The Clinical Impact of Adverse Event Reporting Oct 1996 by FSray


Provided as a service by the Staff College, Center for Drug Evaluation and Research, Food and Drug Administration                October 1996

                                                        omifensine (MeritalR), an antide-         from preclinical animal testing and med-
 Learning Objectives:
 Upon completion of this program,
                                                 N      pressant that had been available in
                                                 Germany since 1976, had been prescribed
                                                                                                  ical device bench testing to final tests in
                                                                                                  humans, have inherent limitations no mat-
 health professionals should be able to:         to an estimated ten million patients prior       ter how well they are designed or con-
 • Identify underlying principles of             to its marketing in the U.S. in July, 19851,2.   ducted. The need for postmarketing sur-
   postmarketing surveillance                    Initial labeling for the product reflected a     veillance is a direct result of these limita-
 • Understand reporting requirements             variety of long-recognized hypersensitivi-       tions.
   (health professionals, manufact-              ty reactions, including fever, liver injury,
   urers, user facilities) regarding             hemolytic anemia and eosinophilia, that          Premarketing Animal Studies
   regulated medical product safety              were apparently all readily reversible3.              Most medical products are first tested
 • Discuss basic limitations/strengths of              At the time of U.S. approval, FDA was      in animals prior to introduction into
   data derived from postmarketing               aware of reports of less than twenty             humans. Animal studies have limitations
   surveillance                                  hemolytic anemia cases, all non-fatal;           in their ability to predict human toxicity;
 • List examples of FDA regulatory               however, in 1985, when foreign adverse           this is demonstrated by the case of prac-
   actions that have been based on               reaction reports showed the hemolytic            tolol, a ß1-adrenoreceptor blocking agent
   postmarketing surveillance                    anemia might be fatal, labeling was              withdrawn from the U.K. market in 1976
 • Describe how FDA disseminates                 revised to reflect the potential seriousness     after several years of widespread use6,7,
   information regarding medical                 of the reaction3. Due to an increase in          and never marketed in the U.S.
   product safety                                serious hemolytic anemia cases seen in                The U.K. action was prompted by the
 • Understand how a national postmar-            Europe, marketing of nomifensine was             serious adverse reactions of dermatitis,
   keting surveillance program impacts           reconsidered by the manufacturer, who            keratoconjunctivitis and sclerosing peri-
   clinical practice                             announced a worldwide withdrawal of the          tonitis, collectively termed the oculomu-
                                                 drug on January 21, 19863,4.                     cocutaneous syndrome6,7. This syndrome
 Stephen A. Goldman, MD                                The case of nomifensine illustrates        had not been seen during extensive pre-
 Assoc. Dir. for Medicine, MEDWATCH              that the safety profile of a drug evolves        clinical animal testing conducted within
 Office of the Commissioner, FDA                 over its lifetime on the market. Even after      required guidelines7.
                                                 almost ten years experience, or longer,               Subsequent toxicity studies in several
 Faculty:                                        new information that will impact the clin-       small animal species (both those that
 Dianne L. Kennedy, RPh, MPH                     ical use of a medical product can be             metabolize practolol similarly to humans
 Director, MEDWATCH                              detected. Consequently, all medical prod-        and those whose practolol metabolism is
 Office of the Commissioner, FDA                 ucts need to be continually assessed for         more extensive than humans) found no
 David J. Graham, MD, MPH                        safety within the context of their per-          animal model for the observed human
 Acting Chief, Epidemiology Branch               ceived benefit.                                  adverse reactions8. The lack of reproduc-
 Center for Drug Evaluation and                        Medical product safety monitoring is       tion of these particular adverse reactions
 Research, FDA                                   an ongoing process accomplished through          in any laboratory animal species9 demon-
                                                 Postmarketing Surveillance, the collec-          strates that animal studies, no matter how
 Thomas P. Gross, MD, MPH
 Director, Division of Postmarket                tion of data about drugs [or any other           appropriate or well-performed, are not
 Surveillance, Center for Devices and            medical product] once they are marketed          necessarily predictive of human path-
 Radiological Health, FDA                        and thus available to the general popula-        ology.
                                                 tion5. This process encompasses adverse
 Richard M. Kapit, MD                            event reports evaluation, generation of          Premarketing Human Clinical Studies
 Chief, Adverse Events Section
                                                 safety-related hypotheses and use of tech-            There are intrinsic limitations to pre-
 Center for Biologics Evaluation and
 Research, FDA                                   niques to evaluate these hypotheses.             marketing human clinical trials with
                                                                                                  respect to their ability to detect adverse
 Lori A. Love, MD, PhD                           THE NEED FOR POST-                               events. Short duration, narrow population,
 Director, Clinical Research and                 MARKETING SURVEILLANCE                           narrow set of indications and small size
 Review Staff, Center for Food Safety
 and Applied Nutrition, FDA                           While the U.S. has one of the most          are major factors in this regard10, irrespec-
                                                 rigorous approval processes in the world,        tive of the type of medical product being
 Gale G. White, MS, RN                           it is not possible to detect all potential       studied.
 Deputy Director, MEDWATCH                       problems during premarketing clinical                 The capability of premarketing clini-
 Office of the Commissioner, FDA                 trials. Medical product studies, ranging         cal trials to discover rare adverse events is
  2      The Clinical Impact of Adverse Event Reporting

