This article discusses past and present congressional legislation and FDA regulations pertaining to reporting dietary supplement adverse events. It also focuses on the value of post-market surveillance to protect consumers and defines and clarifies the regulatory professional's role in communicating product safety as technology continues to expand data access.
Current laws regarding Dietary Supplement (DS) regulation by the US Food and Drug Administration (FDA) are robust and comprehensive as they relate to the agency's ability to ensure a product's consumer safety. FDA has multiple areas of oversight and can exert regulatory authority to prevent or remove from market products or ingredients that pose a safety issue. In addition to premarket regulations identifying which ingredients are appropriate for the DS market, additional regulations ensure those ingredients are placed into formulated products within the framework of current Good Manufacturing Practices (cGMPs). FDA also enforces mandatory Adverse Event (AE) reporting requirements for manufacturers of dietary supplements and monitors other requirements of the Dietary Supplement and Nonprescription Drug Consumer Protection Act(DSNDCPA) of 2006, such as record keeping, data archiving, establishment of policies and procedures related to AE management and documentation, and timely submissions of required adverse events directly to the agency.1
Independent of obligations associated with FDA's regulatory oversight regarding AE management practices, manufacturers must implement internal systems of post-market surveillance based on sound principles of pharmacovigilance as related to monitoring reports of AEs. Regulatory professionals within the manufacturer ranks are routinely tasked with providing oversight for company sponsored AE programs. Understanding not only the regulatory landscape, but also application of pharmacovigilance principles specific to adverse events unique to dietary supplements is imperative for effective safety surveillance.
Principles of Dietary Supplement Pharmacovigilance and Post-Market Surveillance
As with all regulated industries, there is a need for government regulatory officials and regulatory professionals within the manufacturer ranks to monitor the safety of ingredients and the corresponding finished DS products to confirm, protect and ensure consumer safety. This has resulted in a regulatory framework to ensure FDA has appropriate jurisdiction over which ingredients can be included in a DS and remain in dietary supplements. There is also recognition that manufacturers must take an active role to ensure products meet their intended health benefits without unintended consequences. Accordingly, the overall framework for post-market surveillance includes a role for all stakeholders, including regulators, manufacturer regulatory professionals, healthcare professionals, consumers, and even product liability insurers. Given the unique characteristics related to ingredients, product design, marketing, sale, and promotion of DSs, there are additional implications for safety monitoring, including application of sound principles of pharmacovigilance designed to account for the product category difference as compared to drugs.
Ongoing monitoring and collection of surveillance data once the product is in commerce to document and/or identify potential safety issues is the cornerstone of effective post-market surveillance. Although AE regulatory reporting is a prescriptive process, post-market surveillance is a multifactorial, performance-based process whereby manufacturers, regulators, health professionals, the public at- large, and others monitor the performance and experience related to a given product's lifecycle in the open market. DS post-market surveillance is also a passive system of surveillance. There are no prerequisites for reporting and essentially all reports from consumers or health professionals to the manufacturer are voluntary and spontaneous. Only the manufacturer has a mandatory responsibility to report to FDA certain AEs.
To better understand what types of data are needed to monitor safety, it is imperative to understand what the goals of a post-market surveillance initiative that primarily involves direct-from-consumer reports of AEs should be, and what types of events one might be attempting to identify, manage, mitigate, or prevent. It is important for manufacturers and regulators to share common safety surveillance goals. Accordingly, the first step in establishing a system of surveillance is to define what the system should accomplish. For DSs, the list includes features highlighted in Table 1.
Table 1. Goals and Objectives of an Ideal DS Post-Market Surveillance System
|Ensures pre-market assessments or beliefs of inherent safety are realized during consumer use of the product.|
|Ensures known safety concerns have been identified, considered, and if appropriate, warned of on product labeling.|
|Ensures post-market surveillance system is sufficiently "sensitive" such that potential threats or safety concerns are included in the monitored events.|
|Ensures post-market surveillance system is sufficiently "specific" to allow detection, differentiation and ultimately determination of real vs. perceived threats.|
|Identifies intended and unintended use patterns that may potentially contribute to "unintended effects."|
|Allows assessment of how the product performs by itself or in the presence of other products or substances previously - or not previously - encountered.|
|Helps ensure effects in "unique" populations are considered when monitoring safety.|
|Further defines, documents, and confirms a relative "safety profile" for the product during real life use conditions.|
To achieve these goals and objectives, manufacturers must implement a corporate post-market surveillance program that includes best practice efforts to monitor product safety while also meeting mandatory reporting obligations.
