Postmarket Monitoring of Protein Therapeutics · Postmarket Monitoring of Plasma Protein...
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Postmarket Monitoring of Plasma Protein Therapeutics Ginette Y. Michaud, M.D. Deputy Director, Office of Blood Research and Review US Food and Drug Administration International Plasma Protein Conference Dublin, Ireland March 5, 2013
Transcript of Postmarket Monitoring of Protein Therapeutics · Postmarket Monitoring of Plasma Protein...
Postmarket Monitoring of Plasma Protein Therapeutics
Ginette Y. Michaud, M.D.
Deputy Director, Office of Blood Research and Review
US Food and Drug Administration
International Plasma Protein Conference
Dublin, Ireland
March 5, 2013
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Outline
Pharmacovigilance
& Pharmacoepidemiologic Studies in Support of Regulatory Actions
FDA’s Sentinel Initiative
Immune Globulins & Hemolysis
Immune Globulins & Thrombosis
Other FDA News
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Pharmacovigilance
& Pharmacoepidemiologic
Studies in Support of Regulatory Actions
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Postmarket Safety Data Collection & Risk AssessmentOnce a product is marketed, there is generally a large
increase in the number of patients exposed, including those
with co‐morbid conditions and those being treated with
concomitant medical products.
Therefore, postmarket safety data collection and risk
assessment based on observational data are critical for
evaluating and characterizing a product's risk profile and for
making informed decisions on risk mitigation and
minimization.
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Pharmacovigilance
Pharmacovigilance
principally involves the identificationand evaluation of safety signals.
Safety Signal:
generally indicates the need for further investigation, which may or may not lead to the conclusion that the product caused the event & whether other action is
indicated
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Routine Pharmacovigilance
All‐inclusive surveillance for medical products conducted by both
the US FDA and sponsors
Continuous safety monitoring with passive surveillance
Disproportionality
analyses of spontaneous reports
Periodic reports (PAERS or DSURS)
Signal detection and evaluation
Medical literature review
Contact with international public health and regulatory agencies
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Good Pharmacovigilance Practices
•
Identifying & describing safety signals
•
Investigating a signal through observational
studies
•
Interpreting safety signals
•
Developing a pharmacovigilance plan
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf
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Signal Evaluation
Initial evaluation performed through careful review
of cases & search for additional cases.
Additional cases may be identified from:
sponsor’s global adverse event databases
the published literature
other available databases, such as FDA’s Adverse Event Reporting System (FAERS)
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Signal Evaluation
Emphasis usually placed on review of
serious, unlabeled adverse events
Other events may warrant further investigation, e.g.,
apparent increase in severity of a labeled event
occurrence of serious events that are extremely rare in
general population
new product‐product interactions
identification of a previously unrecognized at‐risk
population (e.g., populations with specific racial or genetic
predispositions or co‐morbidities)
concerns arising from the way a product is used (e.g.,
higher than labeled doses; off‐label indication)
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Searching FAERS
In assessing case reports, it is important to look for features
that may suggest a causal relationship, including:
Occurrence of the adverse event in the expected time
Absence of symptoms related to the event prior to exposure
Evidence of positive dechallenge
or positive rechallenge
Consistency of the event with the established pharmacological and/or
toxicological effects of the product
Consistency of the event with the known effects of other products in
the class
Existence of other supporting evidence from preclinical studies,
clinical trials, and/or pharmacoepidemiologic
studies, and
Absence of alternative explanations for the event (e.g., no
concomitant medications that could contribute to the event; no co‐
or
pre‐morbid medical conditions).
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Searching FAERS
For any individual case report, it is rarely possible to
know with a high level of certainty whether event was caused by the product.
Pharmacoepidemiologic
studies may be employed
to further examine the potential association between a product and an adverse event.
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Searching FAERS
Use of Data Mining to Identify Product‐Event Combinations:
Systematic examination of reported adverse events by using statistical or mathematical tools, or data mining, can provide additional information about the existence of
an excess of adverse events reported for a product.
