integrated analyses of safety data needed! marie louise valentin, md director of corporate drug...
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Integrated Analyses of Safety Integrated Analyses of Safety Data needed!Data needed!
Marie Louise Valentin, MDDirector of Corporate Drug Safety
AgendaAgendaAgendaAgenda
Integrated Safety Outputs (ISOs):• Regulatory purposes
• Signal Detection
• Presentations: Consistency and Clarity
• Risk Management Plans (RMPs)
MedDRA:– Standardised MedDRA Queries (SMQs)
The IssueThe IssueThe IssueThe 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 Purpose of Integrated Safety OutputsOutputsPurpose of Integrated Safety Purpose of Integrated Safety OutputsOutputs
Many regulatory documents require reporting of safety information:
1. IND Annual Report (FDA)2. Annual Safety Report (EMEA)3. Investigator’s Brochure4. Risk Management Plans5. DMC Data Packages6. Investigational Medical Product Dossier
(Risk/Benefit)7. Integrated Safety Summary – CTD
Integrated Safety OutputsIntegrated Safety OutputsIntegrated Safety OutputsIntegrated 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 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 Considerations for Pooling or Combining DataData
Considerations for Pooling or Combining Considerations for Pooling or Combining DataData
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 The AE profile may be related to… to…
The AE profile may be related The AE profile may be related to… to…
• 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 DetectionSignal DetectionSignal DetectionSignal 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 (Liver)
– Nephrotoxicity (Kidney)
– Haematotoxicity (Blood)
Operational IssuesOperational IssuesOperational IssuesOperational Issues• Maintenance of treatment blind
– Should not be an impediment to a full ongoing 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 Risk Management Plans (RMP)(RMP)
Risk Management Plans Risk Management Plans (RMP)(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 PlansRisk Management PlansRisk Management PlansRisk 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 PlansRisk Management PlansRisk Management PlansRisk Management Plans
• Be product-specific
• Balance assessment of risks and benefits
• Monitor difference between clinical trials and ”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 What we know and don’t knowknow
What we know and don’t What we know and don’t knowknow
Know:• Population treated• Time treated• Time to adverse events• Identify specific risk groups• Stratify analysis by dose, duration etcDon’t know:• Interactions• Populations not studied: Children, elderly, pregnancy
• Relevance of class effects• Long term effects
When do we need aWhen do we need aRisk Management Plan?Risk Management Plan?
When do we need aWhen do we need aRisk Management Plan?Risk Management Plan?
When initiating trials in
• New active substances
• New indications – incl extension to a different population
• New routes/formulations
Standardised MedDRA Standardised MedDRA Queries Queries
Standardised MedDRA Standardised MedDRA Queries 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
defined medical condition– Include terms related to signs, symptoms,
diagnoses, syndromes, physical findings, laboratory test data
Standardised MedDRA Standardised MedDRA QueriesQueries
Standardised MedDRA Standardised MedDRA QueriesQueries
• 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 ProductionSMQ’s in ProductionSMQ’s in ProductionSMQ’s in Production
• Rhabdomyolysis/myopathy
• Torsade de pointes/QT prologation
• Acute renal failure
• Hepatic disorders
• Haemolytic disorders
• Severe cutaneous adverse reactions
• Anaphylactic reactions
• Acute pancreatitis
• Agranulocytosis
• Angioedema
• Asthma/bronchospasm
• Dyslipidaemia
• Haematopoietic cytopenias
• Lack of efficacy/effect
• Lactic acidosis
• Peripheral neuropathy
SMQs in 2nd phase of SMQs in 2nd phase of developmentdevelopment
SMQs in 2nd phase of SMQs in 2nd phase of developmentdevelopment
• Adverse pregnancy outcome/reproductive toxicity
• Anticholinergic syndrome
• Cardiac arrhythmias
• Cerebrovascular disorders
• Convulsions
• Dementia
• Embolic and thrombotic events
• Pseudomembranous colitis
• Retroperitoneal fibrosis
• Shock
Standardised MedDRA Standardised MedDRA QueriesQueries
Standardised MedDRA Standardised MedDRA QueriesQueries
Available in
MedDRA version 9.0
QuestionsQuestions