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Vaccine Adverse Event Reporting System


Statement of

Joseph A. Levitt
Director
Center for Food Safety and Applied Nutrition
Food and Drug Administration
Department of Health and Human Services

before

the House Committee on Government Reform

May 27, 1999

INTRODUCTION

Mr. Chairman and Members of the Committee, my name is Joseph A. Levitt, Director, Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA or Agency). I am joined by Janice F. Oliver, Deputy Director, CFSAN and Elizabeth A. Yetley, Ph.D., Director, Office of Special Nutritionals, CFSAN. I am pleased to be here today to discuss FDA's adverse event reporting systems generally, and specifically, CFSAN's Adverse Event Monitoring System called SN/AEMS, which is for special nutritional products, including dietary supplements. In meeting the Agency's mission, one of our responsibilities is to monitor marketed medical products, foods, cosmetics, and dietary supplements for unexpected adverse events. FDA surveillance programs alert the Agency to potential threats to the public health and help Agency experts identify the need for preventive actions.

As Jane E. Henney, M.D., Commissioner of Food and Drugs, stated on March 25, 1999 during a hearing before this Committee, the Dietary Supplement Health and Education Act of 1994 (DSHEA) amended the Federal Food, Drug, and Cosmetic Act to define the term "dietary supplement" and to establish a regulatory framework for dietary supplements. DSHEA provides broad access to dietary supplements for consumers and recognizes that there is a need for a rational regulatory framework that provides FDA authority to remove from the market products that pose a "significant or unreasonable" risk to consumers and that are otherwise adulterated, and to require that labeling for dietary supplements be accurate. The SN/AEMS system is a critical part of FDA's ability to meet the consumer protection provision of the law. While the current system has served the Agency well thus far, we believe there are enhancements to the SN/AEMS system that certainly should occur. We welcome this opportunity to continue that dialogue with you.

BACKGROUND

Let me begin by providing a brief overview of the adverse event reporting system for drugs, highlighting the purpose and differences of that system compared to the system for special nutritionals, which include dietary supplements. Then, I will specifically discuss the system at CFSAN for monitoring adverse event reports for dietary supplements. For your information, a brief summary of the adverse event reporting systems for all other FDA-regulated products is included in an Appendix to this testimony.

As you know, FDA's responsibilities include postmarketing evaluation, which includes risk surveillance and assessment that rely primarily on two methods of adverse event reporting to the Agency: 1) direct, voluntary reporting by concerned parties, including health professionals and consumers; and, 2) mandated reporting by drug (including biologics) and device manufacturers, distributors, and medical device user facilities. Under the current system, FDA shares this responsibility with manufacturers, healthcare providers, user facilities, patients and consumers. Each participant has a role in monitoring and evaluating adverse events associated with medical products, foods, and cosmetics. The roles assigned to manufacturers and FDA are defined primarily by statute, while the roles of others are not.

The specific objectives of FDA's postmarketing risk assessment programs are to:

  • detect adverse events not previously observed,
  • for drugs, biologics, or medical devices, improve understanding of the potential severity of previously anticipated risks, listed on the product's labeling,
  • detect adverse events resulting from multiple possible interactions, such as drug interactions or drug-food interactions.

These reporting systems serve as an early warning signal for identifying potential problems.

CHANGES IN THE POSTMARKET SURVEILLANCE ENVIRONMENT

Changes are occurring in several areas that will affect the Agency's current postmarketing surveillance systems. First, the Prescription Drug User Fee Act and the FDA Modernization Act of 1997 have resulted in some changes in postmarketing reporting requirements. For example, with regard to medical devices, the Modernization Act directs FDA to move away from universal, mandatory adverse event reporting by user facilities to a system based on reporting by a representative sample of facilities.

In addition, shifts in the health care environment and in international marketplaces are affecting the potential for adverse events caused by medical interventions. For example, with patients now being treated by multiple healthcare providers, a single provider may not have full knowledge of the patient's medical history and use of various medicines and other products. A prescriber's lack of information can lead to increased risk of drug interactions, as one physician may not be aware of what another has prescribed or recommended. The dietary supplement industry has grown dramatically, as has consumption of dietary supplements. Surveys show that more than half of the U.S. adult population uses dietary supplement products. The increasingly global marketplace also could result in a greater potential for rapid, large-scale consumer exposure to new products, which carries a proportional potential for more unexpected adverse events. Finally, the rapid development of new medical interventions for a variety of previously untreatable (or less satisfactorily treatable) conditions results in more individuals using these new interventions. These shifts in the healthcare environment are challenging the existing system and should be considered as we examine FDA's adverse event reporting or monitoring systems.

