observed in the investigational drug group and in the approved drug group must be reported. Fatal or life-threatening adverse events must be reported no later than 7 calendar days after becoming aware of the occurrence.
ImpactFDA’s impact analysis has determined the final rule is not a significant regulatory action and imposes a minimal burden on small entities (less than 0.2 percent of average shipment value for entities with less than 10 employees).1 Implementation of the final rule, and publication of this guidance, is expected to provide clarity for sponsors regarding IND safety report submissions, thus reducing the over- or underreporting of pertinent safety information.
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1. Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans. Fed Regist. 2010;75(188):59935-59963. To be codified at 21 CFR §312 and §320. Available at: http://www.gpo.gov/fdsys/pkg/FR-2010-09-29/pdf/2010-24296.pdf. Accessed on October 10, 2010.
