Adverse Event Reporting for Dietary Supplements and OTCs: What is required and when? How does postm
No over-the-counter (OTC) drug or dietary supplement manufacturer wants a consumer to sicken, become incapacitated or otherwise be harmed by a company product. Further, no OTC drug or dietary supplement company wants even a suspicion that an adverse event has occurred in association with a company product. Such events, as undesirable as they are, do, however, happen. Considering the stance of the law regarding adverse events and planning a company response, not merely from a minimalist position, but from a proactive position can make all the difference in the world regarding outcome when the undesirable occurs.
Regarding the law, the Federal Food, Drug, and Cosmetic Act (FD&C Act) was amended by the Dietary Supplement and Nonprescription Drug Consumer Protection Act (Pub. L. 109-462, 120 Stat. 3469) on December 22, 2006. This new law addressed the reporting and recordkeeping of adverse events associated with dietary supplements and all non-prescription or OTC drug products not subject to application approval under Section 505 of the FD&C Act (i.e., OTC products marketed under monograph review in addition to non-monograph OTCs).
In October 2007, two months before the reporting requirements became effective, the Food and Drug Administration (FDA) issued guidance, “Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act”,[1] specifically for dietary supplement manufacturers, packers, and distributors. An updated version of these nonbinding recommendations was released later in June 2009. In July 2009, FDA issued separate guidance for nonprescription drug products marketed without an approved application, “Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed Without an Approved Application”[2].
In brief, the above guidance “recommends” that dietary supplement, nonprescription OTC and homeopathic drug manufacturers (i.e., non-monograph OTC drugs) keep adverse event reports (AERs) for a minimum of six years and submit all serious adverse event reports (SAERs) in addition to any new medical information obtained within a year of the initial SAER to FDA within 15 days of receiving such a report or information. It is also recommended that the responsible parties (i.e., manufacturers, packers, and distributors whose name(s) appears on the label) also submit a copy of the label of any dietary supplement or OTC associated with a serious adverse event (SAE) along with the initial report which should include at minimum: (1) the description of an identifiable patient (identified by age, age category, sex, initials, birth date, or name[3]); (2) the name, professional position, or contact information of the identifiable initial reporter (e.g., the patient, family member, doctor, pharmacist, etc. who first notified the responsible party); (3) the complete product name including brand and any known descriptive attributes of the suspect drug or dietary supplement; and (4) as detailed a description of the AE, SAE or fatal outcome as is possible, including signs, symptoms, diagnoses, and/or cause of death. For their parts, the FDA Center for Food Safety and Nutrition (CFSAN) and Center for Drug Evaluation and Research (CDER) have the authority under this provision to demand access to a firm’s records for inspection (Section 706 (e) of the Act).
What determines an adverse event? And what differentiates a serious adverse event? Adverse events and serious adverse events are defined by the FDA as follows:
An adverse event is defined as “any health-related event associated with the use of a dietary supplement that is adverse.” (Section 761(a)(1) of the FD&C Act (21 U.S.C. 379aa-1(a)(1))
A serious adverse event is “an adverse event that results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect; or requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above.” (Section 761(a)(2) of the FD&C Act (21 U.S.C. 379aa-1(a)(2)) [4]
What can happen when industry disregards or misinterprets the reporting of SAE? The most recent and comprehensive example would be that of Matrixx Initiatives, an OTC healthcare products company in Scottsdale, Arizona. In June 2009, Matrixx received a warning letter from FDA regarding the safety of two of its top-selling products: Zicam Cold Remedy Nasal Gel and Zicam Cold Remedy Gel Swabs (adult and kids size). The warning letter was FDA’s reaction to more than 130 reports the agency had received from consumers relating anosmia (the long term and potentially permanent loss of the sense of smell) and a number of additional complaints of a loss of taste with use of Zicam intranasal products containing zinc gluconate. In the letter, FDA also indicated awareness of more than 800 AERs regarding anosmia (noticed during a May 26-28, 2009 inspection) that consumers had made directly to Matrixx and that the company had not submitted to FDA (Tan Sheet, June 29, 2009). Although legal counsel for Matrixx is said not to have considered prolonged or potentially permanent cases of anosmia to meet the criteria of a SAE (Tan Sheet, June 22, 2009), this difference in opinion with the FDA has been costly. The warning letter was followed in rapid succession by a voluntary product recall, millions in lost revenue, and still lingering product liability and class action litigation (Tan Sheet, May 17, 2010).
Why postmarket surveillance? The development, distribution and regulation of dietary supplements, herbs and OTC drug products marketed without an FDA-approved application are handled differently than are prescription drugs. Based on the Dietary Supplement Health and Education Act (DSHEA) of 1994, FDA does not have the authority to conduct premarket reviews of safety or efficacy, but does have the authority to require Good Manufacturing Practices and postmarket surveillance. The primary reason for postmarket surveillance is that similar to prescription drugs and medical devices, the safety profiles of supplements and OTC medications evolve over their lifetime on the commercial market. Safety monitoring is therefore a necessary and ongoing process. Even after the rigorous approval process required for prescription drugs, it is broadly recognized that not all potential problems will have been identified premarket. The need for a postmarketing surveillance program is a direct consequence of the limitations of the preclinical and clinical trial phases. An active and proactive postmarketing surveillance program is also the best protection against AER action by FDA.
How to approach postmarket surveillance? For starters, be aware of the importance FDA places on reports of AE. To have a program that is prepared to respond to a consumer-submitted SAE, develop an active process for collecting and documenting detailed information for all complaints beyond the minimum recommended in an SAER submission to CFSAN or CDER. Place importance on the generation of complete reports that include medical conditions the consumer may have and/or other supplements, prescription or OTC drugs the consumer may also be consuming. Realize that postmarket surveillance has its limitations: AERs arrive in an isolated manner and can be difficult to place into context for a product an establishing causality or lack of a causal relationship to an AE can be challenging if not impossible. Finally, even if no consumer-reported complaints meet the criteria of being SAE, evaluate AEs on an ongoing basis – to identify potential trends and stay ahead of the curve. Finally, even if no consumer-reported complaints meet the criteria of being SAE, evaluate AEs on an ongoing basis – to identify potential trends and stay ahead of the curve.
References
[1] <http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm171383. htm >; site accessed March 3, 2011.
[2]<http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM171672.pdf>; site accessed March 3, 2011.
[3] If a name or address is given, any AERs and all SAERs that are not held internally should be assigned a code to protect privacy but still allow for cross-reference in case new medical information is received.
[4] <http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm072966. htm#adverse >; site accessed March 2, 2011.