ADVERSE EVENT REPORTING SYSTEMS

MedWatch

While the U.S. has one of the most rigorous premarket approval processes in the world, it is not possible to detect all potential problems during premarketing clinical trials of drugs and medical devices, or premarketing evaluation of the safety of food additives. In addition, not all products that FDA regulates require premarket approval--such as dietary supplements, conventional foods, and cosmetics. The need for postmarketing surveillance is the direct result of these limitations.

FDA receives spontaneous reports of suspected adverse events from manufacturers, user facilities, healthcare professionals, and consumers. Through a program called "MEDWATCH, the FDA Medical Products Reporting Program," healthcare professionals and consumers are encouraged to report serious adverse events and product problems to FDA, the manufacturer, or both. MEDWATCH has established four methods for the public to report to FDA: phone (via a toll-free number), fax (via a toll-free number), direct mail (using a postage paid form), and Internet (via the interactive form on the MEDWATCH website).

MEDWATCH was announced June 3, 1993. While FDA's longstanding postmarketing surveillance programs predate MEDWATCH, this educational initiative was designed to enhance the identification and reporting of adverse events related to the use of FDA-regulated products. Through the MEDWATCH program, health professionals can report serious adverse events and product problems that occur with such medical products as drugs, biologics, medical and radiation-emitting devices, and special nutritional products (i.e., medical foods, dietary supplements and infant formulas). When a health care professional suspects that a product may be related to a serious event, FDA encourages the health professional to submit a MEDWATCH report. Health professionals, however, are welcome to report any adverse event that they judge to be clinically significant.

Adverse Event Reports come into FDA in many ways--either through MEDWATCH, where they are transferred to the appropriate Center; directly to the Center; or through an FDA District or Field Office. Regardless of the path into the Agency, reports are directed to the appropriate Center to be recorded and reviewed.

Strengths and Limitations of Spontaneous Reports Data

For medical devices and drugs (including biologics) adverse event reporting or monitoring systems serve as critical tools to identify potential health hazards that were not anticipated or identified in pre-market safety evaluations. In the absence of premarket review data, the SN/AEMS serves as a critical source for gathering data about the safety of dietary supplements. These systems serve to augment, not replace, other systems and tools for determining the safety of products. Like all passive surveillance systems, however, there are strengths and certain limitations.

The strengths include:

  • Generation of Hypotheses and Signals: The great utility of spontaneous report-based surveillance programs is to generate signals of potential public health problems that warrant further investigation. For this reason, adverse event reports must be evaluated in the context of other information, which may include controlled clinical trials, case reports in the scientific literature, the known physiological and pharmacological effects of the substance suspected of being associated with adverse events, market and consumer surveys, and product analysis.
  • Clinician Contribution: Health professionals often identify and document adverse events in the clinical settings in which they work. They can provide in-depth information in the adverse event report, thereby providing key input to any postmarketing surveillance system. Thus, while possessing inherent limitations, postmarketing surveillance based on spontaneous report data from clinicians is a particularly powerful tool for detecting adverse event signals of direct clinical impact.

The limitations include:

  • Underreporting: Adverse events associated with product use are known to be significantly underreported, since many consumers and health professionals may not recognize a link between the use of a particular product and a subsequent injury or illness, or they do not report the adverse event to appropriate health care agencies. Indeed, because reporting is voluntary (except in the case of certain adverse events that childhood vaccine health care providers, device user facilities, and drug and device manufacturers must report), adverse events which are not reported almost certainly occur.
  • Report Quality: Under research protocols, information is collected in a systematic and standardized manner to test a particular hypothesis, and such protocols include numerous quality control procedures to assure reliability and validity of data collected. By contrast, a passive surveillance system is dependent on information contained in voluntary reports from consumers, family, friends, or from health professionals based on patient information and evaluations. FDA attempts to obtain follow-up data to add to the completeness, clarity, and relevance of a report that associates a clinically serious event with the use of regulated products. Success in obtaining such information, however, is variable. Thus, information received in a passive reporting system is not standardized and often is incomplete. Nonetheless, the reports provide valuable public health information on potential safety problems. Where there is a basis for concern, prudent public health policy leads FDA to take action to protect against unsafe uses of marketed products.
  • Adverse Event Recognition: An attribution between the product and the observed event may not be assumed with all spontaneously reported events. This consideration emphasizes the crucial need for careful, thoughtful review of adverse event reports upon their receipt by FDA or the manufacturer and the review of other available scientific information.
  • Biases: Unlike clinical trial data, which are obtained under strictly controlled conditions, spontaneously reported information is uncontrolled, and therefore subject to the possible influence of a number of biases that can affect reporting. These biases include the length of time a product has been on the market, country, reporting environment, and quality of the data.
  • Estimation of Population Exposure: As a general matter, accumulated case reports cannot be used to calculate incidence rates. Numerator and denominator limitations described above make incidence rates computed from spontaneously reported data problematic. Compounding these numerator limitations is the lack of denominator data, such as user population and product exposure patterns, that would provide the exact number of consumers exposed to the medical product, and thus at risk for the adverse event of interest. Even if the exposed population is not precisely known, however, estimation of the exposure can be attempted through the use of product utilization data, when it is available for the product. This approach, whose basic methodologies are applicable to medical products in general, can be of great utility. Such utilization data are not available, however, for dietary supplement products, and so making confident estimates of overall exposure in the population is generally not feasible.
FDA Evaluation of Reports of Adverse Events