particularly affected by their size. In order   to detect adverse events possibly related to   CLINICAL SYNOPSIS 1
to have a 95% chance of detecting an            interactions with other medical products                       BIOLOGICS
adverse event with an incidence of 1 per        than is available in the premarketing
                                                                                                 Intravenous Immunoglobulin and
1,000, 3,000 patients at risk are               phase.
                                                                                                   Aseptic Meningitis Syndrome
required11; with no more than 3,000 to               The major changes in the size and
4,000 individuals usually exposed to a          nature of the exposed patient popula-                In early 1994, FDA learned of a
medical product prior to marketing, only        tion that occur once a medical product          report from the National Institutes of
those adverse events with approximately         is available for widespread use empha-          Health (NIH), which described a high
1/1,000 or greater incidence can be             size the great importance of adverse            rate of aseptic meningitis syndrome
expected to be found.                           event detection and reporting by health         (AMS) occurring in patients being treat-
     While medical products are usually         professionals.                                  ed for neuromuscular diseases with high
studied for several years before they are                                                       doses of intravenous immunoglobulin
marketed, an individual patient in a clini-     MEDWATCH                                        (IGIV). The patients had been receiving
cal trial is generally exposed to the prod-          It is with these considerations in mind    doses of 2 g/kg of IGIV, which is five to
uct for less than a year. Even long-dura-       that MEDWATCH, the FDA Medical                  ten times higher than the normally rec-
tion premarketing clinical trials, which        Products Reporting Program, was estab-          ommended dosage. Six of 54 patients
can last several years, do not provide the      lished12. While FDA's longstanding post-        developed severe headache, meningis-
degree of patient exposure that will occur      marketing surveillance programs predate         mus, and fever within 24 hours of dos-
postmarketing with a chronically used           MEDWATCH, this educational/promotional          ing. Cerebrospinal fluid (CSF) was con-
medical product. In addition, the relative-     initiative was designed to emphasize the        sistent with AMS in four of the six.
ly short durations of clinical trials miti-     responsibity of healthcare providers to              Following this lead, 22 cases of
gate against the detection of adverse           identify and report adverse events related      IGIV-associated AMS which had been
events with long latency.                       to the use of medical products. Through         reported to the FDA were reviewed.
     Because of these limitations, premar-      the MEDWATCH program health profession-         Symptoms included fever and photo-
keting clinical trials seldom detect or         als can report serious adverse events and       phobia, and prominent painful
define the frequency of all important           product problems that occur with such           headache. Twenty of the cases were
adverse events. As a result, the official       medical products as drugs, biologics,           associated with positive CSF findings,
labeling/product information at the time        medical and radiation-emitting devices,         including leukocytosis (predominantly
of approval of a medical product reflects       and special nutritional products (e.g.,         neutrophilic) and elevated protein.
what is known about that product's risk at      medical foods, dietary supplements and               Unexpectedly, 19 of the reports
that point in time. The controlled environ-     infant formulas).                               indicated that normal doses of IGIV had
ment under which clinical trials are con-            Causality is not a prerequisite for        been administered (0.2 - 0.4 g/kg). The
ducted means that the safety data present-      MEDWATCH reporting; suspicion that a            patients had been treated by withdrawal
ed in the original labeling of a product        medical product may be related to a seri-       of the medication and administration of
usually represents actual occurrence rates      ous event is sufficient reason for a health     analgesics. Of particular note was the
in the defined population that has been         professional to submit a MEDWATCH               characteristic time course of IGIV-asso-
studied.                                        report. However, a report on every adverse      ciated AMS. The illnesses all began
                                                event is not sought - what is desired is an     between 12 and 24 hours after adminis-
Postmarketing Experience                        increase in the reporting of serious events.    tration, and recovery ensued within sev-
     Health professionals should be aware       In that regard, TABLE 1 offers a guideline      eral days following withdrawal of the
that this is not the case with postmarket-      for adverse event reporting. However,           medication.
ing data. Once a product leaves the con-        health professionals are welcome to report           As a result of this work, FDA and
trolled study environment and enters gen-       any adverse event that they judge to be         NIH workers published two articles on
eral clinical use, the ability to detect the    clinically significant.                         IGIV-AMS simultaneously in the same
actual incidence of an adverse event can        TABLE 1                                         journal45,46. The FDA also directed
essentially be lost. On the other hand,                     MEDWATCH
                                                      What is a Serious Event?                  IGIV manufacturers to modify labeling
once a new product is marketed, there are                                                       to include a Precaution statement about
great increases in the number and variety        Any event that is
                                                                                                the occurrence of the syndrome.
of patients exposed, including those with          • Fatal
multiple medical problems and undergo-             • Life-threatening
ing treatment with numerous concomitant            • Permanently/significantly                 POSTMARKETING REPORTING
medical products.                                    disabling                                 OF ADVERSE EVENTS
     As a result, the population experience        • Requires or prolongs                           The FDA has the regulatory responsi-
with the product will be much broader                hospitalization                           bility for ensuring the safety of all market-
than that derived from the clinical trials.        • Cogenital anomaly                         ed medical products. Health professionals
One particular safety-related advantage            • Requires intervention to prevent          are critical to this process, in that the first
this offers is a generally greater capability        permanent impairment or damage            hint of a potential problem originates with

                         Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
                                                                               A   MEDWATCH   Continuing Education Article          3

the perceptive clinician who then reports      tient treatment facility and outpatient        tion's procedures for device-related
the case to the appropriate source. It is      diagnostic facility) should be aware of the    reporting, and actively participate in the
important for all health professionals to be   legal requirements for medical device-         program.
aware that some reporting is mandated by       related reporting by user facilities mandat-        Confidentiality: The FDA acknowl-
federal law and regulation while other         ed by the Safe Medical Devices Act of          edges that health professionals have con-
reporting, although considered vital, is       1990 (SMDA) (see TABLE 218). Under             cerns regarding their confidentiality as
strictly voluntary.                            the SMDA, physicians' offices are exclud-      reporters, and that of the patients whose
                                               ed from the user facility definition and       cases they report. In order to encourage
By Health Professionals                        thus exempt from mandatory reporting           reporting of adverse events, FDA regula-
     Any postmarketing surveillance pro-       requirements. The FDA likewise excludes        tions offer substantial protection against
gram depends on health professionals to                                                       disclosure of the identities of both
                                                TABLE 2
report serious adverse events observed in                                                     reporters and patients. This was further
the course of their everyday clinical work.     Medical Device Reporting (MDR)
                                                          Requirements18                      strengthened on July 3, 1995, when a reg-
Except for adverse events associated with                                                     ulation went into effect extending this pro-
specified vaccines, reporting by an indi-      NB: days refers to working days, unless
                                                   otherwise specified                        tection against disclosure by preempting
vidual health professional is voluntary.                                                      state discovery laws regarding voluntary
     Given the clinical importance of post-      • User Facility:                             reports held by pharmaceutical, biological
marketing surveillance, all healthcare              • Deaths (to FDA and manufacturer         and medical device manufacturers19.
providers (physicians, pharmacists, nurs-             within 10 days)
es, dentists and others) should look upon           • Serious injuries/illnesses (to          By Hospitals
adverse event reporting as part of their              manufacturer within 10 days; to              The FDA, recognizing the valuable
professional responsibility. The American             FDA if manufacturer unknown,            role that hospitals play in the detection of
Medical Association13 and American                    also within 10 days)                    adverse events and problems with medical
Dental Association14 advocate (respec-              • Semiannual Reports (to FDA) of          products, views every active hospital mon-
tively) physician and dentist participation           all reports sent to FDA and/or          itoring program as a vital component of
in adverse event reporting systems as an              manufacturer (due January 1 and         the national postmarketing surveillance
obligation13,14. Further, The Journal of the          July 1)                                 system. Hospital reporting of adverse
American Medical Association instructs           • Manufacturer:                              events, both within and outside an individ-
its authors that adverse drug or device            • Deaths, serious injuries,                ual facility, is a mixture of voluntary and
reactions should be reported to the appro-           malfunctions (to FDA within 30           mandatory reporting.
priate government agency, in addition to             calendar days of becoming aware               Adverse event monitoring by hospi-
submitting such information for publica-             of event)                                tals is linked to Joint Commission on
tion15.                                              • “5-day Report” [to FDA if              Accreditation of Healthcare Organizations
     Health professionals can use the vol-            become aware of 1) event(s)             (JCAHO) standards. In order to be accred-
untary MEDWATCH form to report adverse                necessitating “remedial action to       ited, JCAHO requires each hospital to
events or product problems related to any             prevent an unreasonable risk of         monitor for adverse events involving phar-
medical product, with the exception of                substantial harm to the public          maceuticals and devices, with medication
                                                      health” or 2) reportable event for      monitoring to be a continual collaborative
those occurring with vaccines. Reports
                                                      which FDA has requested 5-day
can be sent to FDA either directly or, in                                                     function20. JCAHO standards indicate that
most cases, via the manufacturer.                                                             medical product adverse event reporting
     Reports concerning vaccines should             • Annual Certification of number          should be done per applicable law/regula-
be sent to the Vaccine Adverse Event                  of reports                              tion, including those of state/federal regu-
Reporting System (VAERS), a joint pro-           • Distributor:                               latory bodies20.
gram of the FDA and the Centers for                 • Deaths (to FDA and manufacturer              The American Society of Health-
                                                      within10 days)                          System Pharmacists (ASHP) has also
Disease Control and Prevention16. Certain
events following immunization (e.g., par-           • Serious injuries/illnesses (to          been instrumental in the evolution of
alytic poliomyelitis after oral poliovirus            FDA and manufacturer within 10          active internal hospital adverse drug event
vaccine)17 are mandated by the National               days)                                   (ADE)-monitoring systems. ASHP guide-
Childhood Vaccine Injury Act of 1986 to             • Malfunctions (to FDA and                lines include delineated criteria for classi-
be reported, but VAERS accepts all reports            manufacturer within 10 days)            fying an adverse drug reaction (ADR) as
of suspected significant adverse events                                                       significant21, unlike JCAHO standards,
after any vaccine administration16. For        other groups that perform similar func-        which do not mandate a specific definition
more information on VAERS, call 1-800-         tions to physicians' offices (e.g, dentists,   for a serious ADE. ASHP guidelines
822-7967.                                      optometrists, nurse practitioners) from        specifically state serious or unexpected
     Health professionals working in a         mandatory reporting18. However, health         ADRs should be reported to FDA, manu-
hospital or other user facility (nursing       professionals within a user facility should    facturer, or both21.
home, ambulatory surgical facility, outpa-     familiarize themselves with their institu-          As user facilities, hospitals are sub-

