Chlamydia Sexually Transmitted Disease Surveillance 2008 Division of STD Prevention.
POST-MARKETING SURVEILLANCE: ONE DIVISION DIRECTOR’S VIEW
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Transcript of POST-MARKETING SURVEILLANCE: ONE DIVISION DIRECTOR’S VIEW
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POST-MARKETING SURVEILLANCE: ONE DIVISION
DIRECTOR’S VIEW
RUSSELL KATZ, M.D.
DIRECTOR
DIVISION OF NEUROLOGY
PRODUCTS/CDER
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POST-MARKETING SURVEILLANCE IS:
• Detecting a signal• Determining causality/frequency• Doing something about it • Informing relevant parties about the problem
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TYPES OF SAFETY SIGNALS WE SEE
• Adverse Events• Medication Errors• Product Failures• Labeling Failures
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WAYS THAT WE BECOME AWARE OF A SAFETY SIGNAL
• Literature• Spontaneous Reports (AERS)• Manufacturer• Private citizen• Trials• Registries
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ADVERSE EVENTS
• Tysabri and Liver Injury• Botox and “Botulism”• Dopamine Agonists and Cardiac Valvulopathy• Pathological Gambling• Tysabri and Progressive Multifocal
Leukoencephalopathy (PML)• Anticonvulsants and Suicidality
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ADVERSE EVENTS-SPONTANEOUS REPORTS (AERS)
• Tysabri and Significant Liver Injury– Several individual cases of elevated LFTs and
Bilirubin– Examination of individual cases for alternative
causes; two positive re-challenges• Botox and “Botulism”
– Several cases consistent with known pharmacology
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ADVERSE EVENTS-SPONTANEOUS REPORTS (AERS)
• Adverse Events with “known” background rates
– Tolcapone and liver failure– Felbamate and aplastic anemia
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HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS
REPORTS• Someone (clinical reviewer, safety reviewer, etc.)
detects a serious (possibly unlabeled) adverse event
• Task is to assess causality (also examine RCTs)• Review of individual case report usually not
definitive– Incomplete information– Logically flawed
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HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS
REPORTS• EB 05
– Lower limit of the 90% Confidence Interval around the following metric:
– # of cases of event of interest/ # of total ADRs for the drug DIVIDED BY
– # of cases of event of interest of all drugs/ # of total ADRs for all drugs
– If >2, considered a possible signal
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HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS
REPORTS• Calculation of a Reporting Rate (Not an
incidence)• RR = #cases reported/patient-years of exposure• Patient-years = #prescriptions/12 (assume each
prescription for 30 days)• Compare RR to background rate and other drug(s)
– Assume background rate is relevant– May not be (e.g., nefazadone)
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HOW WE EVALUATE A SAFETY SIGNAL FROM SPONTANEOUS
REPORTS
• Any RR approaching the background rate is presumptive evidence that the drug caused the adverse event due to underreporting (many factors influence reporting or lack thereof)
• In many cases, the spontaneous reports serve as the basis for a definitive decision: i.e., spontaneous reports are not always just hypothesis generating
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ADVERSE EVENTS-SPONTANEOUS REPORTS-LITERATURE
• Dopamine Agonists and Valvulopathy– One case control study, one echocardiographic
prevalence study in NEJM, 2007– Previous studies and AERS search in 2004 led
to conclusion about ergot-derived agonists– Recent AERS search for other agonists, 5HT2B
agonists
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ADVERSE EVENTS-LITERATURE
• Dopamine agonists and Pathologic Gambling– Case series in the literature; mostly Mirapex
(some Requip)– AERS searched for all dopaminergic drugs for
impulse control disorders– Adequate background rates not available
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VARIANT OF ADVERSE EVENT ASSESSMENT-LITERATURE
• Stevens-Johnson Syndrome known to occur with carbamazepine
• Literature reports of a marked increased incidence in Han Chinese patients
• Additional corroboration from international spontaneous reports
• Data “established” HLA B-1502 as an important risk factor for SJS
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ADVERSE EVENTS-CLINICAL TRIALS
• Tysabri and PML– Three cases observed in open-label extensions
of controlled trials being done in Phase 4– Marketing discontinued and entire database
examined for any additional cases-none found – Causality assumed from mechanism
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ADVERSE EVENTS-CLINICAL TRIALS
• AEDs and Suicidality– Sponsor notified us of a signal from their
controlled trials– Submission of a citizen petition raising
questions about another AED– All controlled trials from 11 recently approved
AEDs examined
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ADVERSE EVENTS-CLINICAL TRIALS
• Hypnotics and cancer– Individual academic performed analyses of data
for recently approved hypnotics on the basis of which he concluded that they are associated with an increased risk for cancer
– Resulted in detailed review of numerous databases that did not confirm his conclusions
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ADVERSE EVENTS-REGISTRIES
• Possible teratogenicity (cleft lip/palate) with Lamictal– Sponsor informed division of data from two
pregnancy registries– Analyses of other registries did not reveal
confirmatory findings
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ADVERSE EVENTS-REGISTRIES
• Amendments to monitoring requirements for agranulocytosis for Clozapine– Requested by an interested party based on
family member’s experience– Resulted in detailed review of accumulated data
to date and ultimately a change to the monitoring regimen
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MEDICATION ERRORS
• Lamictal/Lamisil• Reminyl/Amaryl• Fosphenytoin
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HOW WE EVALUATE MEDICATION ERRORS
• Here, detailed review of cases can help pinpoint how the problem arises, and point the way to possible solutions
• Name confusion– Lamictal/Lamisil
• Written/verbal prescription
• Carton appearance; overlapping strengths
