Biological Products

Review of Adverse Events

A sponsor must ''promptly review all information relevant to the safety of [a] drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations". 21 C.F.R. § 312.32(b). The safety information that sponsors receive from clinical investigations often is in the form of reports relating to experiences of the clinical study subjects.

In contrast to the criteria for sponsor reporting of adverse events to the FDA, the regulations specify different criteria for what investigators must report to the Investigational New Drug (IND) sponsors. An investigator has no obligation to report adverse events to the FDA. Under FDA regulations, investigators must only evaluate adverse experiences based on two criteria: whether the event is serious and whether it was caused by the drug. FDA regulations require investigators to ''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 adverse effect immediately.'' Id. at § 312.64(b).

Depending on several criteria discussed below, FDA regulations provide two mechanisms for reporting adverse event and other safety information about investigational drugs to the Agency. Sponsors report adverse experiences to the FDA either as (1) an expedited report, or (2) as part of an IND annual report. 21 C.F.R. §§ 312.32-33. Adverse experiences that are not reported to the FDA under one of these two mechanisms are usually included in listings submitted to FDA as part of a final study report.

Expedited Reports—Telephone and Written IND Safety Reports

The goal of expedited safety reporting is to ensure timely communication to the FDA of the most important new information about the safety of investigational drugs. 52 Fed. Reg. 8798, 8815 (1987). There are two types of expedited reports: telephone IND safety reports and written IND safety reports. 21 C.F.R. § 312.32(c). Sponsors must make a telephone IND safety report to the FDA as soon as possible, but in no event later than seven calendar days after the sponsor's initial receipt of the reportable information. Id. at § 312.32(c)(2). IND sponsors must submit written IND safety reports within 15 calendar days after the sponsor's initial receipt of the reportable information. Id. at § 312.32(c)(1).

Expedited reports are required for adverse events experienced by subjects taking investiga-tional drugs if the event is (1) serious, (2) associated with the use of the drug, and (3) unexpected. The regulatory standards for these three criteria are discussed below. Expedited safety reports also are required when the sponsor receives reports of pre-clinical findings that suggest significant risk for human subjects including reports of mutagenicity, teratogenicity or carcinogenicity. 21 C.F.R. § 312.32(c)(1)(i)(B).

Serious Adverse Events

The type of expedited safety report that is required depends on the seriousness of the event. A telephone IND safety report is required when an adverse event is fatal or life-threatening. A written IND safety report is required if the event is serious. Id. at § 312.32(c). FDA regulations define a serious adverse event for subjects receiving investigational drugs as one that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitaliza-tion may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient ... and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 21 C.F.R. § 312.32(a).

Because adverse events that are fatal or life-threatening are included in the definition of a "serious" event, they must be submitted to the FDA as a written report in addition to a telephone report.

Unexpected Adverse Events

Telephone and/or written IND safety reports are required only for adverse events that are unexpected. FDA regulations define an unexpected adverse drug experience with an investigational drug as one for which the specificity or severity ... is not consistent with the current investigators' drug brochure or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. Id.

Associated with the Use of the Drug

Neither telephone nor written IND safety reports are required for an adverse event unless it is associated with the use of the drug. For purposes of IND safety reporting, an event is associated with the use of a drug if "there is a reasonable possibility that the experience may have been caused by the drug''. Id. at § 312.32(a).

Follow-up Reports

In addition to reviewing promptly adverse safety information that it receives, an IND sponsor also must "promptly investigate" all safety information. Id. at § 312.32(d). If the investigation reveals additional "relevant" follow-up information, the information must be submitted to the FDA as soon as it is available. Id.

Determining the relevance of information is invariably a matter of judgment. In this case, relevant information is information that explains or clarifies the circumstances of the reported adverse experience. For example, each follow-up might include reports of autopsy findings or reports of their results of additional blood tests. 52 Fed. Reg. 8798, 8818 (1987).

If a sponsor initially determines that safety information does not meet the criteria for an expedited report to the FDA, but a subsequent investigation reveals that the information should be reported to the FDA, the sponsor must report it as soon as possible "and in no event later than 15 calendar days after the determination is made.'' 21 C.F.R. § 312.33(d).

Annual Reports

Sponsors also report adverse experiences with investigational drugs and preclinical findings suggesting a significant risk for human subjects to the FDA as part of the IND annual reports. FDA regulations require the IND sponsors to submit a summary of the status and progress of investigations each year within 60 days of the anniversary date on which the IND went into effect. Id. at § 312.33. A purpose of the requirement for submitting annual reports is to provide both sponsors and the FDA with insight into the status and progress of the studies conducted under an IND. 52 Fed. Reg. at 8819. In furtherance of this purpose,

FDA believes it is important periodically to aggregate all [adverse] experiences, whether or not the individual events are thought to be drug related, for review and analysis. Such groupings may show an increased incidence of an adverse experience or other problem that would not be readily ascertainable in a review of single, discrete adverse events. Id.

The regulations require that annual reports include a brief summary of the status of each clinical study that is in progress or completed. The information must at least include the total number of subjects who initially planned the study, entered into the study, completed the study as planned, and dropped out of the study for any reason.

The regulations also require that annual reports include a narrative or tabular summary of the most frequent and most serious adverse experiences by body system and a list of pre-clinical studies completed or in progress during the previous year. Id. at § 312.33(b). FDA regulations and the preamble to those regulations provide no guidance about what the Agency expects sponsors to include among the most frequent and most serious events. Sponsors also must list all patients who died during participation in the investigation and all who discontinued the study in association with any adverse experience, regardless of any conclusions regarding whether or not the event was related to the drug. Id. at §§ 312.33(b)(3)-(4). Annual reports also include a summary of all IND safety reports submitted during the preceding year. Id. at § 312.33(b)(2).

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