The very nature of spontaneously reported data places great importance on the evaluation of submitted reports of adverse events. This process is perhaps most accurately characterized as a method, applied on a case-by-case basis, that is based on experience, knowledge of the product being monitored, and awareness of the strengths and limitations of the data.

Spontaneous reporting systems--Center for Drug Evaluation and Research

In the case of pharmaceuticals, FDA pays particular attention to all reported serious adverse events that are not in product labeling. Other reports are entered into the database for use in aggregate analysis. In focused evaluation of adverse events, the postmarketing surveillance database is searched for other reports, and further steps are taken, such as literature searches and use of medical product utilization databases.

Adverse Event Reporting System (AERS)

The Center for Drug Evaluation and Research (CDER) uses a passive, spontaneous reporting system to provide monitoring capability to detect rare and unexpected adverse reactions to marketed drugs. Data are generated primarily as "spontaneous" reports observed and reported by practicing health care practitioners-- i.e., reports that originate from observations made in the usual practice of medicine.

FDA began computerizing adverse drug reaction reports (ADRs) in the mid-1960s and legacy data is available dating back to 1969. This computerized system, called the Spontaneous Reporting System (SRS), was replaced by the newer Adverse Event Reporting System (AERS) in November 1997. It is the cornerstone system providing technology for safety monitoring of "spontaneous" data for CDER and the Center for Biologic Evaluation and Research (CBER) therapeutic agents. Currently, adverse drug reactions are reported to FDA in a variety of ways and provide a database of some two million reports that can be analyzed individually or in the aggregate. In FY1998, more than 230,000 reports of suspected adverse events were received by AERS.

Reports of adverse events on marketed human drugs and non-vaccine biologics include prescription drugs (whether or not they are the subject of an approved New Drug Application (NDA)), generic drugs, over-the-counter (OTC) drugs that are the subject of an approved NDA and non-vaccine biologics. These reports reach FDA through either the drug/biologic manufacturers or direct contact (MEDWATCH). When a health practitioner notifies a manufacturer about a possible reaction, the manufacturer is required by law and regulations to report these observations to FDA.

There are two major sources of OTC drug adverse event reports in FDA:

  • Manufacturers of OTC drugs with NDA's are required by the postmarketing regulation (21 CFR 314.80) to report any serious and unexpected adverse events in 15 days and other type reports periodically as specified by the regulations ñ the same as for prescription drugs. Given that most of these agents have been on the market for many years and safety of the drugs have been monitored extensively, very rarely are new and rare adverse events identified. More frequently reports are consumers' complaints of lack of expected effect, which is usually a subjective measurement of efficacy (or lack thereof).
  • Voluntary reporting of OTC monographed drugs by consumers or manufacturers is a second source of data. These are greater than 300,000 individual OTC products with more than 700 active ingredients under OTC monographs in place or under development. As expected where these drugs are used appropriately, most adverse events are not serious but in an effort to standardize safety reporting, FDA is considering a proposed regulation mandating reporting of all serious reports, expeditiously, to monitor the rare adverse events and potential product or manufacturing problems.

A minimum data set for a report is currently defined as a report having an identified drug/therapeutic, a definable reaction, a reporter and a patient or subject. For an adverse reaction report to be interpretable, it must contain descriptions of the reaction, the exposure to the drug/therapeutic, the temporal relationship between exposure and reaction, and the underlying disease.

Substantial effort is placed on the review of the case reports for purposes of identifying those with serious outcomes involving adverse event reports not currently in a drug/therapeutic product's labeling. The goal of evaluation of "spontaneous" data is to provide a signal that can be evaluated, quantified and validated as a drug/therapeutic outcome and to ensure appropriate dissemination of risk management information and initiation of regulatory action. Typically, this information may result from as few as several well-documented cases to a very large number of reports that are then evaluated and subjected to signal development. This process involves application of epidemiological methods and includes clinical evaluation of cases for the conditions relating to drug exposure and for the identification of potential risk factors, and confounders of the adverse event report's occurrence. It also includes demographic description and quantification of the exposed population. In the best of circumstances, estimates of reporting rates are possible, using the reported number of adverse event report cases as the numerator and an estimate of prescription drug use as the denominator. At this point in the process, additional data, derived from literature sources, observational or clinical studies, linked databases or other sources of drug usage data are considered to strengthen or clarify the reported observations for regulatory action.