Regulatory Requirements Related to Dietary Supplement Post-Market Surveillance
In 1994, the United States Congress enacted the Dietary Supplement Health and Education Act (DSHEA) that extended and further defined the regulation of DSs under the food provisions of the Food, Drug and Cosmetic (FD&C) Act of 1938.2, 3
DSHEA was intended to continue the regulation of DSs under the FD&C Act, but established separate safety requirements. Subsequent amendments further provided for additional authority by FDA to ensure the safety of supplements. However, the most significant regulation was the 2006 passage by Congress of the DSNDCPA, which required mandatory AE monitoring and the reporting of serious AEs by manufacturers to FDA.4
After congressional passage of the mandatory AE reporting legislation, FDA interpreted the legislation and provided manufacturers with guidance as to how the law would be interpreted and enforced by FDA once fully implemented.
There were many key features in the rules and regulations stating manufacturer requirements related to mandatory reporting of AEs. First, only "serious" AEs were included in the mandatory reporting component of the legislation. Although only serious AEs are required to be reported, the manufacturer is also obligated to document and assess each allegation of an adverse effect associated with a DS to determine whether it meets the criteria for serious and report to FDA within prescribed reporting timelines. For non-serious events, the manufacturer must maintain records of all information and communications regarding any allegation of an AE associated with the use of the company's products and ensure these records are saved and archived for a period of six years. They also were required to be available for inspection by FDA compliance officers upon demand. Key features of this regulation and implications for manufacturers are as follows:
The manufacturer, packer or distributor whose name appears on the label is responsible for the reporting obligations associated with this legislation. Retailers, whose names appear on labels, may send AE reports back to the manufacturer for those entities to complete the reporting process. FDA expects that there would be a written agreement in place indicating that this procedure has been agreed upon by both parties.
Data Collection and Maintenance of Records
The regulation specifies the responsible person shall maintain records related to each report of an AE.
Minimum Information for Incident to be Reportable
For an event to be subject to a reporting obligation, the following criteria must be met including:
- an identifiable patient
- an identifiable reporter
- a suspect product
- an adverse experience or fatal outcome suspected to be due to a product that is being used
In addition, FDA guidance on the legislation does not require the initial reporter be identified in reports, as some reporters may wish to remain anonymous based on privacy or other concerns. In this context, the reporter may request that the manufacturer keep their information confidential, but the manufacturer is still required to report the AE with patient identifiers redacted or indicated as "requested anonymity."
Collection Process and Role of Third Parties
The required reporting system utilizes the current prescription AE reporting process which entails the collection and submission of data using the current FDA MedWatch 3500a form. It was expected the form would be periodically modified by the Secretary of Health and Welfare to accommodate DSs. Although the form has not been changed to include DS specific information, an electronic submission portal has been created allowing manufacturers the option of either electronic or paper filing.
The Senate committee that drafted the intent of Congress as relates to this legislation also acknowledged that manufacturers of DSs that were responsible for reporting may not have the expertise to determine if an AE falls within the definition of "serious."5 The committee further recognized that many manufacturers had indicated they will contract the reporting function to a third party which has greater medical expertise. The legislation as drafted allowed such contracting for services.
Definition of AE vs. Reportable Serious AEs
Congress and FDA have defined an AE as "any health-related event associated with the use of a DS that is "adverse." The legislation further delineated exactly which allegations of adverse effects must be reported to FDA which includes any serious AE (SAER), defined as an adverse health consequence that results in any of the following:
- a life-threatening experience
- inpatient hospitalization
- a persistent or significant disability or incapacity
- a congenital anomaly or birth defect
- an incident that, "requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above"
Of note, FDA acknowledges that reported AEs are not intended to confirm or demonstrate causation and allows a disclaimer on Form 3500a to indicate submission of a SAER is not an admission that a product has "caused" the alleged AE.