                        Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
  4      The Clinical Impact of Adverse Event Reporting

ject to mandatory federal medical device       TABLE 3                                            requirements.
adverse event reporting. TABLE 2 (on                Adverse Event (AE) Reporting                       TABLE 3 outlines mandatory report-
previous page) outlines these require-           Requirements for Pharmaceuticals22,23            ing regarding pharmaceuticals22,23. By
ments, which include reporting by the           • 15-day "Alert Reports": each AE both            regulation, these companies are required
facility of suspected medical device-relat-       serious and unexpected (i.e, not in the         to report all adverse events of which they
ed deaths to both FDA and the manufac-            product's current labeling) must be re-         are aware to the FDA and to provide as
                                                  ported to the FDA within 15 working days
turer, and serious injuries/illnesses to the                                                      complete information as possible. As can
manufacturer or to FDA, if the manufac-         • Periodic AE Reports: all non-15 day AE          be seen, mandated pharmaceutical report-
                                                  reports must be reported periodically
turer is unknown18. However, there are no         (quarterly for the first three years after      ing relies heavily on information provided
federal laws or regulations that require          approval, then annually)                        by health professionals through both vol-
hospitals to report pharmaceutical-related      • Other: the frequency of reports of 1) AEs       untary reporting and the scientific litera-
adverse events to the FDA, although they          that are both serious and expected, and 2)      ture.
are strongly encouraged to do so regarding        therapeutic failures must be periodically            In the case of over-the-counter (OTC)
                                                  monitored, and any significant increase
those events deemed serious.                      must be reported within 15 days                 drugs, reports are only required on OTC
                                                                                                  products marketed under an approved
                                                • Scientific Literature: a 15-day report
Reporting Required By Law or                      based on scientific literature (case reports;   New Drug Application (NDA), including
Regulation                                        results from a formal clinical trial;           those prescription drugs that undergo a
     Reporting by individual healthcare           epidemiology-based studies or "analyses         switch to OTC status. Reports are not
                                                  of experience in a monitored series of
providers is essentially voluntary.               patients")                                      required for other OTC drugs (i.e., older
However, manufacturers and distributors                                                           drug ingredients which are marketed with-
                                                • Postmarketing Studies: no requirement
of FDA approved pharmaceuticals (drugs            for a 15-day report on an AE acquired           out an NDA), although voluntary report-
and biologics) and medical devices, plus          from a postmarketing study unless               ing is encouraged.
pharmaceutical packers and device user            manufacturer concludes pharmaceutical                Both prescription and OTC drugs
                                                  causation for AE "reasonable possibility"
facilities, all have mandatory reporting                                                          require FDA safety and efficacy review
                      MEDICAL DEVICES                                     cuffs was requested, as was the use of non-cuffed tips whenever
                                                                          possible. Physicians were urged to screen patients for latex aller-
          Barium Enema Kits and Sudden Death                              gy histories and concomitant drug use.
     Three reports of sudden death associated with the use of
barium enema kits were reported to the FDA. The first case,               Further regulatory actions were subsequently taken:
reported in 1989, involved a 49 year-old female with a history                 1) Health Hazard Evaluation of the tips/cuffs lead to the rec-
of atopic dermatitis, allergic rhinitis and asthma who was under-         ommendation that the Medical Alert be expanded to include
going a barium enema for occult blood in her stool when she               more health professionals and organizations. The firm added an
reported the onset of an allergic reaction47. The study was               additional washing of the cuffs in the manufacturing process and
immediately terminated, but within minutes she began to have              wrote a letter to all health professionals concerning allergic
increasing dyspnea, then became cyanotic. The patient was                 reactions associated with the use of barium enema products with
intubated, and underwent unsuccessful resuscitation efforts47.            latex cuffs;
     In April 1990, two more cases of sudden death associated
                                                                               2) After a second Health Hazard Evaluation determined that
with the use of barium enema kits were reported. A 41 year-old
                                                                          the problems associated with these devices presented a high risk
female complained of nausea shortly after insertion and infla-
                                                                          of serious adverse health consequences, the firm initiated a
tion of the tip/cuff assembly, went into cardiac arrest within 30
                                                                          recall of all latex cuffed enema tips;
seconds and underwent unsuccessful resuscitation efforts. In the
third case, a 72 year-old female had an immediate reaction after               3) An ad hoc FDA committee that was formed to consider
the tip portion of the tip/cuff assembly was inserted prior to            additional action developed an FDA Medical Alert which out-
introduction of the barium contrast agent, went into vascular             lined the occurrence of several severe allergic reactions to med-
collapse and died.                                                        ical devices containing latex and suggested ways to screen and
     Review of the adverse event database revealed no other               protect allergic patients. This was sent to approximately 1,000
reports of reactions to barium enema procedures. However, lit-            radiological and medical organizations, and was published in the
erature review showed a potential problem with reactions to               July 1991 FDA Medical Bulletin;
devices containing latex48, of which the barium enema cuffs are                4) Manufacturers of latex devices received an FDA letter
made. Various FDA investigations were undertaken, including               discussing how to manufacture latex products in order to mini-
collection of samples of gloves, devices and lubricants.                  mize the possibility that latex contaminants are either a source
     As a result, the manufacturer of the enema tips voluntarily          of, or contributing factor to, adverse reactions to various types
agreed to send out an urgent Medical Alert to approximately               of latex devices.
10,000 radiologists that notified them of adverse reactions pos-                These events led to a 1992 International Conference on
sibly associated with latex allergy that could occur during bari-         latex sensitivity and the practice of physicians testing patients
um enema procedures. Minimizing use of tips with retention                for latex sensitivity prior to undergoing surgical procedures.

                        Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
                                                                                A   MEDWATCH   Continuing Education Article         5