When a signal of a potential adverse reaction is detected, safety evaluators consult with product reviewers, medical officers, and epidemiologists to review available data and consider further options. Focused studies may be undertaken using various epidemiological and analytical databases and other resources. Based on the results of these studies and evaluations, FDA may decide to disseminate risk information, such as Dear Healthcare Professional letters, and may initiate regulatory action.

Characteristics That Support Drug Spontaneous Reporting

The following characteristics are important in ensuring that the current system is effective in identifying serious, unlabeled events of interest via the spontaneous system for drugs. In general, these are not features of Special Nutritional products reporting:

  • Manufacturer Reporting vs. Direct Reporting
    Spontaneous reporting of Adverse Event for drugs is heavily driven by Manufacturer Reporting (some 90 percent of all reports received). Manufacturer reporting (except for OTC monograph drugs) is required by regulation, is well accepted, and leverages the firm's resources in identifying, assessing, and following up on reports of drug injury.
  • Quality Assurance
    Current good manufacturing practice requirements for all firms manufacturing, labeling, and distributing drugs in the U.S. provides a basis for assuring that the agent identified in the report is the drug in question with the contents meeting the appropriate standards of potency, strength, and purity.
  • Drug Label
    The Drug Label provides information for the indication and safe and effective use of the product as well as information on the known adverse effects and contraindications.
  • Premarket Clearance
    Premarket clearance for drugs (except for OTC monograph drugs) provides data for an initial assessment at the point of approval of the benefit--risk assessment and a good starting point for evaluating the agent when it goes beyond the target population after commercialization.
  • Benefit-Risk Assessment
    The benefit-risk assessment is the continuing process of evaluating the new risks seen postmarketing against the known benefits of the drug. Again, premarket clearance provides a basis for comparison as the safety picture evolves.
  • Additional Aspects of Drug Pharmacovigilance
    By regulation, serious unlabeled foreign reports are reported to CDER, providing a broader view to the overall benefit--risk picture, sometimes world-wide. In addition, the benefits of 30 years of reporting have resulted in a system that is widely accepted by corporate culture. The Agency also provides regulation, guidance, and compliance oversight to ensure good reporting practices. Finally, evolving regulations reflecting the International Conference on Harmonization (ICH) initiatives and focusing on standardization of requirements have been widely discussed and accepted by industry.
  • Learned Intermediary
    For prescription drugs, the intervention of a "learned intermediary" (variety of health practitioners) provides a mechanism to supply ongoing individual risk-benefit assessment in the practice of medicine, pharmacy, etc., and to provide a conduit for reporting adverse events.

Let me now address FDA's spontaneous reporting system for dietary supplements.

SPONTANEOUS REPORTING SYSTEM -- FOR DIETARY SUPPLEMENTS

Special Nutritionals Adverse Event Monitoring System (SN/AEMS)

The SN/AEMS was established in early 1993, following the establishment of the Office of Special Nutritionals. The SN/AEMS system, while formally part of CFSAN's Adverse Reaction Monitoring System, is still in its infancy when compared to the more formal and well-developed adverse event reporting systems that exist for other products regulated by FDA. It provides, however, an essential monitoring tool for identifying potential serious public health issues that may be associated with the use of a particular product or type of products already in the marketplace that need to be investigated and critically evaluated.

SN/AEMS is limited to those adverse events reported with the use of special nutritional products, which include dietary supplements, infant formulas, and medical foods. The adverse events received on special nutritional products include a variety of both acute and chronic adverse effects. Typically, special nutritional products are used for prolonged periods and often by special or vulnerable populations. Furthermore, dietary supplements often contain multiple substances that may have physiological or even pharmacological effects. The adverse events seen with these products, therefore, tend to require extensive follow-up and evaluation.

Because of these factors, when a serious adverse event is reported in association with a dietary supplement product, considerable resources are expended by FDA to obtain even basic information on the product (e.g., the product name, manufacturer, ingredients, and directions for use). Information is also needed on how the consumer used the product and the nature, severity, patterns, and outcome of the adverse event. Given that reported safety information is limited for most dietary supplement products, SN/AEMS is a critical tool for identifying new or emerging public health problems that may be associated with the use of particular products. Further, the signals generated by SN/AEMS help focus Agency resources on products needing further investigation. Compared to the CDER adverse event reporting system, the SN/AEMS lacks many of the tools at CDER's disposal--premarket testing database, mandatory reporting by manufacturers, registration of firms and listing of products, good manufacturing practice requirements, and a mature internal database system with which to manage the wealth of information they receive.