Responsible parties are required to report to FDA each serious AE experience received as soon as possible, but in no case later than 15 business days of initial receipt of the information by the entity whose name appears on the product label (the day the minimum required elements are received counts as Day 0). Each report shall be accompanied by a copy of the current labeling for the product. Reports of medical updates to the original record also will be required to be reported within the same reporting timelines.
The legislation set forth requirements for record-keeping including the maintenance of records related to each report of an AE (serious or non-serious) received by the responsible person for a period of six years. These records must include raw data and any correspondence relating to the AE and if the applicant fails to establish and maintain records and make reports, FDA has the authority to apply sanctions.
FDA stipulated that clear deviations, such as failureto submit AE reports, inaccurate information including incomplete disclosure of available information, lack of written procedures, or failing to adhere to reporting requirements, will result in manufacture penalties. The penalties can include, but are not limited to, product seizure, injunction, and/or civil/criminal penalties.
For manufacturers to comply with the rules and regulations related to mandatory AE reporting, they must engage in a number of proactive steps to ensure reported allegations of adverse effects are properly documented and, when appropriate, submitted to FDA. Many necessary steps must be taken to ensure compliance - Table 2.
Table 2. Necessary Steps Dietary Supplement Manufacturers Must Take to Implement Post-Market Surveillance and Procedures for AE Regulatory Reporting
|Design or implement a FDA Part 11 compliant database to manage collected reports and ensure that all reports are maintained and/or archived for a period of six years.6|
|Design or adopt appropriate data fields within the database to allow capturing of incident details, coding and categorizing of reported events, and consistently applying regulatory criteria for severity outcomes that identify AEs potentially reportable to FDA.|
|Design an "intake system" (either internal or external) and develop policies and procedures for triage of all AE related communications to appropriate designated staff.|
|Conduct an organization-wide employee training program regarding AE policies and procedures to ensure that any company personnel that might be notified or contacted regarding an AE knows what to do and how to respond.|
|Establish internal policies and procedures to ensure that all "expedited reports" are filed within the required 15 business day reporting period.|
|Implement a system to manage and document all incoming incidents from all methods of consumer communications, including phone calls, e-mail, postal mail, phone calls, and company sponsored social media portals.|
|Hire or assign qualified medically trained personnel to manage and monitor AEs. |
Although not specifically required by legislation, civil laws related to product liability suggest it prudent for manufacturers to apply best practices to further refine and implement product specific safety strategies to monitor the AE reports received for any trends that might develop. This aspect of safety surveillance not only ensures a company is meeting regulatory requirements while monitoring the safety of their consumers, but also ensures business needs are met for continued consumer acceptance of the product and company financial viability.
Best Practices for Manufacturers Monitoring AEs for Safety Signals
Meeting regulatory requirements for reporting of "serious" AEs to FDA will ensure a manufacturer is not subject to enforcement actions related to under-reporting of AEs. But meeting regulatory reporting requirements alone will not ensure a product will not be the subject of a safety issue or violation. Safety or quality issues identified by either FDA or others may lead to further scrutiny of some or all of the incidents a manufacturer may have in its AE database. Accordingly, establishing best practices to not only meet regulatory requirements for reporting, but also to meet expectations of overall safety, is a critical element of post-market surveillance. As such, the goal of the AE surveillance system is to identify intended and unintended product use patterns or conditions that give rise to unintended adverse effects, and to characterize their relative incidence rates compared to market penetration, units sold, or other denominator-generating benchmarking data.
In some cases, regulatory professionals may be focused on the safety profile of a specific ingredient or blend contained in a product and miss signals that suggest other safety issues independent of the inherent safety of the product or its ingredients. Acknowledging the possibilities that may give rise to AEs is the first step to rapid identification and mitigation of risk should safety issues present themselves - Table 3. In addition to the listed items there also can be adverse effects associated with long-term use not been previously identified during short-term use of the product or ingredient under different circumstances.