prior to marketing, unlike dietary supple-            Reaching a firm conclusion about the     ported cases in characteristics such as time
ments (which include vitamins, minerals,        relationship between exposure to a med-        to onset or severity35.
amino acids, botanicals and other sub-          ical product and the occurrence of an
stances used to increase total dietary          adverse event can be difficult. In one         Estimation of Population Exposure
intake). By law24 the manufacturers of          study, clinical pharmacologists and treat-          Compounding these numerator limi-
dietary supplements do not have to prove        ing physicians showed complete agree-          tations is the lack of denominator data,
safety or efficacy, so the onus is on the       ment less than half the time when deter-       such as user population and drug exposure
FDA to prove that a particular product is       mining whether medication, alcohol or          patterns35, that would provide the exact
unsafe. As a result, direct-to-FDA volun-       "recreational" drug use had caused hospi-      number of patients exposed to the medical
tary health professional reporting of seri-     talization29.                                  product, and thus at risk for the adverse
ous adverse events possibly associated                Such considerations emphasize the        event of interest. Numerator and denomi-
with dietary supplements is particularly        crucial need for careful, thoughtful review    nator limitations make incidence rates
important.                                      of adverse event reports upon their receipt    computed from spontaneously reported
     TABLE 2 (on page 3) lists the med-         by FDA or the manufacturer. It is through      data problematic35, if not completely
ical device-related reporting required          this process that causality, or at least a     baseless. However, even if the exposed
of user facilities, manufacturers, and dis-     high degree of suspicion for a product-        patient population is not precisely known,
tributors18.                                    adverse event association, is put to the       estimation of the exposure can be attempt-
     All unsolicited reports from health        test.                                          ed through the use of drug utilization
professionals received by FDA via either                                                       data36.
the voluntary or mandatory route are            Underreporting                                      This approach, whose basic method-
called spontaneous reports. A sponta-                Another major concern with any            ologies are applicable to medical products
neous report is a clinical observation that     spontaneous reporting system is underre-       in general, can be of great utility. Major
originates outside of a formal study25. The     porting of adverse events16,30-32. It has      sources of data on the use of drugs by a
combination of adverse event information        been estimated that rarely more than 10%       defined population include market surveys
generated by all reporting makes up the         of serious ADRs, and 2-4% of non-serious       based on sales or prescription data, third-
database upon which postmarketing sur-          reactions, are reported to the British spon-   party payers or health maintenance
veillance depends.                              taneous reporting program30. A similar         organizations, institutional/ambulatory
                                                estimate is that the FDA receives by direct    settings or specific pharmacoepidemio-
LIMITATIONS & STRENGTHS                         report less than 1% of suspected serious       logical studies36. Cooperative agreements
OF SPONTANEOUS REPORTS                          ADRs32. This means that cases sponta-          and contracts with outside researchers
DATA                                            neously reported to any surveillance pro-      enable FDA to utilize such databases in its
     As with clinical trials, there are         gram, which comprise the numerator,            investigations. Device utilization studies
important limitations to consider when          generally represent only a small portion of    employ the same sources of data, as well
using spontaneously reported adverse            the number that have actually occurred.        as Medicare-derived information.
event information. These limitations            The effect of underreporting can be some-           Care must be taken in interpreting
include difficulties with adverse event         what lessened if submitted reports, irre-      results from studies utilizing these data-
recognition, underreporting, biases, esti-      spective of number, are of high quality.       bases. That drug prescribing does not nec-
mation of population exposure and report                                                       essarily equal drug usage36, and the
                                                Biases                                         applicability of results derived from a spe-
quality.                                             Unlike clinical trial data, which are     cific population (such as Medicaid recipi-
             LIMITATIONS                        obtained under strictly controlled condi-      ents) to the population at large, need to be
                                                tions, spontaneously reported information      weighed carefully.
Adverse Event Recognition                       is uncontrolled, and therefore subject to
     The recognition of ADEs [or any            the possible influence of a number of bias-    Report Quality
other medical product-associated adverse        es that can affect reporting. These biases          The ability to assess, analyze and act
event] is quite subjective and imprecise26.     include the length of time a product has       on safety issues based on spontaneous
While an attribution between the medical        been on the market, country, reporting         reporting is dependent on the quality of
product and the observed event is assumed       environment, detailing time and quality of     information submitted by health profes-
with all spontaneously reported events,         the data33. A striking illustration of the     sionals in their reports. A complete
every effort is made to rule out other          impact one such factor can have is the         adverse event report should include the
explanations for the event in question. It is   finding that the peak of spontaneous ADR       following: product name (and information
well known that placebos27 and even no          reporting for a drug is at the end of the      such as model and serial numbers in the
treatment28 can be associated with adverse      second year of marketing, with a subse-        case of medical devices); demographic
events. In addition, there is almost always     quent precipitous decline in reporting34       data; succinct clinical description of
an underlying background rate for any           despite a lack of apparent decline in usage    adverse event, including confirmatory/rel-
clinical event in a population, regardless      or change in ADR incidence34,33. In addi-      evant test/laboratory results; confounding
of whether there was exposure to a              tion to these biases, it is possible that      factors (such as concomitant medical
medical product.                                reported cases might differ from nonre-        products and medical history); temporal
                         Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
  6      The Clinical Impact of Adverse Event Reporting

information, including date of event onset        Generation of Hypotheses and Signals              TABLE 4
and start/stop dates for use of medical                Making the best possible use of the           Useful Factors For Assessing Causal
product; dose/frequency of use (as applic-        data obtained through monitoring under-             Relationship Between Drug and
able); biopsy/autopsy results (as applica-        lies postmarketing surveillance38. To-                 Reported Adverse Event40
ble); dechallenge/rechallenge information         wards that goal, the great utility of sponta-
(if available); and outcome.                      neous reports lies in hypothesis genera-           • Chronology of administration of
     Given the limitations of spontaneous-                                                             agent, including beginning and
                                                  tion31, with need to explore possible
                                                                                                       ending of treatment and adverse
ly reported data, what are its strengths?         explanations for the adverse event in ques-          event onset
                                                  tion. By fostering suspicions39, sponta-
                                                  neous report-based surveillance programs           • Course of adverse event when
                                                  perform an important function, which is to           suspected agent stopped
Large-Scale and Cost-Effective                    generate signals of potential problems               [dechallenge] or continued
     Two vital advantages of surveillance         that warrant further investigation.                • Etiologic roles of agents and diseases
systems based on spontaneous reports are               Assessment of the medical product-               in regard to adverse event
that they potentially maintain ongoing            adverse event relationship for a particular
surveillance of all patients, and are rela-       report or series of reports can be quite dif-      • Response to readministration
tively inexpensive37. In fact, they are                                                                [rechallenge] of agent
                                                  ficult. TABLE 4 lists factors that are help-
probably the most cost-effective way to           ful in evaluating the strength of associa-         • Laboratory test results
detect rare, serious adverse events not dis-      tion between a drug and a reported
covered during clinical trials.                                                                      • Previously known toxicity of agent
                                                  adverse event40.
                                                                                On November 17, FDA requested a nationwide recall of all
                   SPECIAL NUTRITIONALS                                    over-the-counter dietary supplements in capsule or tablet form
                                                                           providing 100 mg or more of L-tryptophan in a daily dose. On
        L-tryptophan Related Eosinophilia-Myalgia                          March 23, 1990, because of the identification of one case of EMS
                                                                           associated with a dietary supplement containing less than 100 mg,
      In July 1989, a healthy 44 year-old woman in Santa Fe with a         and continued efforts by some firms to circumvent the recall, the
 history of allergic rhinitis started taking L-tryptophan, an essential    agency requested an expansion of the recall to all marketed prod-
 amino acid available as an dietary supplement, for insomnia. By           ucts containing added manufactured L-tryptophan. Excepted were
 early September she was reporting onset of cough, shortness of            those that were permitted to contain added L-tryptophan under
 breath and weakness. When first seen by a physician in late               existing food additive regulations. Additionally, on March 22, the
 September, she presented with a puffy, flushed face, abdominal            agency had imposed an import alert to detain all foreign shipments
 pain, mucosal ulcers, myalgia and weakness. Her white blood cell          of manufactured L-tryptophan.
 (WBC) count was 11,900 cells/mm3, with an eosinophil count of                  Because virtually all manufactured L-tryptophan is imported
 42%. Her condition worsened through October, with her WBC ris-            into the U.S., the practical effect of the recall and import alert was
 ing to 18,200 and eosinophil count to 45%.                                to effectively eliminate the availability of L-tryptophan-containing
      Her physician consulted with a rheumatologist, who while             dietary supplements. Eventually, more than 1,500 cases of EMS,
 not knowing what was wrong with this patient, did know of a sec-          including 38 deaths, have been reported to the CDC, although the
 ond patient who had been hospitalized in Santa Fe with similar            true incidence of the disorder is thought to be much higher.
 symptoms and eosinophil count. In mid-October, a third patient in              The recognition of a cluster of cases was the key to the detect-
 New Mexico, who had an eosinophil count of 9,000 and had also             ing of EMS. Interactions among various specialists, including a
 been taking L-tryptophan, was discovered. While one patient was           family physician, hematologist, rheumatologist, clinical immunol-
 unusual and two was suspicious, three made it a cluster of a very         ogist and epidemiologists, was crucial to this process49.
 uncommon disease.                                                              Of equal importance is ongoing basic and clinical research to
      All three original patients were middle-aged women.                  explain the etiology and pathogenesis of this disorder. Although it
 Although the severity differed, all had the common features of            is widely believed that contaminants or impurities in the L-trypto-
 myalgia, weakness, oral ulcers, abdominal pain, shortness of              phan are responsible for EMS, continuing research indicates a role
 breath and skin rash. While the doses of L-tryptophan they had            for "pure" tryptophan itself50-52, as well as for certain host factors
 used were similar, the duration of use prior to onset of illness var-     in the etiology of the disorder53,54. These findings support sugges-
 ied from a few weeks to 2 years. Common laboratory features               tions that the L-tryptophan-associated EMS was caused by sever-
 included striking leukocytosis, eosinophilia, elevated aldolase           al factors and is not necessarily related to a contaminant in a sin-
 [with a normal creatine kinase (CK)] and abnormal liver function          gle source of L-tryptophan.
 tests.                                                                         FDA concerns about the safety of L-tryptophan-containing
      An article about the condition appeared in the November 7            products and the possibility of potential new cases of L-trypto-
 Albuquerque Journal News. On November 11, FDA issued a                    phan-related EMS are underscored by recent information indicat-
 Public Advisory against the use of L-tryptophan, followed four            ing the availability of L-tryptophan by American sources. Both
 days later by the Centers for Disease Control and Prevention              EMS's clinical seriousness, and uncertainties surrounding its eti-
 (CDC) establishment of a system of national state-based surveil-          ology, indicate the need for health professionals to remain vigilant
 lance for the newly named eosinophilia-myalgia syndrome                   regarding adverse events possibly associated with the use of L-
 (EMS)49.                                                                  tryptophan-containing dietary supplements, and to report such
                                                                           events to MEDWATCH.