Data mining is not a tool for establishing causal attributions between products & adverse events.
Data mining approaches are inherently exploratory or hypothesis generating.
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Data Mining
Voluntary adverse event reporting systems such as FAERS are
subject to a variety of reporting biases, including:
observations that reflect concomitant treatment, the disease
being treated, other co‐morbidities
unrecorded confounders that cause the events to be
reported
Other limitations:
submission of incomplete or duplicate reports,
underreporting,
or reporting stimulated by publicity or litigation.
Reporting biases may differ by product and change over time, andcould change differently for different events.
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Putting the Signal into Context
Calculating Reporting Rates vs
Incidence Rates
Putting a signal into context – the hallmark of pharmacoepidemiologic
risk assessment
Calculating the rate at which new cases of adverse events occur in the product‐exposed population (i.e.,
the incidence rate)
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Putting the Signal into Context
In passive reporting databases
the size of the population at risk is at best, an estimate due
to under‐reporting
limitations in national denominator estimates arise
because:
accurate national estimates may not be available;
difficult to exclude patients not at risk e.g., brief
exposure; low dose
use estimates not available for specific population of
interest
In pharmacoepidemiologic
studies, the numerator (number of
cases) and denominator (number of exposed patients and
time of exposure) may be readily ascertainable.
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Beyond Case Review: Investigating a Signal Through Observational Studies
FDA recognizes that there are a variety of methods for investigating a safety signal. Signals warranting additional investigation can be further evaluated
through:
carefully designed nonrandomized observational studies of the product’s use in the “real world”
(e.g., pharmacoepidemiologic
studies, registries, and surveys)
randomized trials
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Beyond Case Review: Investigating a Signal Through Observational Studies
When conducting a pharmacoepidemiologic
study of a signal
warranting additional investigation, a variety of data sources
may be used:
prospective collection of data
use of existing data, such as data from previously
conducted clinical trials or large databases
use of automated claims databases (e.g., HMO, Medicare,
Medicaid) that allow retrieval of records on product
exposure and patient outcomes (retrospective analyses)
comprehensive electronic medical record databases
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Beyond Case Review: Investigating a Signal Through Observational Studies
Pharmacoepidemiologic
study (unlike case series) has:
protocol
control group
pre-specified hypotheses
can allow estimation of the relative risk of an outcome and in some studies, estimates of risk (incidence rate) for an adverse event
allows the identification of other potential risk factors
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Signal detection
Signal evaluation: hypothesis testing in a formal pharmacoepidemiologic
study
Active Surveillance
Medical Literature
Signal refinement
FAERS Prelicensure safety data Other sources
Data Mining
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Interpreting Safety Signals: From Signal to Potential Safety Risk
Factors that are typically considered include:
Strength of the association (e.g., relative risk of the adverse event associated with the product)
Temporal relationship of product use and the event
Consistency of findings across available data sources
Evidence of a dose-response for the effect
Biologic plausibility
Seriousness of the event relative to the disease being treated
Potential to mitigate the risk in the population
Feasibility of further study using observational or controlled clinical study designs; and
Degree of benefit the product provides, including availability of other therapies
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Regulatory Action
the assessment may point to the need for
further investigation of the signal through additional
studies, and/or
risk mitigation actions
potential actions include
providing additional safety information to the public,
updating drug labeling,
requiring postmarket studies or trials,
requiring additional risk management interventions (e.g.,
REMS), or,
(on rare occasions) removing a drug from the market.