These are some of the challenges CFSAN faces with the current system and we are working to address the many areas that will make the system stronger. Specifically, based on the Agency's FY 2000 budget request, CFSAN is developing plans to recruit and train additional appropriate medical staff, and enhance the SN/AEMS system, including integration into an FDA-wide system. A major emphasis will be placed on upgrading and improving the computer infrastructure to facilitate signal and report generation. In addition, as you know, FDA now provides summary information on its special nutritionals AER database on its homepage [visit CFSAN's page on Dietary Supplements on the Website]. Interested persons may either browse the web report or search for specific ingredients, reports, or types of adverse events. Since its inception, this web site has been very popular. On average it is accessed approximately 3,000 - 4,000 times per month.

We heard the concerns the Committee raised at the March 25 hearing regarding correcting errors to records on the web, and concerns both the Committee and industry have raised about access to those records under the Freedom of Information Act (FOIA). Providing industry access to accurate information in a timely manner, within the boundaries of the FOIA, and having sufficient resources to apply to maintaining accurate web site records on a real time basis are issues CFSAN is grappling with. We would welcome further discussion with the Committee on these issues.

Like the adverse event reporting system for CDER, the SN/AEM system also receives information from a variety of sources, as identified in Chart A. For dietary supplements, all such reporting is voluntary. As you can see in Chart B, when CFSAN receives a suspected adverse event report on a dietary supplement, it conducts an initial review to determine the seriousness or clinical significance of the report. If the report is considered serious or clinically significant, immediate follow-up information is requested if needed.

The requested follow-up information may include copies of the product(s) label and labeling, information on how the consumer used the product(s), and available medical or other clinical records concerning the reported adverse event. As noted above, the Agency's ability to follow-up has potential limitations based on a variety of factors, e.g., the product sample has often been discarded. After the initial review, CFSAN conducts a medical/clinical review and evaluation to determine whether the report signals a potential public health problem, and if so, what action the Agency should take.

In addition to efforts within FDA to ensure the safe use of dietary supplements, education of the public in an appropriate and timely manner about potential adverse effects associated with these products is critical. In an era of limited resources, the coordinated efforts of Federal agencies, academia, public health groups, industry, and consumers will be required. As you may recall, when Dr. Henney testified on March 25, she mentioned the Agency's commitment to developing, this calendar year, an overall strategy for achieving effective regulation of dietary supplements under DSHEA. Dr. Henney also stated that in doing so, FDA will provide ample opportunity for public input. As part of this ongoing consultation with FDA's stakeholders, the Agency will hold public meetings on June 8, 1999, in Washington, D.C., and on July 20, 1999, in Oakland, California, to solicit comments that will assist CFSAN in the development of that strategy, including input on the SN/AEM system. Finally, as noted last year in FDA's response to the Report of the Commission on Dietary Supplement Labels, FDA has asked our Foods Advisory Committee (FAC) to play an active role in two important issues: First, to consider how best to gather data on how consumers use information on dietary supplement labels to make decisions as to whether or not a dietary supplement is appropriate for them. FDA asked the FAC to consider the development of guidelines or criteria that could be used by the dietary supplement industry and others to conduct consumer research studies or to evaluate the results of consumer research studies; and, Second, to consider the issue of postmarket surveillance and particularly how best to collect and share surveillance information. The FAC considered these issues at their February 1998 meeting and referred them to FAC working groups to develop recommendations for consideration by the full Committee. The Agency also is considering whether to establish a separate Advisory Committee or Expert Panel devoted to dietary supplement issues, an idea that was also raised at the March 25 hearing.

How AER's Benefit Public Health

While there certainly are limitations to passive spontaneous reporting systems, as I have outlined above, I would like to discuss a few examples of how these systems have provided a great benefit to public health.

ADVERSE EVENT REPORTING SYSTEM (AERS)

Tasmar

Tasmar (tolcapone) was approved on January 29, 1998, as adjunct therapy (with levodopa and carbidopa) for the treatment of the signs and symptoms of idiopathic Parkinson's disease. The labeling included (in the Precautions Section) a statement on reversible hepatic enzyme abnormalities and recommended monthly monitoring during the first three months of treatment and every six weeks for the following three months. Recommendations also included discontinuing the drug when enzyme elevations equaled or exceeded five times the upper limit of normal, or at the appearance of jaundice. Postmarketing surveillance identified 17 cases of liver-related adverse events following approval including: five hepatitis, three jaundice, and nine other liver function abnormalities. Five pivotal cases were identified with hepatitis documented with increased hepatic transaminase levels and biopsy/radiographic examination suggesting likely drug induced hepatitis related to Tasmar therapy. Two of the five cases reported fatalities from fulminate hepatitis or liver failure from less than three months of therapy- one from Switzerland and one from the U.S. All five pivotal cases experienced hepatitis within six weeks of therapy that was initially undetected, potentially due to lack of adequate monitoring of liver functions as recommended in the labeling.