                         Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
                                                                                A   MEDWATCH    Continuing Education Article                         7

     The stronger the drug-event relation-          All reports from health professionals
ship in each case and the lower the inci-      (direct reports) and specific reports from
dence of the adverse event occurring           manufacturers are individually reviewed
spontaneously, the fewer case reports are
needed to perceive causality41. It has been
found that for rare events, coincidental
                                               by an FDA health professional safety eval-
                                               uator, with particular attention to all
                                               reported serious adverse events that are
drug-event associations are so unlikely        not in labeling in the case of pharmaceuti-
that they merit little concern, with greater   cals44. All other reports are entered into
than three reports constituting a signal       the database for use in aggregate analysis.
requiring further study35. In fact, it has     In focused evaluation of adverse events,
been suggested that a temporal relation-       the postmarketing surveillance database is
ship between medical product and adverse       searched for other reports, and further
event, coupled with positive dechallenge       steps such as literature searches and use of
and rechallenge, can make isolated reports
conclusive as to a product-event associa-
tion42. Biological plausibility and reason-
                                               medical product utilization databases may
                                               be taken.
                                                    Based on careful review of sponta-
                                                                                                      If it’s
able strength of association aid in deem-
ing any association as causal30.
     However, achieving certain proof of
causality through postmarketing surveil-
                                               neous reports, the FDA can initiate vari-
                                               ous actions, including a "Dear Health
                                               Professional" letter or Safety Alert; label-
                                               ing, name or packaging change(s); con-
lance is unusual41. Attaining a prominent
degree of suspicion is much more likely,
and may be considered a sufficient basis
                                               ducting further epidemiologic investiga-
                                               tions; requesting manufacturer-sponsored
                                               postmarketing studies; conducting inspec-
                                                                                                    we need
for regulatory decisions41.

Clinician Contribution
                                               tions of manufacturers' facilities/records;
                                               or working with a manufacturer regarding
                                               possible withdrawal of a medical product
                                                                                                    to know.
     The reliance of postmarketing sur-        from the market.
veillance systems on health professional            Four clinical synopses44-55 provided
reporting enables an individual to help        by each of the four participating FDA
improve public health. This is demonstrat-     Centers that outline examples of regulato-
ed by one study that found direct practi-      ry actions based on postmarketing surveil-
tioner participation in the FDA sponta-        lance are presented throughout the article.
neous reporting system was the most            The clinical synopses demonstrate the
effective source of new ADR reports that
led to changes in labeling43. Ensuring that
                                               step-wise process of spontaneous reports
                                               evaluation that is utilized at the FDA. In        1-800-FDA-1088.
the information provided in the adverse        addition, these cases clearly illustrate that
event report is as complete and in depth as    a single adverse event report from a health
possible further enhances postmarketing        professional can often lead to an FDA
surveillance.                                  action that has clinical importance.
     Thus, while possessing inherent
limitations, postmarketing surveillance
                                                    At times signals generated by the                            MED           WATCH
                                                                                                                  THE FDA MEDICAL PRODUCTS REPORTING PROGRAM
                                               spontaneous reporting system are of suffi-
based on spontaneous reports data is a         cient strength that further epidemiologic          If it’s serious, we need to know.
powerful tool for detecting adverse            investigation is not necessary, a situation
event signals of direct clinical impact. It    exemplified by the clinical synopses.
is dependent not only on health                However, non-epidemiologic types of
professional participation, but also on        studies may be indicated, such as those          DISSEMINATION OF SAFETY-
the quality of the reports that are            attempting to explain the etiology of
submitted.                                                                                      RELATED INFORMATION
                                               eosinophilia-myalgia syndrome50,53,54.
                                                                                                      Keeping medical product labeling/
                                                    Should formal epidemiologic study
FDA EVALUATION OF REPORTS                      be deemed useful in regard to an adverse         package inserts up to date is an ongoing,
OF ADVERSE EVENTS                              event, well-validated methods can be uti-        dynamic process that depends on new
     The very uncontrolled nature of spon-     lized by FDA, industry, and academia in          information gleaned from spontaneous
taneously reported data places great           their investigations*. For example, FDA          adverse event reports. Remaining current
importance on the evaluation of submitted      regulation of oral contraceptives has relied     with changes in medical product informa-
reports of adverse events. This process is     heavily on the findings of case-control and      tion can be an imposing task for the busy
perhaps most accurately characterized as a     cohort studies56.                                health professional. As a result, an impor-
method, applied on a case-by-case basis,                                                        tant public health aspect of postmarketing
that is based on experience, knowledge of      *A future MEDWATCH Continuing Education          surveillance is the dissemination of safety-
                                               Article will focus on the use of epidemiologic
the medical product being monitored and        principles and methods in the study of medical   related information to the clinical commu-
awareness of the limitations of the data.      product safety.                                  nity.
                        Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
  8        The Clinical Impact of Adverse Event Reporting