Table 3. Examples of Product Issues Potentially Giving Rise to Adverse Events
|Quality control issues including pathogen contamination:|
- GMP breaches during manufacturing
- Product integrity breaches subsequent to or during market distribution
|Direct but predictable or previously recognized adverse effects based on inherent toxicology/pharmacology of the product or an ingredient including effects that are:|
- Dose dependent
- Dose independent (idiosyncratic)
|Direct but previously unrecognized toxic effect of the product or an ingredient that are:|
- Idiosyncratic, unpredictable in occurrence
- Long-term effects secondary to chronicity of use
|Interaction related event involving use of the product/ingredient and concomitantly involving:|
- Pharmaceuticals (Rx and OTC)
- Pre-existing or emerging disease
- Environmental toxins
- Biologic (gene expression) related effects
- Other non-drug consumer product
- Another botanical or DS ingredient not previously combined with the suspect ingredient
|Counterfeit Product: introduction of counterfeit versions of name brand products into the market by others with criminal intent for economic gain. These products may be adulterated and contain potentially harmful ingredients. Consumers and others may mistakenly attribute any reported AEs to unaffected and properly manufactured brand name products.|
A manufacturer should expect to engage appropriately trained and experienced medical personnel in the management and monitoring of the corporate AE experience, as encouraged in FDA's guidance on the subject.7 This includes assigning frontline staff with appropriate medical training to receive and document AE allegations according to standardized operating procedures. Some organizations may employ such staff internally, but seek outside experts to review and/or offer independent assessment of reported AEs to confirm findings. Other organizations may choose to engage outside professionals to perform and/or assist in the process, a practice endorsed and recommended by the Congressional Senate Committee during passage of the DSNDCPA of 2006.
Analyzing the AE Experience
Because of differing product profiles and consumer use patterns, spontaneously reported AEs involving DSs are typically quite different than AEs involving drugs. Of specific importance is that DS AEs are more likely to involve direct-from-consumer reports to the manufacturer rather than higher integrity reports made by medical professionals. Drug adverse effects are more likely to be identified and reported by healthcare professionals who monitor the safe and effective use of products they prescribe or recommend for their patients in practice or as part of a clinical trial. Compared to drug post-market surveillance a variety of other unique DS characteristics can influence or bias report quality and accuracy - Table 4.
Table 4. Factors Impacting Spontaneous and Other AE Reports – Drugs vs. Dietary Supplements
|Majority of AEs from clinicians, clinical trials, studies and anecdotal published case reports||Majority of suspected AEs "spontaneously" reported by consumers directly to the manufacturer|
|Products prescribed and/or recommended by "learned" medical professional monitoring drug effects and AEs (physician, pharmacist, nurse, etc.)||Consumer use through self-care and self-choice typically independent of medical providers|
|Use can be tracked and corroborated through pharmacy dispensing records and in some cases Therapeutic Drug Monitoring (TDM).||Reports of use must be taken at face value by the reporter and rarely can be corroborated through Therapeutic Drug Monitoring (TDM).|
|Usually single entity substance of well described identity and dose||Variation in individual ingredient profile for botanical extracts for which the full composition may not be described. For multiple ingredients in a proprietary blend, labeling is limited to identity and the total amount of all combined ingredients.|
|National compendium of products identified through pre-registration with FDA||No national compendium, registry or list of ingredients or products which can confound reports made by consumers or medical professionals|
|Possibility of toxicity/side effects expected and typically accepted by prescribers and patients||Toxicity/side effects unexpected and less acceptable to consumers|
|Manufacturer is intimately familiar with proprietary and/or published safety data from patented ingredient.||Manufacturer may rely on data from non-company products or ingredients and inherits risk from others manufacturing/selling same ingredient or similar combination of ingredients.|
These factors require manufacturers to institute screening processes for identifying adverse effects, more likely than not, signal a potential safety concern requiring further investigation.
Events potentially representing either a causal link or association, must be identified and separated from reports of injury or illness, which may be more representative of "background noise," loosely defined as coincidental or temporal occurrences or allegations of unrelated effects or illness. DSs may be prone to a higher percentage of incidents in the latter category as they often involve lifestyle wellness products routinely consumed over extended periods of time. As such, they may be erroneously associated with emergence of medical conditions more likely associated with life changes or aging.
Sorting out background noise requires screening of all AEs to identify those most productive in developing hypotheses regarding factors potentially contributing to the reported effects. Once identified, these incidents can be subjected to more intense investigation and comparison to other similarly evaluated events, this in an effort to develop and test hypotheses specifically designed to assess confirmation and causation of injury and evaluate potential methods of prevention similar to what may be done with drug AEs.