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Impact of FDA Amendments Act of 2007 on Postmarket Safety Activities
Authority to require postmarket studies and trials
Communication:
Authority to require label changes based on new safety information
Quarterly publication of potential safety signals
Published conclusions from an 18‐month post‐ approval safety review
Pediatric Advisory Committee review
Risk Mitigation:
Authority to require Risk Evaluation and Mitigation Strategies to ensure benefits outweigh risks
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FDA CBER Product Safety Communication
MedWatch
Safety Alerts ‐
timely new actionable safety
information that may impact treatment
Biologics Safety and Availability Information ‐
notices about
recalls, shortages, adverse events, and biological product
deviations.
Potential Signals of a Serious Risk from the FAERS (FDAAA
Title IX, Section 921) in quarterly report on the Adverse Event
Reporting System Website of any new safety information or
potential signal of a serious risk identified by FAERS within the
last quarter.
Comprehensive 18‐month safety review (Section 915) of
recently approved drug and biologic products (what the FDA
has learned 18 months after approval or after the medicine
was used in 10,000 patients, whichever occurs later).
Post‐approval Pediatric Safety Reviews for Pediatric Advisory
Committee (PAC).
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FDA’s Sentinel Initiative
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Sentinel Initiative
FDA’s response to the FDAAA 2007 mandate
Launched in May 2008
Development of an active electronic safety monitoring system to:
strengthen FDA's ability to monitor postmarket performance of medical products and detect and refine safety signals
implement a proactive system that will complement existing systems to track reports of adverse events
enable FDA to access existing automated healthcare data by partnering with data holders (e.g., insurance companies with large claims databases, owners of electronic health records, others)
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Sentinel Initiative
Enables FDA to actively query diverse automated healthcare data holders to evaluate possible medical product safety issues quickly and securely.
Data continue to be managed by its owners and questions are sent to the participating data holders who evaluate their information and send summary results to FDA within pre-established privacy and security safeguards.
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Sentinel Initiative Public-private partnership
Mini-Sentinel•
Collaboration of data partners, academia, non-profit organizations• Covers all FDA regulated medical products
Federal Partners Collaboration• Department of Defense (DoD)• Department of Veterans Affairs (VA)• Centers for Medicare & Medicaid Services (CMS)
OMOP*
Brookings Institution
Postlicensure Rapid Immunization Safety Monitoring program (PRISM)
Blood Safety Continuous Active Surveillance Network (Blood-SCAN)
Components of the Sentinel Initiative
* Observational Medical Outcomes Partnership
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Basic Distributed Database Model
Health Plan 2
Health Plan 3
Health Plan N
Health Plan 1
Coordinating Center FDA
Privacy Firewall
Informatics (e.g. SAS code) Epidemiologic and statistical study design
Management
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Basic Distributed Database Model
Health Plan 2
Health Plan 3
Health Plan N
Health Plan 1
Coordinating Center FDA
Privacy Firewall
Aggregate data transfer to ensure privacy
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Mini‐Sentinel Distributed Database
Comprised of quality-checked data held by 17 partner organizations
126 million individuals (December 12, 2011)
345 million person-years of observation time from 2000–2011
43 million individuals enrolled, accumulating new data
27 million individuals having ≥3 years of data
Potential uses
Immediate “next step”
after passive surveillance/data mining findings
Estimate incidence rates of health outcomes of interest
Enables FDA to prioritize safety issues
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Blood‐SCAN
Blood Safety Continuous Active-Surveillance Network (Blood-SCAN)
Under development to meet the requirement for an active surveillance network
Collection of blood product exposure codes
Literature scan of health outcomes of interest
Structured interactions with data partners
Planned expansion of data sources underway
Preparation for protocol driven pharmacoepidemiologic
studies underway
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Blood‐SCAN
Coming protocol based assessment of thromboembolic
events
after Immune Globulins (IGs) in Blood‐SCAN.