                                                                                                CLINICAL SYNOPSIS 4
     The FDA, in concert with the prod-          ing the most recent notifications.
uct's manufacturer, informs health profes-            In addition, MEDWATCH utilizes its                           DRUGS
sionals of the most serious and pressing         Partner program to disseminate new safe-
safety issues through such mechanisms as         ty-related information. To date, over 100          Temafloxacin and Hemolytic
“Dear Health Professional” letters, Safety                                                                   Anemia
                                                 health professional organizations have
Alerts, Public Health Advisories, Talk           joined FDA as Partners and work with                 Temafloxacin, a fluoroquinolone
Papers and Urgent Notices. Two recent            MEDWATCH to increase awareness of, and          antibiotic, was first marketed in
examples demonstrating this educational          participation in, postmarketing surveil-        January, 1992. By early April, FDA
process are outlined in TABLE 5.                 lance. Notifications like Safety Alerts are     had received a few reports of hemolyt-
 TABLE 5                                         provided to the Partners as they are            ic anemia occurring in patients treated
   Examples of Safety-Related FDA                released, with the information in turn dis-     with this drug. Over the next two
            Notifications                        tributed by the Partners to their members.      months, many additional cases were
 • Retinal Photic Injuries From Oper-                 It is important for health profession-     reported, eventually totaling nearly
   ating Microscopes During Cataract             als to be aware that not all changes in         100. These provided a clear picture of
   Surgery:                                      medical product information necessitate         what was subsequently called the
 Despite all efforts taken to minimize the       use of mechanisms such as a “Dear Health        “temafloxacin syndrome”55.
 risks of retinal damage, retinal photic                                                              The typical patient was a young
 injuries from the light sources used in oper-   Professional” letter. These are reserved for
 ating microscopes during cataract surgery       only the most serious and pressing adverse      woman with no underlying medical
 and other intraocular procedures may occur.     events. While the Physicians' Desk              conditions who was treated for urinary
 Several factors appear to be important          ReferenceR contains official labeling for       tract infection with temafloxacin.
 determinants of photic retinal injury. These                                                    Within 7-10 days of starting treatment,
 include: angle of light incidence, light        most drugs and can be reviewed periodi-
                                                 cally for changes, FDA is currently look-       dark colored urine was often noted,
 intensity, exposure time, and intensity of
 the blue light component. FDA recom-            ing at other ways, including the Internet,      sometimes with accompanying flank
 mends several actions to reduce the risk of                                                     pain and chills. There was typically a
                                                 by which new safety-related information
 retinal photic injury and reminds physicians                                                    drop in hemoglobin of 3 grams or
 about the reporting requirements of the         can be made more readily available to
                                                                                                 greater. Acute renal failure developed
 Safe Medical Devices Act of 1990.               health professionals.
                                                                                                 in nearly two thirds, with hemodialysis
 [October 16, 1995 FDA Public Health
 Advisory]                                                                                       usually required. Mild hepatobiliary
                                                 SUMMARY                                         changes were noted in half the patients,
 • FDA Requires Labeling Change on                    The effectiveness of a national post-      and coagulopathy in one third.
   Lindane-Containing Lice Treatments:           marketing surveillance program is                    A subset of patients experienced
 Lindane is generally safe and effective         directly dependent on the active participa-
 when used according to the approved direc-
                                                                                                 the syndrome after their first dose of
 tions, but its overuse can be harmful. FDA      tion of health professionals. The limita-       temafloxacin. That these patients were
 has recommended labeling changes that           tions of premarketing clinical trials in        more likely to have had prior exposure
 encourage lindane's use only for patients       detecting adverse events make the safety        to a fluoroquinolone antibiotic provid-
 who have either failed to respond to ade-       profile of any medical product an evolv-        ed support for an antibody-mediated
 quate doses of, or are intolerant of, other
 approved therapies. In addition, product        ing, ongoing process contingent on the          basis for massive hemolysis.
 labeling will advise health care providers      availability of up-to-date information               On the basis of spontaneously
 and parents not to confuse prolonged itch-      derived from postmarketing clinical expe-       reported cases, the manufacturer, in
 ing with reinfestation. The label already       rience.                                         consultation with FDA, voluntarily
 warns parents that neurotoxicity is possible                                                    withdrew temafloxacin from the mar-
 for certain patients, especially infants.            Despite the limitations of sponta-
 [April 3, 1996 FDA Talk Paper]                  neous reports, FDA's program for the sur-       ket worldwide in June, barely six
                                                 veillance of regulated medical product          months after initial marketing.
                                                 safety provides vital information of clini-          In 1994, FDA staff published a
                                                 cal importance. The identification of prob-     multicase review article describing the
     The population of health profession-
                                                 lems, and the subsequent dissemination of       “temafloxacin syndrome”55.
als to whom individual notifications are
distributed is not always universal, and is      safety-related information to the clinical
dependent on the medical product and the         community at large, begins with reports
provider specialties most likely to be           from astute health professionals.
involved. As a result, other methods are              By viewing adverse event reporting
used to reach the broadest possible health                                                      The MEDWATCH program would like to
                                                 as a professional responsibility, and recog-
                                                                                                thank Mary W. Brady, RN, MSN, Suzanne E.
professional audience. The MEDWATCH              nizing that the quality of data generated      Rich, RN and Marie H. Reid, RN, BSN
column in the FDA Medical Bulletin,              from spontaneous reports is determined         (CDRH) for their contributions to the medical
which is distributed to 1.2 million health       by the quality of the submitted informa-       device clinical synopsis. In addition, the edito-
professionals nationwide, seeks to                                                              rial contributions of Vincent F. Guinee, MD,
                                                 tion, health professionals can play a major
enhance general awareness by summariz-                                                          MPH and Robert C. Nelson, PhD (CDER)
                                                 role in improving the public health.           are gratefully acknowledged.

