FDA Publishes Two Draft Guidance Documents on the Reporting of Serious Adverse Events Associated with OTC Drugs and Dietary Supplements

October 26, 2007

On October 15, 2007, FDA issued two Federal Register notices announcing the availability of draft guidance documents related to serious adverse event reporting for OTC drugs and dietary supplements.  The first draft guidance is titled “Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed without an Approved Application” and concerns the reporting of serious adverse events associated with certain Over-the-Counter (“OTC”) drugs.  The second draft guidance document is titled “Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act.”  Both draft guidance documents stem from the December 22, 2006 enactment of the Dietary Supplement and Nonprescription Drug Consumer Protection Act.  The reporting requirements described in the guidance documents become effective on December 22, 2007.

OTC Drug Draft Guidance

Consistent with FDC Act § 760, the OTC drug draft guidance provides that the “manufacturer, packer, or distributor whose name . . . appears on the label of an OTC drug marketed in the United States without an approved application . . . must submit to FDA any report received of a serious adverse event associated with such drug when used in the United States,” with a copy of the product’s label “on or within the package.”  The statutory reporting requirement does not apply to OTC “switch” drugs, such as CLARITIN (loratadine), approved under a New Drug Application (“NDA”) (i.e., either a 505(b)(1) NDA or a 505(b)(2) application).  In addition, retailers whose names appear on OTC drug labels may authorize the drug manufacturer or packer to submit these reports on the retailer’s behalf. 

In accordance with the requirements of the FDC Act, the draft guidance provides that “[s]erious adverse event reports received through the address or telephone number described on the product label, as well as all follow-up reports of new medical information, must be submitted to FDA no later than 15 business days after a report of a serious adverse event or the new medical information is received” (emphasis added).  The guidance clarifies, however, that “[a]lthough the [FDC Act] does not expressly provide a timeframe for serious adverse event reports that [are received] by other means (such as by e-mail or fax), the reporting of such adverse events is required by the plain language of [FDC Act §] 760(b)(1).”  Accordingly, FDA “strongly recommends” that all such reports be submitted to the Agency within 15 business days of their receipt.      

The draft guidance duplicates the FDC Act’s definition of “serious adverse event” – that is, (1) death, (2) a life-threatening experience, (3) inpatient hospitalization, (4) a persistent or significant disability or incapacity, or (5) a congenital anomaly or birth defect – but clarifies that “[i]npatient hospitalization includes initial admission to the hospital on an inpatient basis, even if released the same day, and prolongation of an existing inpatient hospitalization.”  Furthermore, the draft guidance indicates that, at a minimum, each serious adverse event report requires: (1) an identifiable patient; (2) an identifiable reporter; (3) a suspect drug; and (4) a serious adverse event or fatal outcome.  The draft guidance clarifies these elements in detail.  In addition, the draft guidance advises that companies should “actively seek information on any minimum data element not initially provided . . . and wait to submit a report on the incident to FDA until the information is obtained.”   However, FDA guidance is not legally binding, and as a practical matter, compliance with this advice could prove difficult.  The FDC Act requires that companies maintain records related to reports of any adverse event, whether serious or not, for 6 years.

According to the FDC Act, new medical information related to a previously submitted serious adverse drug event report must be submitted to FDA if the information is received within 1 year of the initial report.  The draft guidance provides direction on how to correct inaccurate information and highlight new information in follow-up reports. 

Reports must be made on FDA Form 3500A and can be submitted either by regular mail or electronically.   


Dietary Supplement Draft Guidance

The reporting of serious adverse events for dietary supplements is very similar to the reporting requirements for OTC drugs.  Dietary supplement serious adverse event reports must also be made using FDA Form 3500A, and the reporting timeframe is generally the same as well.  Unlike OTC drugs, however, the draft guidance for dietary supplement reporting states that FDA will only accept reports via regular mail (i.e., dietary supplement reports cannot be submitted electronically or by facsimile).  There appears to be no rational reason for FDA’s refusal to accept electronic filings for OTC drugs but not dietary supplements, and companies submitting comments on the draft guidance might insist on equal treatment for both OTC drugs and dietary supplements.  Companies that submit reports or simply store reports electronically should keep in mind, however, that such electronic reports are subject to FDA’s regulations pertaining to electronic records, 21 C.F.R. Part 11.

Serious adverse events for dietary supplements are defined the same as for OTC drugs, and the manufacturer, packer, or distributor whose name “appears on the label of a dietary supplement marketed in the United States is required to submit to FDA” all such reports “associated with use of the dietary supplement in the United States.” 

The “minimum data elements” that should be included in a serious adverse event report for dietary supplements are:  (1) an identifiable injured person, (2) an identifiable initial reporter, (3) identity and contact information for the reporting firm (i.e., the manufacturer, packer, or distributor), (4) a suspect dietary supplement, and (5) a serious adverse event or fatal outcome.  Both this draft guidance and the OTC drug draft guidance provide that FDA “encourage[s companies] to attach the following, as appropriate,” as part of the serious adverse event report:  (1) hospital discharge summaries, (2) autopsy reports, (3) relevant laboratory data, and (4) other critical clinical data.  As with OTC drug serious adverse event reports, dietary supplement serious adverse event reports should not be submitted until all five elements listed above are obtained.  The FDC Act requires that all records relating to each report of an adverse event, which would include documented efforts that the companies make to obtain any missing information, be maintained for 6 years.  The draft guidance provides more detail on each of the five elements of a report.

The draft guidance provides that FDA Form 3500A must be used for the reporting of serious adverse events.  However, FDA Form 3500 can be used for the reporting of adverse events by consumers, health care providers, or any other entity that is not a dietary supplement manufacturer, packer, or distributor; a report of a non-serious adverse event by a company for one of its products; or to report a serious adverse event by a manufacturer, packer, or distributor for one of its products, where the company is not the “responsible person” (i.e., the company’s name does not appear on the label).

FDA will not confirm receipt of serious adverse event reports but “is working to implement processes that will provide a confirmation of receipt and [a] tracking number to the responsible person.”

By Cassandra A. Soltis