In November 1998, FDA asked the sponsor of Tasmar to revise the labeling to include the new warning on hepatotoxicity and a "Dear Doctor" Letter was sent to alert the prescribing physicians and patients with a new requirement of liver function monitoring every two weeks during Tasmar treatment. Since November 1998, FDA has not received any more serious case reports of liver related injuries associated with Tasmar.

SPECIAL NUTRITIONALS/ADVERSE EVENT REPORTING SYSTEM

Digitalis

In our March 25 testimony, we referenced this case as an example of how the Agency uses a variety of regulatory tools from enforcement actions to rulemaking when it has found dietary supplements that cause safety concerns. This case also is a good example of how AERS serve as our early warning signal and how just one AER can be a powerful indicator of a safety concern.

In 1997, FDA received an AER regarding a young woman with life-threatening abnormal heart function who required hospitalization for six days. FDA immediately conducted an investigation. The Agency detected the botanical Digitalis lanata in samples of raw material labeled "plantain" that was an ingredient in one of the dietary supplement products used by this young woman. Digitalis is a powerful heart stimulant whose effects may include nausea, vomiting, dizziness, headache, confusion, hypotention (low blood pressure), vision disturbances, and abnormal heart rate and rhythm.

FDA then traced all uses of the contaminated ingredient and asked manufacturers and retailers to recall these products from the market. FDA issued several press releases warning consumers not to purchase or ingest certain dietary supplement products labeled as containing plantain because these products may contain Digitalis lanata, a plant that can cause life-threatening heart reactions, including cardiac arrest, if ingested. While fast and effective actions by FDA prevented further serious adverse effects, which would have likely occurred if these contaminated products remained in the marketplace, it was a single AER that led the Agency to take action.

GBL

Gamma butyrolactone (GBL) is a metabolic precursor to gamma-hydroxybutyrate (GHB), an unapproved new drug and one of the "date rape" drugs. GBL is promoted as a dietary supplement with claims to stimulate growth hormone release, fight stress, increase athletic performance, combat aging, promote sleep, as well as other uses. It is a manufacturing intermediate and industrial solvent. Products containing GBL have been marketed under various brand names, including Renewtrient, Revivarant or Revivarant G, Blue Nitro or Blue Nitro Vitality, GH Revitalizer, Gamma G, Invigorate, and Remforce. GBL has been associated with serious, life-threatening adverse events and the Agency has initiated action to remove it from the marketplace.

FDA had received 55 reports of adverse events by January 13, 1999 (95 AER's as of February 26, 1999), including one death. In 19 of those cases, the consumers became unconscious or comatose and several required intubation for assisted breathing. Other reported effects included seizures, vomiting, slow breathing, and slow heart rate. There were reports of at least five children under 18 years of age who have been injured or who have suffered these kinds of effects.

FDA's analysis of available scientific information, including the opinion of independent outside scientific/medical experts, concluded that GBL's presence in the marketplace represented a serious public health hazard due to its steep dose response curve, ability to induce respiratory arrest and coma, and its serious abuse potential. The Agency concluded that label information, such as warning/caution statements and directions for use, could not provide for its safe use. FDA issued a public warning on January 21, 1999, alerting consumers of the potential hazards from consumption of GBL-containing products.

Firms known to produce or distribute GBL were contacted beginning on January 19, 1999. Warning letters were delivered, beginning on January 27, 1999, to firms not voluntarily recalling their products. The warning letters state that FDA considers GBL to be an unapproved new drug, that these products do not meet the statutory requirement to be marketed as a dietary supplement, and that, even if they could be considered dietary supplements, they do not meet the safety requirements of the law. As of May 20, 1999, FDA has initiated two court-ordered seizures of GBL-containing products.

Ephedra

As you know, on June 4, 1997, FDA published in the Federal Register a proposed rule on Dietary Supplements Containing Ephedrine Alkaloids (62 FR 30678). There are a variety of opinions about the proposed rule and the direction the Agency should take. One cannot dispute, however, the shear volume of the reports of illness and injuries that FDA received reported to be associated with the use of dietary supplements suspected to contain ephedrine alkaloids.

Between 1993 and mid-1996, FDA received about 1,600 AER's reported to be associated with the use of dietary supplement products in general. Of these, over half of the AER's were reported to be associated with the use of dietary supplements that contained, or were suspected to contain, ephedrine alkaloids. These adverse events tended to involve cardiovascular system effects and nervous system effects. FDA evaluated these reports and found that the single most common element was that the products contained, or were thought to contain, a source of ephedrine alkaloids (62 FR 30679).

