Download Analysis of Safety Data

Integrated Analyses of Safety
Data needed!
Marie Louise Valentin, MD
Director of Corporate Drug Safety
Agenda
Integrated Safety Outputs (ISOs):
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Regulatory purposes
Signal Detection
Presentations: Consistency and Clarity
Risk Management Plans (RMPs)
MedDRA:
– Standardised MedDRA Queries (SMQs)
The Issue
• Applications and regulatory documents only summarize
the safety database
• Statisticians today only analyse safety data across
trials, when:
– Potential problems arise or
– The application is for a product from a class with a known
safety concern
Future
• Health Authorities require more regular integrated
safety analyses
Purpose of Integrated Safety Outputs
Many regulatory documents require reporting of
safety information:
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6.
IND Annual Report (FDA)
Annual Safety Report (EMEA)
Investigator’s Brochure
Risk Management Plans
DMC Data Packages
Investigational Medical Product Dossier
(Risk/Benefit)
7. Integrated Safety Summary – CTD
Integrated Safety Outputs
• Regular Integrated Safety Reviews
– To be produced at least annually
– Pool or combine data across studies
– Present data from several studies in a single
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display
Gain
– Provide coordinated and routine review of
integrated safety data
– Assist with the compilation of regulatory documents
reporting safety information/ DMC data/RMP
updates etc.
Considerations for Pooling or Combining Data
Main goal
• More precise estimates by increasing the safety database
In general, ISO produced by indication or formulation:
• Backgound AE may differ according to patient population
• Severity of disease may lead to different assessments of
risk/benefit
• The dose, formulation and duration of treatment may differ
Across indication/formulations beneficial:
• Investigational product developed for related indications
• Characterize a particular AE of interest
• Investigate class effects
The AE profile may be related to…
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Route of administration
Dose
Number of dosages
Duration of exposure
Time since dosing
Indication
Stage of disease treated
Concomitant medication/disease
Effect on target cell/organ e.g. B-lymphocytes
Demography
Signal Detection
• No systematic tools or methods in use within the
industry
• Need to account for all safety data, not just AE records
• Monitor laboratory results for an increase in
abnormalities
• Currently done manually, more efficient and consistent with
standard checks pre-defined and applied to all studies
• Focus on three main areas (the most common reasons
to terminate projects):
– Hepatotoxicity
– Nephrotoxicity
– Haematotoxicity
(Liver)
(Kidney)
(Blood)
Operational Issues
• Maintenance of treatment blind
– Should not be an impediment to a full ongoing
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review of safety data?
Who should have access to data and results?
Should DMCs review un-blinded data?
False signals
– Problem or proactive pharmacovigilance?
• A policy for ’Integrated Safety Outputs’ should
be prepared
Risk Management Plans (RMP)
The overall purpose of a Risk Management Plan
is to describe efforts in:
– Identifying
– Estimating
– Evaluating
– Communicating
– Minimising
risks that may be associated with the product.
Risk Management Plans
EMEA:
• Guideline on Risk Management Systems for
Medicinal Products for human use
– Effective date 20 November 2005
FDA:
• Guidance for Industry: Good
Pharmacovigilance Practices and
Pharmacoepidemiological Assessment
• Pre-marketing Guidance
• Pharmacovigilance Guidance (postmarketing)
• March 2005
Risk Management Plans
• Be product-specific
• Balance assessment of risks and benefits
• Monitor difference between clinical trials and
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”real life”
Identify what is known at licensing
Identify what is not known
Clarify epidemiology of disease and known
adverse effects
What we know and don’t know
Know:
• Population treated
• Time treated
• Time to adverse events
• Identify specific risk groups
• Stratify analysis by dose, duration etc
Don’t know:
• Interactions
• Populations not studied: Children, elderly, pregnancy
• Relevance of class effects
• Long term effects
When do we need a
Risk Management Plan?
When initiating trials in
• New active substances
• New indications – incl extension to a
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different population
New routes/formulations
Standardised MedDRA Queries
• After the initial effort to implement and use
MedDRA, the industry now focuses on data
analysis with MedDRA
– How to produce data summaries based on a more
granular terminology
• Standardised MedDRA Queries (SMQs):
– Groupings of MedDRA terms that are related to a
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defined medical condition
Include terms related to signs, symptoms,
diagnoses, syndromes, physical findings,
laboratory test data
Standardised MedDRA Queries
• Developed in a collaboration with CIOMS, industry and
regulators
(Council for International Organizations of Medical Sciences, WHO
and UNESCO in 1949 )
• Tested in industry and regulatory databases
• Focus on significant safety issues
• Currently, 16 in production and 70 in development
SMQ’s in Production
• Rhabdomyolysis/myopathy
• Torsade de pointes/QT
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prologation
Acute renal failure
Hepatic disorders
Haemolytic disorders
Severe cutaneous adverse
reactions
Anaphylactic reactions
Acute pancreatitis
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Agranulocytosis
Angioedema
Asthma/bronchospasm
Dyslipidaemia
Haematopoietic
cytopenias
• Lack of efficacy/effect
• Lactic acidosis
• Peripheral neuropathy
SMQs in 2nd phase of development
• Adverse pregnancy
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outcome/reproductive
toxicity
Anticholinergic
syndrome
Cardiac arrhythmias
Cerebrovascular
disorders
Convulsions
• Dementia
• Embolic and
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thrombotic events
Pseudomembranous
colitis
Retroperitoneal
fibrosis
Shock
Standardised MedDRA Queries
Available in
MedDRA version 9.0
Questions