                          Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
                                                                                     A   MEDWATCH    Continuing Education Article            9
1. Hayes PE, Kristoff CA. Adverse reactions       20. Joint Commission on Accreditation of           41. Auriche M, Loupi E. Does proof of causali-
    to five new antidepressants. Clin Pharm           Healthcare Organizations. 1996 Compre-             ty ever exist in pharmacovigilance? Drug
    1986;5:471-480                                    hensive Accreditation Manual for                   Saf 1993;9:230-235
2. Kinney JL. Nomifensine maleate: a new              Hospitals. Oakbrook Terrace, IL: Joint         42. Temple RJ, Jones JK, Crout JR. Adverse
    second-generation antidepressant. Clin            Commission on Accreditation of Healthcare          effects of newly marketed drugs. N Engl J
    Pharm 1985;4:625-636                              Organizations, 1995                                Med 1979;300:1046-1047
3. Nomifensine withdrawn by manufacturer.         21. ASHP guidelines on adverse drug reaction       43. Rossi AC, Knapp DE. Discovery of new
    FDA Drug Bull 1986;16:7-8                         monitoring and reporting. Am J Health Syst         adverse drug reactions: a review of the
4. Hoechst-Roussel Pharmaceuticals                    Pharm 1995;52:417-419                              Food and Drug Administration's
    Inc. Withdrawal of Merital. Somerville, NJ:   22. 21 CFR 314.80                                      Spontaneous Reporting System. JAMA
    Hoechst-Roussel Pharmaceuticals Inc,          23. 21 CFR 600.80                                      1984;252:1030-1033
    January 1986                                  24. Dietary Supplement Health and Education        44. Turner WM, Milstien JB, Faich GA,
5. Mamelok RD. Drug discovery and devel-              Act (DSHEA) of 1994                                Armstrong GD. The processing of adverse
    opment. In: Melmon KL, Morrelli HF,           25. Faich GA. Adverse-drug-reaction monitor-           event reports at FDA. Drug Information
    Hoffman BB, Nierenberg DW, eds.                   ing. N Engl J Med 1986;314:1589-1592               Journal 1986;20:147-150
    Melmon and Morrelli's Clinical                26. Koch-Weser J, Sellers EM, Zacest R. The        45. Sekul EA, Cupler EJ, Dalakas MC. Aseptic
    Pharmacology: Basic Principles in                 ambiguity of adverse drug reactions. Eur J         meningitis associated with high-dose intra-
    Therapeutics. 3rd ed. New York:                   Clin Pharmacol 1977;11:75-78                       venous immunoglobulin therapy: frequency
    McGraw-Hill, Inc; 1992:911-921                27. Green DM. Pre-existing conditions,                 and risk factors. Ann Intern Med
6. Venning GR. Identification of adverse              placebo reactions, and "side effects".             1994;121:259-262
    reactions to new drugs. II--how were 18           Ann Intern Med 1964;60:255-265                 46. Scribner CL, Kapit RM, Phillips ET,
    important adverse reactions discovered        28. Reidenberg MM, Lowenthal DT. Adverse               Rickles NM. Aseptic meningitis and intra-
    and with what delays? Br Med J                    nondrug reactions. N Engl J Med                    venous immunoglobulin therapy. Ann
    1983;286:289-292                                  1968;279:678-679                                   Intern Med 1994;121:305-306
7. Wallender M-A. The way towards adverse         29. Karch FE, Smith CL, Kerzner B,                 47. Feczko PJ, Simms SM, Bakirci N. Fatal
    event monitoring in clinical trials. Drug         Mazzullo JM, Weintraub M, Lasagna L.               hypersensitivity reaction during a barium
    Saf 1993;8:251-262                                Adverse drug reactions - a matter of               enema. AJR Am J Roentgenol
8. Reeves PR, McCormick DJ, Jepson HT.                opinion. Clin Pharmacol Ther                       1989;153:275-276
    Practolol metabolism in various small ani-        1976;19:489-492                                48. Ownby DR, Tomlanovich M, Sammons N,
    mal species. Xenobiotica 1979;9:453-458       30. Rawlins MD. Pharmacovigilance: paradise            McCullough J. Anaphylaxis associated with
9. Rosenbaum SE, Lindup WE, Orton TC.                 lost, regained or postponed? The William           latex allergy during barium enema exami-
    Practolol and its metabolites: tissue             Withering Lecture 1994. J R Coll                   nations. AJR Am J Roentgenol
    localization and retention in the hamster.        Physicians Lond 1995;29:41-49                      1991;156:903-908
    J Pharmacol Exp Ther 1985;234:485-490         31. Strom BL, Tugwell P. Pharmacoepidem-           49. Hertzman, PA. L-trytophan related
10. MEDWATCH Continuing Education                     iology: current status, prospects, and prob-       eosinophilia-myalgia syndrome.
    Article. Clinical therapeutics and the            lems. Ann Intern Med 1990;113:179-181              In: Drug and Device Induced Disease:
    recognition of drug-induced disease.          32. Scott HD, Rosenbaum SE, Waters WJ,                 Developing a Blueprint for the Future.
    Goldman SA, Kennedy DL, Lieberman                 Colt AM, Andrews LG, Juergens JP, et al.           Proceedings of a MEDWATCH Conference;
    R, eds. Rockville, Md: Food and Drug              Rhode Island physicians' recognition and           1994 Jan 21-22; Rockville, Md. Rockville,
    Administration, June 1995                         reporting of adverse drug reactions. R I           Md: FDA, 1994
11. Lewis JA. Post-marketing surveillance:            Med J 1987;70:311-316                          50. Love LA, Rader JI, Crofford LJ, Raybourne
    how many patients? Trends Pharmacol Sci       33. Sachs RM, Bortnichak EA. An evaluation             RB, Principato MA, Page SW, et al.
    1981;2:93-94                                      of spontaneous adverse drug reaction               Pathological and immunological effects of
12. Kessler DA. Introducing MEDWatch: a               monitoring systems. Am J Med                       ingesting L-tryptophan and 1,1'-ethyli-
    new approach to reporting medication              1986;81(suppl 5B):49-55                            denebis (L-tryptophan) in Lewis rats. J Clin
    and device adverse effects and product        34. Weber JCP. Epidemiology of adverse reac-           Invest 1993;91:804-811
    problems. JAMA 1993;269:2765-2768                 tions to nonsteroidal antiinflammatory         51. Farinelli S, Mariani A, Grimaldi A, Mariani
13. American Medical Association. Reporting           drugs. In: Rainsford KD, Velo GP, eds.             M, Iannessi A, De Rosa F. [Eosinophilia-
    adverse drug and medical device events:           Advances in Inflammation Research.                 myalgia syndrome associated with 5-OH-
    report of the AMA's Council on Ethical            Vol 6. New York: Raven Press; 1984:1-7             tryptophan. Description of a case]. Recenti
    and Judicial Affairs. Food and Drug Law       35. Begaud B, Moride Y, Tubert-Bitter P,               Prog Med 1991;82:381-384
    Journal 1994;49:359-366                           Chaslerie A, Haramburu F. False-positives      52. Lampert A, Joly P, Thomine E, Ortoli JC,
14. Advisory Opinion No. 1 to Section 4-A,            in spontaneous reporting: should we worry          Lauret P. [Scleroderma-like syndrome with
    Devices and Therapeutic Methods, of the           about them? Br J Clin Pharmacol                    bullous morphea during treatment with 5-
    American Dental Association Principles of         1994;38:401-404                                    hydroxytryptophan, carbidopa and fluni-
    Ethics and Code of Professional Conduct       36. Serradell J, Bjornson DC, Hartzema AG.             trazepam]. Ann Dermatol Venereol
15. The Journal of the American Medical               Drug utilization study methodologies:              1992;119:209-211
    Association. JAMA instructions for                national and international perspectives.       53. Flockhart DA, Clauw DJ, Sale EB, Hewett
    authors. JAMA 1996;275:5-12                       Drug Intell Clin Pharm 1987;21:994-1001            J, Woosley RL. Pharmacogenetic character-
16. Chen RT, Rastogi SC, Mullen JR, Hayes         37. Fletcher AP. Spontaneous adverse drug reac-        istics of the eosinophilia-myalgia syndrome.
    SW, Cochi SL, Donlon JA, et al. The               tion reporting vs event monitoring: a com-         Clin Pharmacol Ther 1994;56:398-405
    Vaccine Adverse Event Reporting System            parison. J R Soc Med 1991;84:341-344           54. Okada S, Sullivan EA, Kamb ML, Philen
    (VAERS). Vaccine 1994;12:542-550              38. Finney DJ. The detection of adverse reac-          RM, Miller FW, Love LA. Human leuko-
17. The National Childhood Vaccine Injury             tions to therapeutic drugs. Stat Med               cyte antigen (HLA) DRB1 alleles define
    Act of 1986, at Section 2125 of the Public        1982;1:153-161                                     risk factors for the development of eosino-
    Health Service Act as codified at 42 U.S.C.   39. Finney DJ. Statistical aspects of monitoring       philia myalgia syndrome (EMS) [abstract].
    300aa-25(Suppl 1987)                              for dangers in drug therapy. Methods Inf           Arthritis Rheum 1994;37(Suppl):S274
18. 21 CFR 803 and 807                                Med 1971;10:1-8                                55. Blum MD, Graham DJ, McCloskey CA.
19. Protecting the identities of reporters of     40. Standardization of definitions and criteria        Temafloxacin syndrome: review of 95
    adverse events and patients; preemption of        of causality assessment of adverse drug            cases. Clin Infect Dis 1994;18:946-950
    disclosure rules. Fed Regist 1995;                reactions: drug-induced liver disorders:       56. Sobel S. The role of epidemiology in the
    60(April 3);16962-16968                           report of an international consensus meet-         regulation of oral contraceptives. Public
                                                      ing. Int J Clin Pharmacol Ther Toxicol             Health Rep 1984;99:350-354

                          Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
  10 The Clinical Impact of Adverse Event Reporting

                                                 Self-Assessment Questions
  This program is sponsored by the Center for Drug Evaluation and Research (CDER), Food and Drug Administration.

