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