Food and Drug Administration Reporting Standards For Investigational Drugs and Biological Products

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Chapter: Pharmacovigilance: Legal Basis - United States

Food and Drug Administration Reporting Standards for Investigational Drugs and Biological Products


Review of Adverse Events

FDA regulations require the sponsor of an Inves-tigational New Drug (IND) to ‘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 informa-tion derived from any clinical or epidemiological investigations ’ (21 C.F.R. § 312.32(b)). The safety information that sponsors receive from clinical inves-tigations often is in the form of reports relating to experiences of the clinical study subjects.

An investigator has no obligation to report adverse events to the FDA and is only required to report adverse events to the sponsor. Under FDA regulations, investi-gators evaluate adverse experiences based on two crite-ria: whether the event is serious and whether it was caused by the drug. Investigators are required by the FDA’s regulations 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 spon-sors to report adverse event and other safety information about investigational drugs to the agency. Sponsors report adverse experiences to the FDA either as an expedited report or as part of an IND annual report (21 C.F.R. §§ 312.32–33). Adverse experi-ences 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 – Written and Telephone Investigational New Drug Safety Reports

The goal of expedited safety reporting is to ensure timely communication to the FDA of the most impor-tant new information about the safety of investigational drugs (52 Fed. Reg. 8798, 8815 (1987)). Expedited reports are required for adverse events experienced by subjects taking investigational 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 to human subjects including reports of mutagenicity, teratogenicity or carcino-genicity (21 C.F.R. § 312.32(c)(1)(i)(B)).

There are two types of expedited reports: written IND safety reports and telephone IND safety reports (21 C.F.R. § 312.32(c)). The type of expedited safety report that is required depends upon the seriousness of the event. A written IND safety report informs the FDA of an event associated with the study drug that is serious and unexpected (Id. at § 312.32.(c)(1)). IND sponsors must submit written IND safety reports within 15 calendar days after the sponsor’s initial receipt of the reportable information (Id.). A telephone IND safety report is required when an adverse event is fatal or life threatening (Id. at § 312.32(c)(2)). IND sponsors must make such a report to the agency as soon as possible but in no event later than 7 calendar days after the sponsor’s initial receipt of the reportable information (Id.).

Serious Adverse Events

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 hospi-talization 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 hospitalization may be considered to be serious adverse drug experiences when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical inter-vention 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 threat-ening 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 req-uired 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 investi-gational plan or elsewhere in the current application, as amended (Id.).

Associated with the Use of the Drug

An expedited IND safety report is not required for an adverse event unless the event 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 promptly reviewing adverse safety information that it receives, an IND sponsor must also ‘promptly investigate’ all safety information, regardless of whether the information meets the crite-ria for submitting an expedited safety report (Id. At 312.32(d)). If the investigation reveals additional ‘relevant’ follow-up information, then the information must be submitted to the FDA as soon as it is available (Id.). The preamble to FDA’s final rule sheds light on whether additional information must be submitted:

Determining the relevance of information is invari-ably 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 addi-tional blood tests (52 Fed. Reg. 8798, 8818 (1987)).

If a sponsor initially determines that safety informa-tion does not meet the criteria for expedited report-ing, but a subsequent investigation reveals that the information should be reported to the FDA, then the sponsor must report the information as soon as possi-ble ‘and in no event later than 15 calendar days after the determination is made’ (21 C.F.R. § 312.32(d)).

Annual Reports

As part of the IND annual reports, sponsors report all adverse experiences with investigational drugs and preclinical findings suggesting a significant risk for human subjects to the FDA. Food and Drug Admin-istration regulations require IND sponsors to submit a summary of the status and progress of investiga-tions each year, within 60 days of the anniversary date on which the IND went into effect (Id. at § 312.33). One 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 individ-ual 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 (21 C.F.R. § 312.33(a)).

The information must include, at a minimum, the total number of subjects initially planned for inclusion in the study, the number of subjects entered into the study as of the report’s date, the number who have completed the study as planned and the number who have dropped out of the study for any reason (Id.).

Annual reports must also include a narrative or tabular summary of the most frequent and most seri-ous adverse experiences by body system and a list of preclinical studies completed or in progress during the previous year (Id. at § 312.33(b)). Food and Drug Administration regulations and the preamble to those regulations do not specify what the agency expects sponsors to include among the most frequent and most serious events. The FDA has, however, issued guidance on good risk-assessment practices, includ-ing the generation, acquisition, analysis and presenta-tion of pre-marketing safety data [FDA CDER/CBER Guidance for Industry, Premarketing Risk Assessment (March 2005)]. Sponsors also must list in the annual report all patients who died during participation in the investigation and all who discontinued the study in association with any adverse experience, regard-less of any conclusions about whether the event was related to the drug (Id. at §§ 312.33(b)(3)–(4)). Annual reports must also include a summary of all IND safety reports submitted during the preceding year (Id. at § 312.33(b)(2)).

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