For example, AE reports should undergo high-level screening to assess potential relationships between product use and reported effects using standard factors of association including:
- biological, pharmacological, or physiological plausibility
- confounding variables
This nature of screening is critical for all direct-from-consumer reports of AEs, especially those not involving independent corroboration by medical professionals.
Assessment of Safety Data for Determination of Unreasonable Risk
Although legislation dictates it is the regulator's responsibility to determine if a DS product or ingredient in commerce is unsafe or poses an unreasonable risk to consumers, in many cases, it is the manufacturer who preemptively identifies products with safety or quality issues either before or after market introduction, and advises FDA of planned mitigations.8 Actions may include product withdrawal from market, reformulation, or consumer-level recall depending on the nature of the safety issue.
For both the regulator and the manufacturer to effectively monitor for product-related issues, a number of sources of data in addition to AE reports are routinely accessed by both the manufacturer and the regulators. Figure 1 highlights items typically monitored to assess risk and develop a health hazard evaluation to determine whether or not an "unreasonable risk" may exist regarding any DS product or ingredient in commerce.
Figure 1. Health Hazard Evaluation (HHE) Data Elements
In this context, each piece of information contributes to the overall assessment and allows for an informed opinion. There is no specific formula to determine the individual weighting of evidence suggesting a product poses an "unreasonable risk." Rather, an overall weight of evidence approach is used. Typically, multiple streams of evidence are required to establish a pattern of concern. It is unusual that any one data stream establishes "unreasonable risk" for a given product or ingredient, but it can happen, as in the case of confirming laboratory analysis (e.g., identifying pathogen contaminants) or a limited clinical trial that identifies a reproducible, statistically and clinically significant adverse clinical effect. Unfortunately, clinical trials are often not significantly powered or involving sufficient numbers of subjects to identify either serious or non-serious adverse effects that affect small numbers of exposed populations. This leaves the post-market surveillance system as an important "safety net" to aid in the identification of safety issues.
Regulators routinely monitor marketed products to identify signals, sentinel events, supporting research or other factors suggesting a safety issue exists. Throughout this process, the manufacturer also may be called upon to provide data or other information to support, explain, and otherwise scrutinize information signaling a suspected safety issue. In this context, the manufacturer's regulatory professionals and their risk management colleagues must use their intimate familiarity with the product, its design, and ingredient combination to further investigate safety whether concerns or signals may exist. If the signal was generated by FDA when evaluating AEs submitted by the manufacturers and others, the manufacturer can evaluate the balance of AEs in their system to aid in the evaluation. This becomes crucial as regulators are often left to draw conclusions regarding safety related concerns based on small numbers of submitted spontaneously reported events, which are typically limited to allegations of "serious" adverse effects. This is especially an issue when regulators may not be familiar with market penetration, incidence rates, or other denominator considerations related to market distribution of a given product. In order for manufacturers to adequately address safety signals that may be identified in one or more of the listed information venues, manufacturers should be prepared to provide the following post-market surveillance information details including:
- provision of normalized to sales incidence rates for all allegations of AEs broken down by age and outcome
- historical incidence rates used to determine an acceptable range for likely events and identify unexplained variations to that range in any given time period
- an up-to-date product/ingredient dossier documenting the known toxicology or pharmacology of the product or its ingredients
- identification of incidents potentially signaling a safety issue as well as those reported AEs more likely to be representative of background noise and why
- an assessment regarding the level of concern for any identified AEs and provide an evaluation of likely adverse health impact to consumers using the product
As regulators, manufacturers and other stakeholders review post market-surveillance data, it is important that regulators and manufacturers understand the importance of having a "sensitive" reporting system. An effective post-market surveillance system should encourage and accommodate all consumers wishing to report to the manufacturer or regulator any event where there is a suspected relationship between product use and any unexpected or spontaneously appearing adverse health condition. It is equally important that all stakeholders recognize that appropriately designed and sensitive surveillance systems will demonstrate a high level of "background noise." Given the high level of "background noise" in data collected exclusively through spontaneously reported post-market surveillance systems, these data should not form the primary basis for determining that a safety issues exists; rather, this nature of data should be used to create or support a safety hypothesis generated or being further investigated in one or more of the remaining data information venues.