FDA used the information available in the approximately 600 AER's that were in the Agency's possession as of June 7, 1996, to describe patterns associated with these reports. A review of the demographic information showed that in over half of the reported adverse events, the injured party was under 40 years of age. Almost 75 percent of the adverse events were reported to occur in females, often using products promoted for weight loss (62 FR 30683). About 59 percent of the adverse events were reported to occur within 4 weeks of starting to use the product. About 14 percent of the reported adverse events occurred on the first day of using the dietary supplement and, in a few cases, on the initial use (62 FR 30684). Overall, the reported signs and symptoms associated with these AER's included those in which clinically serious events occurred, including heart attack, stroke, psychoses, seizure, and in a few cases, death, as well as those with less clinical significance, including rapid and irregular heart rhythms, increased blood pressure, anxiety, nervousness, tremor, hyperactivity, and insomnia (62 FR 30683).

The Agency recognized that these reports could be indicative of early warnings of serious cardiovascular or nervous system risks if product use were to continue. Notably, the information from these adverse events revealed consistent patterns of signs and symptoms in both healthy individuals and in those with underlying diseases or conditions. Many of these reported signs and symptoms occurred in young adults who generally would not have been expected to be at high risk for such conditions (e.g., heart attack and stroke). Included were the deaths of two young adult males in which the medical examiners attributed the cause of death to ephedrine toxicity (ARMS Nos. 10862 and 11134 at 62 FR 30720 and 30722, respectively). In some cases, particular events appeared to reflect individual sensitivities related to dose levels, frequency, or duration of use of ephedrine alkaloids (62 FR 30684).

As depicted in Chart C, the ephedra AER's generated an important "signal", but were just one small component (the "tip of the iceberg") of FDA's overall analysis of the potential public health risk associated with this product. To better understand the nature and types of products associated with these AER's, FDA conducted a review of the marketplace (62 FR 30679). Over a two-year period, FDA collected and analyzed over 25 dietary supplement products labeled as containing a known source of ephedrine alkaloids. FDA also searched the scientific literature for relevant clinical studies, case reports, and the expected physiologic and pharmacologic effects. In addition, FDA also convened an ad hoc working group of its Food Advisory Committee (Working Group) and its Food Advisory Committee to consider the public health problems associated with the use of ephedrine alkaloid-containing dietary supplements (62 FR 30680). In the proposed rule, FDA requested comments containing data, particularly clinical data, on the safety of the use of ephedrine alkaloids in dietary supplements. (62 FR 30694).

As noted above, while the AER's served as the warning signal of potential hazard associated with the use of dietary supplements containing ephedrine alkaloids, the Agency's evaluation of those hazards was comprised of multiple sources of scientific information. This evaluation included the AER's, a search of the scientific literature, published case reports, controlled clinical studies, and published reports of adverse events associated with traditional uses of ephedrine alkaloids. All of these sources of scientific information revealed a consistent pattern of cardiovascular and nervous system effects associated with ephedrine alkaloids. That view was affirmed by FDA's Food Advisory Committee.

CONCLUSION

Mr. Chairman, thank you for the opportunity to participate in this public dialogue on passive spontaneous reporting systems. It is my hope that through this forum, you, Members of the Committee, and the public will appreciate both the value and the challenges these systems offer.

To effectively provide us with an early warning signal as to possible public health dangers associated with a given product, these systems need to be healthy. To achieve and maintain healthy systems requires the computer infrastructure to support the data, and sufficient staff with the clinical expertise to review and analyze the data. In addition, it must be recognized that these adverse event reports are but one piece of a postmarketing/risk assessment process. Health care providers, manufacturers, and the individuals must each take responsibility for the contribution they must make to ensure FDA's passive reporting systems continue to provide the value they add to a broader postmarketing surveillance system.

I will be happy to answer any questions you may have.


Appendix

SPONTANEOUS REPORTING SYSTEMS--FOR BLOOD AND BLOOD COMPONENTS

The blood bank and source plasma industry submits the majority of error and accident reports received by the Center for Biologics Evaluation and Research (CBER). Most of these reports relate to donor suitability. A proposed rule that published in 1997 would expand the reporting requirement for licensed facilities to include unlicensed blood establishments and transfusion services.

When a blood transfusion (or blood collection) complication is confirmed to be fatal, it must be reported to FDA within 7 days. This information is used for risk assessment and communication of risk to blood establishments, transfusion services, and physicians. Adverse events associated with therapeutic plasma-derivative products (such as hemoglobin) are reported in the same way as adverse events associated with drugs and other therapeutic biological products.

SPONTANEOUS REPORTING SYSTEMS--FOR VACCINES

Vaccine Adverse Event Reporting System (VAERS)

Postmarketing surveillance for vaccines is handled by the Vaccine Adverse Event Reporting System (VAERS), a system independent of other FDA spontaneous reporting systems. Established in 1990, VAERS is jointly managed by FDA (CBER's Division of Biostatistics and Epidemiology) and Centers for Disease Control and Prevention (Vaccine Safety Activity, National Immunization Program). Representatives of both agencies oversee data processing and database management performed by a contractor.