Objectives:
follow up of safety signals from pilot work in the Healthcore
claims database with additional work in the larger Blood‐
SCAN distributed database
development of improved pharmacoepidemiologic
assessment capability for IGs
should efforts to reduce
Factor XIa
not eliminate procoagulant
activity.
http://minisentinel.org/assessments/medical_events/details.aspx?ID=187
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Immune Globulins & Hemolysis
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Immune Globulins (IG) and Hemolysis
Hemolysis
is a long‐recognized complication of IG infusion
Increased reports to FDA and other agencies in 2011
Attributed to IgG
isoagglutinins
in IG products
Risk factors include high doses, recipient blood type A, AB, or
B; possibly patient factors (inflammatory diseases)
Complications can include severe anemia, renal failure, DIC
US & EU products are required to have specifications for Anti‐A &Anti‐B antibodies of </= 1:64 in direct hemagglutinin
assay
IGIV‐associated hemolysis
occurs although products meet
licensed specifications
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Immune Globulins and HemolysisSafety Communication on risks of hemolysis
potentially related toadministration of intravenous, subcutaneous & intramuscular human immuneglobulin products; 11‐13‐2012
FDA recommendations:
Heightened awareness of the potential for hemolysis
in individuals receiving immune globulin products, particularly those determined to be at
increased risk.
Patients at increased risk for hemolysis
include those with non-O blood group types, those with underlying associated inflammatory conditions,
and those receiving high cumulative doses of immune globulins over several
days.
As noted in product labeling, patients receiving immune globulin
products should be monitored for hemolysis, particularly those at increased risk.
Clinical symptoms and signs of hemolysis
include fever, chills and dark urine. If these occur, appropriate laboratory testing should be obtained.
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm327934.htm
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Immune Globulins and Hemolysis
Case reports appear to be declining compared to 2011
Continued monitoring of all events
Selected implicated and non‐implicated lots received for
testing
Focus on lots common to more than one hemolytic event
Anti‐A, Anti‐B, aggregates, complement
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Hemolysis
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Risks
Hemagglutinin
dose = Product titer x volume infused
Patient risk factors – not well understood
Indication, dose, and “underlying inflammatory state”
are
strongly linked
High doses are given mostly for autoimmune diseases;
underlying inflammatory state as a risk is difficult to prove
Do certain manufacturing steps influence risk?
Plasma pool antibody titers
Are titers driven by a few donors or many?
Are certain donors at risk of having particularly high
titers?
Does manufacturing influence risk independently of donor
titers?
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Risk Mitigation – Short Term
Communication
FDA Web posting on 11/13/2012 highlights risk information: http://www.fda.gov/BiologicsBloodVaccines/S
afetyAvailability/ucm327934.htm
Is there a role for labeling changes regarding?
risk associated with high dose, non-O blood group, and underlying inflammatory state
possibility of renal dysfunction/failure or DIC as a consequence of hemolysis
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Risk Mitigation – Long Term
Is there a threshold isoagglutinin
dose that increases risk of
clinically significant hemolysis?
Multiple lots frequently administered to a single
patient; difficult to know exact isoagglutinin
dose
Feasibility of identifying low anti‐A, anti‐B lots for patients
receiving high doses IGIV ‐
logistical challenges
Can manufacturing changes result in lower titer products?
Plasma selection? Specific removal of isoagglutinins?
Are there product‐related characteristics that confer greater
hemolysis
risk at any given hemagglutinin
dose?
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Other Considerations
FDA considering holding a workshop in fall of 2013 for public
discussion of IG products, hemolysis
and its mitigation.
What could be gained from a workshop?
data/proposals for additional evaluation of recipient risk factors
better understanding of IG product risk factors
exploration of different strategies for lowering risk of products:
Eliminating “high titer”
isoagglutinin
plasma
Providing low titer isoagglutinin
products for high dose IG
recipients
Removing isoagglutinins
during manufacturing
Identifying other contributory product characteristics
PPTA joining steering committee along with other organizations
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Immune Globulins & Thrombosis
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Immune Globulins and ThrombosisSafety Communication on risks of thrombosis potentially related toadministration of intravenous, subcutaneous and intramuscular humanimmune globulin products; 11‐13‐2012FDA Recommendations:
Care should be used when immune globulin products are given to individuals
determined to be at increased risk of thrombosis.