Future Challenges and Opportunities for Industry in Monitoring AEs
Recently, FDA released excerpts of AE reports received through FDA's Center for Food Safety and Applied Nutrition (CFSAN) AE Reporting System (CAERS) system.9 Although intended to increase transparency, the information is limited to four elements including demographic and administrative information and the CAERS report ID number; product information from the case reports; symptom information from the reports translated into MedDRA medical terminology; and patient outcome information from the reports. This new endeavor will undoubtedly have significant implications for manufacturers whose company name and products appear in the database along with the reports of adverse effects suspected to be associated with product use. Given the limited accompanying data and lack of any narrative, it will be difficult to determine what, if any, role the products may have played in the reported event. That kind of determination requires a more in-depth analysis of the events and all supporting documentation. Also, since FDA provides no indication of which reports have been assessed to represent a safety issue, the likelihood of data misinterpretation is significantly increased. It remains to be seen how releasing data in this format will impact safety surveillance for these products. Manufacturers will need to "mine" their own incident data to be prepared to respond to various stakeholders who rely on the CAERS data to draw safety conclusions regarding their products.
One new area of significant importance relating to AE reporting involves the Council for Responsible Nutrition (CRN) national program to create the Supplement Online Wellness Library (OWL).10 The Supplement OWL is an industry-wide, self-regulatory initiative to create a comprehensive product registry. Available to all stakeholders, this registry will aid in more accurate identification of supplement products suspected to be involved in AE reports. This will be especially relevant for correct identification of products for those AEs submitted directly to FDA by consumers or others. It also will aid in providing an accurate depiction of products in published reports involving supplement AEs. As technology continues to expand access to AE data involving DSs, the regulatory professional will continue to play a vital role in communicating supplement safety by being intimately familiar with all aspects of AE surveillance.
- Dietary Supplement and Nonprescription Drug Consumer Protection Act. FDA website. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/ucm148035.htm. Accessed 31 October 2017.
- Dietary Supplement Health and Education Act (DSHEA). https://www.congress.gov/bill/103rd-congress/senate-bill/784. Accessed 31 October 2017.
- Food, Drug and Cosmetic (FD&C) Act of 1938. https://www.congress.gov/bill/103rd-congress/senate-bill/784. Accessed 31 October 2017.
- Guidance for Industry: Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act. FDA website. https://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm171383.htm. Accessed 31 October 2017.
- S. Rept. 109-324 - Dietary Supplement and Nonprescription Drug Consumer Protection Act.https://www.congress.gov/congressional-report/109th-congress/senate-report/324/1. Accessed 31 October 2017.
- Op cit 4.
- Op cit 4.
- Op cit 2.
- FDA Notice of Posting Adverse Event Report Data Associated With Conventional Foods, Dietary Supplements, and Cosmetics on the Internet. https://www.federalregister.gov/documents/2016/12/07/2016-29277/posting-adverse-event-report-data-associated-with-conventional-foods-dietary-supplements-and?source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed 31 October 2017.
- Supplement OWL: Online Wellness Library. https://supplementowl.ulprospector.com/en/na/Nutritional. Accessed 31 October 2017.
About the Author
Rick Kingston, PharmD, is the president, regulatory and scientific affairs at SafetyCall International PLLC, a multidisciplinary healthcare firm academically affiliated with the University of Minnesota and focused on providing consumer product manufacturers' services in post-market medical surveillance and regulatory reporting support for adverse events. He is also a clinical professor of pharmacy at the University of Minnesota and an adjunct professor at the University of Mississippi, College of Pharmacy and its FDA co-funded National Center for Natural Product Research (NCNPR). His professional expertise spans the areas of consumer product post-market surveillance, natural product toxicology, clinical toxicology and pharmacology, injury prevention, poison control, and toxicology related regulatory policy. He can be contacted at email@example.com.
Cite as: Kingston, R. "Surveillance of Adverse Events for Dietary Supplements." Regulatory Focus. October 2017. Regulatory Affairs Professionals Society.