Effective March 28, 2011 – New Safety Reporting Requirements for Certain Drug and Biological Products

March 16, 2011

By Nisha P. Shah

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  Simultaneous to finalizing the regulations, FDA issued draft guidance on the topic, “Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies,” and published a Q&A on the agency’s website.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.


Under the existing IND safety reporting regulations, sponsors were required to notify FDA and all investigators of any adverse event “associated with the use of the drug” that was both serious and unexpected and any results from animal studies which suggested a significant risk for humans.  FDA believed that sponsors were reporting frequently serious adverse experiences for which there was little evidence of a causal relationship between the drug and the event.  The final regulations, available at Revised 21 C.F.R. § 312.32, set forth five new or revised definitions which help clarify when a safety report should be submitted:

“Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”

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.

An adverse event or suspected adverse reaction is considered “serious” if the investigator or sponsor believes any of the following outcomes may occur: “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. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require  medical or surgical intervention to prevent one of the outcomes listed in this definition.”

“Suspected adverse reaction” is considered “any adverse event for which there is a reasonable possibility that the drug caused” the event. “Reasonable possibility” suggests there is a causal relationship between the drug and the adverse event.  “Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”

An adverse event or suspected adverse reaction is “unexpected” if “it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.  The term ‘unexpected’ also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.”

Safety Reporting Requirements

The new definitions change when sponsors are to submit expedited safety reports and distinguish circumstances in which it is appropriate to submit individual cases compared to cases which should be aggregated and compared to a control group.  Below are some highlights of the final regulations and guidance:

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. 

Submission of Serious Risks: Sponsors will be required to notify FDA and all participating investigators in an IND safety report of potential serious risks from clinical trials or any other source within 15 calendar days after the sponsor determines that it is reportable. Revised 21 C.F.R. § 312.32(c)(1).  The sponsor must identify all other IND safety reports previously submitted to FDA concerning similar suspected adverse reactions and analyze the significance of the suspected adverse reaction in light of the other reports.  The sponsor must submit an IND safety report when any of the following criteria are met:

  1. 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. 

  2. 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.

  3. 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.

  4. 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).