• Drug locations on pharmacy shelf
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HOW WE EVALUATE MEDICATION ERRORS
• Here, detailed review of cases can help pinpoint how the problem arises, and point the way to possible solutions
• Name confusion– Reminyl/Amaryl
• Similar written appearance
• Several deaths due to hypoglycemia
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HOW WE EVALUATE MEDICATION ERRORS
• Here, detailed review of cases can help pinpoint how the problem arises, and point the way to possible solutions
• Product Label– Fosphenytoin
• Total units in vial (100 mg/2 mL) vs concentration (50mg/mL)
• Automated displays still use old description
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PRODUCT FAILURES
• Sometimes, the causes (or the errors) are obvious• Example:
– Diastat Accudial (prefilled syringes of diazepam for rectal administration)
• Leakage from cracked tips
• Inappropriate dialing of doses
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PRODUCT FAILURES
• Potential “failures” of generic AEDs to perform adequately (possible ADRs and/or breakthrough seizures) reported to Agency by expert community
• Personal experience• Surveys• Literature
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LABELING FAILURE-PHASE 4 STUDIES
• Novantrone (mitoxantrone): approved for progressive multiple sclerosis
• Two required Phase 4 studies– A study to evaluate incidence of
cardiomyopathy in patients prospectively monitored
– A “real-life” study to see if patients monitored according to labeling-insurance records for 400+ patients
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LABELING FAILURE-PHASE 4 STUDIES
• Novantrone (mitoxantrone): approved for progressive multiple sclerosis– Data show:
• Cardiomyopathy occurs at much lower cumulative doses than previously believed
• Very few patients are monitored appropriately
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AVAILABLE ACTIONS
• Early communications– Press Release, Public Health Announcement
• Pergolide and valvulopathy• Diastat failures
– Physician information sheets• AEDs and suicidality• Teratogenicity and Lamictal
– Early communications• Botox and botulism
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AVAILABLE ACTIONS
• Labeling changes– Tysabri and PML, Liver injury– Dopamine agonists and impulsive behaviors– Novantrone– Carbamazepine
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AVAILABLE ACTIONS
• Dear Health Care Practitioner Letters• Name Change
– Reminyl to Razadyne• Removal from Market
– Tysabri– Pergolide (“compassionate IND” instituted)
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AVAILABLE ACTIONS
• Require studies– AEDs and generic “failures”
• Restricted distribution/observational studies– Tysabri
• Extensive education campaigns and other changes– Lamictal/Lamisil errors– Change carton appearance
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FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT
• Title IX-Drug Safety• Sec. 901
– FDA may require studies or clinical trials at the time of approval (or after approval if new safety information)
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FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT
• May require studies or clinical trials to:– Assess known serious risk related to drug use– Assess signals of serious risk related to drug
use– Identify an unexpected serious risk when
available data indicates the potential for a serious risk
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FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT
• Before a study/trial may be required, FDA must find:– AE reporting and “active postmarketing risk
identification and analysis system” are not sufficient to meet the purposes;
– A post-approval study is not sufficient before requiring a clinical trial
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FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT
• Required labeling changes– Agency must promptly inform sponsor of new
safety information– Within 30 days, the sponsor must submit a
labeling supplement or tell us why not– Rapid turnaround by Agency
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FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT
• Required labeling changes– Within 15 days of conclusion of discussions,
Agency can issue an order for a labeling change– Within 15 days of an order, sponsor must
submit a labeling supplement, or within 5 days, sponsor may appeal the order
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FOOD AND DRUG ADMINISTRATION AMENDMENTS ACT
• Risk Evaluation and Mitigation Strategies (REMS)-Timetables Required– Pre-approval
• FDA may determine REMS needed to ensure benefits outweigh the risks
– Post-approval (if new safety information)• If needed to ensure benefits outweigh risks
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NEW AGENCY SAFETY INITIATIVES
• Safety First– Associate Directors for Safety– Dedicated Project Manager for Safety– Standardized Record Keeping for Safety Issues– Deadlines to be applied for action on safety
issues
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WHERE AGENCY CAN IMPROVE
• No systematic surveillance outside AERS• Most assessments take too long• Have not consistently followed up requests to
industry adequately (either for review of the data or requested labeling changes)
• Coordination with consulting divisions can be more efficient
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WHERE AGENCY CAN IMPROVE
• May propose action with little prior notification to industry
• May confuse, mislead, (anger?) relevant constituencies with early communications, public announcements
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WHERE INDUSTRY CAN IMPROVE
• Slow to respond to Agency requests• Unnecessary negotiations over labeling
– Class labeling• Often don’t inform Agency of a problem (even if
considerable work has been done)• May meet technical requirements for informing
Agency (e.g., PSUR) but problems not flagged
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WHERE INDUSTRY CAN IMPROVE
• Even if Agency informed, may not have a proposal for a comprehensive plan
• On the other hand, some proposals appear to be overly “negative”– Proposed labeling may describe adverse event
which we all agree is not causally related to drug
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THE FUTURE
CHANGE WE CAN BELIEVE IN
OR
SOLUTIONS FOR AMERICA