  CDER is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for
  physicians. The Center designates this program for 2 credit hours in Category 1 of the Physician's Recognition Award of the American Medical

   CDER is approved by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education
   (ACPE Universal Program No. 601-000-96-091-H01). This program meets the ACPE criteria for .2 continuing education units             R

   (2 contact hours) in pharmaceutical education.

   To receive certification of continuing medical education or pharmaceutical education credit the participant must:
   • Answer at least 7 of the 10 self-assessment questions correctly
   • Provide the required information on the answer sheet on the next page
   • Participants receiving a failing grade will be notified                         NOTE: THIS PROGRAM EXPIRES ON MARCH 31, 1998

1. Which of the following is NOT a              3. Which of the following statements is           5. Which of the following represents a
  known limitation of premarketing                 FALSE with regard to MEDWATCH?                    example of VOLUNTARY adverse
  clinical trials?                                                                                   event reporting?
                                                   A. Causality is a prerequisite for
   A. Narrow population                               reporting an adverse event to                 A. User facility report of serious
                                                      MEDWATCH                                         injury in a patient using a medical
   B. Ability to detect common adverse                                                                 device
      events                                       B. Any adverse event that is fatal,
                                                      life-threatening or requires                  B. Quarterly periodic report from a
   C. Short duration                                  intervention to prevent permanent                manufacturer regarding a drug
                                                      impairment or damage fulfills the                approved less than three years ago
   D. Small size                                      MEDWATCH guideline for being
                                                      considered serious                            C. Health professional report of a
   E. Narrow set of indications                                                                        serious adverse event in a patient
                                                   C. An increase in the reporting of                  taking several different drugs
                                                      serious adverse events is a
2. Which of the following statements is               MEDWATCH goal                                 D. Manufacturer report of a serious
   FALSE?                                                                                              and unexpected adverse event in
                                                   D. The voluntary MEDWATCH form is                   a patient using a biologic
  A. Once a new medical product is                    to be used by health professionals
     marketed, the number of patients                 in reporting adverse events related           E. Health professional report of
     exposed to the product greatly                   to all FDA-regulated medical                     paralytic poliomyelitis occurring
     increases                                        products, except vaccines                        in a patient following vaccination
                                                                                                       against polio
  B. Premarketing clinical trials are              E. Increasing understanding/
     conducted under controlled                       awareness of health professionals
     conditions in defined populations                regarding medical product-induced           6. All of the following are known
                                                      disease is a MEDWATCH goal                    limitations of spontaneous reports
  C. The capability to detect adverse                                                               data EXCEPT:
     interactions with other medical
     products is generally enhanced             4. Which of the following products                  A. Very costly to obtain
     once a new medical product is                 does NOT require FDA safety and
     marketed                                      efficacy review prior to marketing:              B. Lack of denominator data

  D. Once a new medical product is                 A. Prescription drugs                            C. Biases
     marketed, its initial labeling/
     product information remains                   B. Biologics                                     D. Subjectivity of adverse event
     unchanged                                                                                         recognition
                                                   C. Dietary supplements
  E. Differences between the                                                                        E. Underreporting
     premarketing and postmarketing                D. Over-the-counter (OTC) drugs
     environments make adverse event
     detection and reporting by health             E. None of the above - they ALL
     professionals very important                     require FDA safety and efficacy                           Continued on next page...
                                                      review prior to marketing

                        Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
                                                                                                           A   MEDWATCH   Continuing Education Article          11

7. Which of the following statements is                                     8. All of the following are FDA actions         C. Ongoing potential monitoring of
   FALSE?                                                                     that can result from careful analysis            all patients
                                                                              of spontaneous adverse event reports
   A. The importance of adverse event                                         EXCEPT:                                       D. Allow for major contributions by
      reports evaluation derives from                                                                                          clinicians
      the uncontrolled nature of spon-                                         A. Conducting of further epidemio-
      taneously reported information                                              logic investigations                      E. Cost-effective in detecting rare,
                                                                                                                               serious adverse events
   B. Literature searches and use of                                           B. Requesting manufacturer-
      medical product utilization                                                 sponsored postmarketing studies
      databases can be part of the                                                                                        10. All of the following are methods by
      adverse event reports evaluation                                         C. Changing labeling/product                   which the FDA disseminates
      process                                                                     information                                 safety-related information to health
                                                                                                                              professionals EXCEPT:
   C. Awareness of the limitations of                                          D. Working with the manufacturer on
      spontaneous data is important in                                            the issuance of a “Dear Health            A. Work with manufacturers on the
      adverse event reports evaluation                                            Professional” letter that outlines           issuance of “Dear Health
                                                                                  the serious safety issue involved            Professional” letters, Safety Alerts
   D. Biological plausibility and                                                                                              and Urgent Notices
      strength of association are                                              E. None of the above - ALL are
      unimportant in adverse event                                                actions the FDA can initiate in this      B. Use of the MEDWATCH Partner
      reports evaluation                                                          regard                                       program

   E. Full assessment of reported                                                                                           C. Publications in the scientific
      unlabeled serious adverse events                                      9. All of the following are known                  literature
      is an important aspect of adverse                                        strengths of postmarketing
      event reports evaluation                                                 surveillance systems based on                D. The MEDWATCH column in the
                                                                               spontaneous reports EXCEPT:                     FDA Medical Bulletin

                                                                               A. Hypothesis generation                     E. None of the above - ALL are used
                                                                                  (signaling function)                         by the FDA to inform health
                                                                                                                               professionals of new safety
                                                                               B. Relatively immune to bias                    information

Please Note:                                  ADVERSE EVENT REPORTING
• Do not mail answer
  sheet if it was
  previously faxed.
                                                                                          MED       WATCH
                                                                      APPLICATION FOR CONTINUING EDUCATION CREDIT
• Continuing education
  credit for this article
  can be awarded only                                  1. ______ 2. ______ 3. ______ 4. ______ 5. ______ 6. ______ 7. ______ 8. ______ 9. ______ 10. ______
                                                        Date:_________________________         Phone Number:___________________________________________
• To check on the
  status of your                                        Name (including degree):___________________________________________________________________
  certificate, call
                                                        Type of Health Professional:_________________________________________________________________
  Gale White at
  (301) 443-0117.                                       Address:_________________________________________________________________________________

                      ¡ Please cut along dotted line

                                                        City:_____________________________ State:____________________ Zip Code:____________________

                                                        The article met the stated learning objectives:

                                                            ___ Strongly Agree ___ Agree ___ Disagree ___ Strongly Disagree ___ Cannot Decide

                                                        The information presented is relevant to my clinical practice:   ___ Agree   ___ Disagree

                                                        t Please send me a free copy of The FDA Desk Guide for Adverse Event and Product Problem Reporting
                                                          (contains forms and instructions)
                                                                                         Mail the completed answer sheet by 3/31/98 to:
                                                         MEDWATCH, HF-2, Rm 9-57, FDA, 5600 Fishers Lane, Rockville, MD 20857 or FAX it to 1-800-FDA-0178.

                                                   Report Serious Adverse Events and Product Problems to MEDWATCH 1-800-FDA-1088
                                                              of patients
     The Food and Drug Administration (FDA)'s
                                                               by doing
     monitoring of the continued safety of market-
     ed medical products depends greatly upon                 one thing.
     reporting of adverse events by health profes-
     sionals. An understanding of how FDA
     uses this information, and of the limitations/            adverse
     strengths of the national postmarketing sur-             reactions.
     veillance system, underscores the importance
     of this professional responsibility to the
     public health.
                                                                  MED          WATCH
                                                                  THE FDA MEDICAL PRODUCTS REPORTING PROGRAM
                                                      If it’s serious, we need to know.
Public Health Service
Food and Drug Administration, HF-2
Rockville, MD 20857
Official Business
Penalty for Private Use $300
    Complimentary CE Article

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