Transcript SECTION 506(b)

POST-MARKETING
SURVEILLANCE: ONE DIVISION
DIRECTOR’S VIEW
RUSSELL KATZ, M.D.
DIRECTOR
DIVISION OF NEUROLOGY
PRODUCTS/CDER
POST-MARKETING SURVEILLANCE IS:
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Detecting a signal
Determining causality/frequency
Doing something about it
Informing relevant parties about the problem
TYPES OF SAFETY SIGNALS WE SEE
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Adverse Events
Medication Errors
Product Failures
Labeling Failures
WAYS THAT WE BECOME AWARE OF A
SAFETY SIGNAL
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Literature
Spontaneous Reports (AERS)
Manufacturer
Private citizen
Trials
Registries
ADVERSE EVENTS
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Tysabri and Liver Injury
Botox and “Botulism”
Dopamine Agonists and Cardiac Valvulopathy
Pathological Gambling
Tysabri and Progressive Multifocal
Leukoencephalopathy (PML)
• Anticonvulsants and Suicidality
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
ADVERSE EVENTS-SPONTANEOUS
REPORTS (AERS)
• Adverse Events with “known” background rates
– Tolcapone and liver failure
– Felbamate and aplastic anemia
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
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
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)
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
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
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
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
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
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
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
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
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
MEDICATION ERRORS
• Lamictal/Lamisil
• Reminyl/Amaryl
• Fosphenytoin
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
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
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
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
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
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
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
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
AVAILABLE ACTIONS
• Labeling changes
– Tysabri and PML, Liver injury
– Dopamine agonists and impulsive behaviors
– Novantrone
– Carbamazepine
AVAILABLE ACTIONS
• Dear Health Care Practitioner Letters
• Name Change
– Reminyl to Razadyne
• Removal from Market
– Tysabri
– Pergolide (“compassionate IND” instituted)
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
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)
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
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
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
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
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
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
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
WHERE AGENCY CAN IMPROVE
• May propose action with little prior notification to
industry
• May confuse, mislead, (anger?) relevant
constituencies with early communications, public
announcements
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
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
THE FUTURE
CHANGE WE CAN BELIEVE IN
OR
SOLUTIONS FOR AMERICA