Patients at increased risk of thrombosis include those with acquired or hereditary
hypercoagulable
states, prolonged immobilization, in‐dwelling vascular catheters,
advanced age, estrogen use, a history of venous or arterial thrombosis, cardiovascular
risk factors (including history of atherosclerosis and/or impaired cardiac output), and
hyperviscosity
(including cryoglobulins, fasting chylomicronemia
and/or high
triglyceride levels, and monoclonal gammopathies).
As noted in product labeling, patients at risk for thrombosis should receive immune
globulin products at the slowest infusion rate practicable, and these individuals
should be monitored for thrombotic complications.
Consideration should also be given to measurement of baseline blood viscosity in
individuals at risk for hyperviscosity.
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm327934.htm
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Thrombosis –
Current Activities
Lot release testing
Thrombin generation test transferred to Lot Release
Branch (DBSQC)
Thrombin Generation Testing in research laboratory
Technical refinements to TGT method
Continued participation in international collaborative
studies to develop standards and methods for
procoagulant
testing of IG products
In‐house IGIV comparators
Low detectable activity batch
High activity batch (containing levels of activity
associated with thrombosis)
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Thrombosis –
Current Activities
Risk‐based research testing for procoagulant
activity (IG
products & manufacturing processes) –
ongoing
Research testing of IG primarily focused on products with:
Increased TEs
by spontaneous reports
Products with high levels reported by other authorities
High reporting rates in insurance database
All IND products with new manufacturing methods or
for use in vulnerable populations
Lower priority for research testing of IG if:
No current or historically high TE rates by spontaneous
reporting
Lower signal in insurance database data
Low volumes or very low doses administered
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Thrombosis –
Current Activities
Manufacturing process –
ongoing work
Active work with individual manufacturers to
change manufacturing to lower procoagulant activity in products
Evaluation of manufacturer procoagulant
activity tests, setting of limit values and provisional
specifications
Process validation review for changed and new
manufacturing processes, to assure removal of procoagulant
activity is not affected
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Thrombosis – Current Activities
Risk communication
Additional detail about risk factors added to IG product
labels
Ad hoc communications with patient groups
Various other actions:
Dear Healthcare Provider letters,
Updated safety information for IG product related
thrombosis and hemolysis, 11/13/2012:
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm327934.htm
Consideration of enhanced labeling to address:
thrombosis risk and risk factors
potential mitigations
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Other FDA News
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Guidance for Industry
(Draft) Recommendations for Screening, Testing, and
Management of Blood Donors and Blood and Blood
Components Based on Screening Tests for Syphilis
(Final) Implementation of an Acceptable Full‐Length and
Abbreviated Donor History Questionnaires and
Accompanying Materials for Use in Screening Donors of
Source Plasma
(Final) Use of Nucleic Acid Tests on Pooled and Individual
Samples from Donors of Whole Blood and Blood
Components, Including Source Plasma, to Reduce the Risk of
Transmission of Hepatitis B Virushttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Bl
ood/default.htm
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Workshops
Public Workshop: Application of Advances in Nucleic Acid and Protein Based Detection; Methods for
Multiplex Detection of Transfusion‐Transmissible Agents and Blood Cell Antigens in Blood Donations;
April 10‐11, 2013, NIH Bethesda Maryland
http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm340812.htm
Immune Globulins and Hemolysis
(planning)
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Patient‐Focused Drug Development
In PDUFA V, FDA committed to a new initiative called Patient‐Focused Drug Development
goal of obtaining patient perspective on certain disease areas during five year period of PDUFA V
seeking perspective on disease severity and currently available therapeutic options
to support FDA decision‐making by establishing context in which regulatory decision is made
four patient‐focused consultation meetings to be led by CBER
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm
