Integrated Analyses of Safety Data needed! - PowerPoint PPT Presentation

Integrated Analyses of Safety Data needed!

Marie Louise Valentin, MD

Director of Corporate Drug Safety

Integrated Safety Outputs (ISOs):

• Regulatory purposes
• Signal Detection
• Presentations: Consistency and Clarity
• Risk Management Plans (RMPs)

MedDRA:

• Standardised MedDRA Queries (SMQs)

• Applications and regulatory documents only summarize the safety database
• Statisticians today only analyse safety data acrosstrials, 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

Many regulatory documents require reporting of safety information:

• IND Annual Report (FDA)
• Annual Safety Report (EMEA)
• Investigator’s Brochure
• Risk Management Plans
• DMC Data Packages
• Investigational Medical Product Dossier (Risk/Benefit)
• Integrated Safety Summary – CTD

• 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.

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

• 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

• 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)

• 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

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.

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

• 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

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 initiating trials in

• New active substances
• New indications – incl extension to a different population
• New routes/formulations

• 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

• 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

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

Anticholinergic syndrome

Cardiac arrhythmias

Cerebrovascular disorders

Convulsions

Dementia

Embolic and thrombotic events

Pseudomembranous colitis

Retroperitoneal fibrosis

Shock

Available in

MedDRA version 9.0