VAERS receives 11,000 to 12,000 reports per year. Approximately 15 percent of the reports describe a serious event, defined as either fatal, life-threatening, or resulting in hospitalization or permanent disability. Selected reports of serious events and all reports of fatalities are followed up individually by a health professional, and autopsy reports, as well as other medical records are retrieved when available. Medical staff carefully monitor trends in adverse event reporting for vaccines, with particular attention to newly licensed vaccines. In addition to monitoring reports according to vaccine type, reports are monitored according to the vaccine lot.

SPONTANEOUS REPORING SYSTEMS--FOR DEVICES

Manufacturer and User Device Experience (MAUDE) Database

In 1984, FDA implemented the Medical Device Reporting (MDR) regulation, which required manufacturers to report device-related adverse events to FDA. In 1990, the Safe Medical Device Act (SMDA) amendments expanded FDA's authority by requiring that user facilities (e.g., hospitals and nursing homes) report device-related serious injuries to the manufacturer and device-related deaths to the manufacturer directly to FDA. The Agency receives approximately 80,000 to 85,000 device-related adverse event reports every year. The bulk of the reports are from manufacturers, with user facilities submitting only about 5,000 of this total. The Manufacturer and User Device Experience (MAUDE) database, established in 195 to support the SMDA, contains approximately 300,000 reports. Another 500,000 reports are in the pre-1995 database.

When received, reports are first triaged by medical professionals. In general, the criteria for taking action relate to the unexpectedness and seriousness of the event, the vulnerability of the population affected, and the preventability of the event. Reports that involve pediatric death, explosion, and/or multiple injuries from one device, are sent immediately to supervisors of the report review staff for evaluation and further action if necessary. All reports are entered into the MAUDE database, subjected to quality control procedure, and then sent to the clinical analysts for review within 48 hours of receipt. Clinical analysts review and assess the adverse event reports. Each analyst is responsible for products within a specific medical specialty or for products that have common design or material features. Here, as with drugs and biological products, the analysts' experience and familiarity with the products play a significant role in the evaluation of these reports.

Alternative Summary Reporting

To evaluate more effectively the large number of medical device reports, FDA has initiated a risk-based alternative reporting system-- summary reporting. Products approved for summary reporting are well known with well-documented adverse event histories. This approach consists of the periodic submission of adverse event data in tabular format and provides significant economies for both the device industry and FDA. In the past year, FDA received approximately 30,000 reports in summary format.

SPONTANEOUS REPORTING SYSTEMS--FOR COSMETICS AND FOODS

Cosmetic Adverse Reaction Monitoring Database (CARM)

The CARM program was initiated in the Office of Cosmetics and Colors, CFSAN, in 1993. This passive program collects consumer adverse reaction reports received by FDA Headquarters, FDA District or Field Offices, and the MEDWATCH program. CARM program information is monitored as it is received for serious adverse reactions that may require immediate follow-up. The CARM computer database is updated quarterly to add reports received by FDA field offices to those received at the Office of Cosmetics and Colors. Typically, FDA headquarters will receive about 125-150 consumer complaints into a computer database to facilitate review and evaluation. A CARM review committee periodically meets and evaluates adverse reaction summary reports for evaluation and possible follow-up actions. The committee includes compliance staff, a toxicologist, a cosmetic chemist, and program management staff. CARM program follow up action may include requesting field support through inspections, sample collections and consumer interviews. Annual CARM summary reports are available for public release and are provided to the cosmetic industry.

SPONTANEOUS REPORTING SYSTEMS--FOR VETERINARY PRODUCTS

Postmarketing surveillance for veterinary products is handled by the Adverse Drug Events (ADE) database, a system independent of other FDA spontaneous reporting systems. The ADE database receives 4,000 to 5,000 reports per year. The bulk of the reports are from manufacturers. All reports are entered in the ADE database. Medical staff track adverse events, with particular attention to reported adverse reactions that are not in product labeling. Medical staff will then often meet with manufacturers to discuss label changes based on new adverse reactions or product defects. Label changes are suggested if needed.

Adverse Reaction Monitoring System

The ARMS system was originally established in 1985 to collect and evaluate potential adverse effects to food and color additives, such as aspartame, monosodium glutamate (MSG), and sulfites. Its use was later expanded to cover other specific food products. ARMS is a form of passive surveillance that is designed as a sentinel system to identify specific areas for focused clinical investigations that can evaluate associations between food and color additives and adverse events. The reports, which tend to be acute in nature and related to food allergies/intolerance, or microbiological infections, are classified by severity of the reaction and by the frequency and consistency of the association with ingestion of the product of interest.