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Integrated Analyses of Safety Data needed!. Marie Louise Valentin, MD Director of Corporate Drug Safety. Agenda. Integrated Safety Outputs (ISOs): Regulatory purposes Signal Detection Presentations: Consistency and Clarity Risk Management Plans (RMPs) MedDRA:

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integrated analyses of safety data needed

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)


    • Standardised MedDRA Queries (SMQs)
the issue
The Issue
  • 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


  • Health Authorities require more regular integrated safety analyses
purpose of integrated safety outputs
Purpose of Integrated Safety Outputs

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
integrated safety outputs
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 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
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
The AE profile may be related 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 detection
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 (Liver)
    • Nephrotoxicity (Kidney)
    • Haematotoxicity (Blood)
operational issues
Operational 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 rmp
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
Risk Management Plans


  • Guideline on Risk Management Systems for Medicinal Products for human use
    • Effective date 20 November 2005


  • Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiological Assessment
      • Pre-marketing Guidance
      • Pharmacovigilance Guidance (postmarketing)
      • March 2005
risk management plans12
Risk 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 know
What we know and don’t 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 do we need aRisk Management Plan?

When initiating trials in

  • New active substances
  • New indications – incl extension to a different population
  • New routes/formulations
standardised meddra queries
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 defined medical condition
    • Include terms related to signs, symptoms, diagnoses, syndromes, physical findings, laboratory test data
standardised meddra queries16
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

Torsade de pointes/QT prologation

Acute renal failure

Hepatic disorders

Haemolytic disorders

Severe cutaneous adverse reactions

Anaphylactic reactions

Acute pancreatitis





Haematopoietic cytopenias

Lack of efficacy/effect

Lactic acidosis

Peripheral neuropathy

SMQ’s in Production
smqs in 2nd phase of development
Adverse pregnancy outcome/reproductive toxicity

Anticholinergic syndrome

Cardiac arrhythmias

Cerebrovascular disorders



Embolic and thrombotic events

Pseudomembranous colitis

Retroperitoneal fibrosis


SMQs in 2nd phase of development
standardised meddra queries19
Standardised MedDRA Queries

Available in

MedDRA version 9.0