Principles of Signal Detection & Risk Management in Pharmacovigilance

Dr Pipasha BiswasMD MFPM DM MRQA

Principal Consultant & DirectorSymogen Limited, UK.

ISPRT & SOPI Conference, Lady Hardinge Medical College, New Delhi26 – 28 November 2010

Topics Covered in This Session

• What is Signal Detection?• Methodologies in Signal Detection.• Usefulness of Signal Detection in

Pharmacovigilance• How is a Signal Identified and what is done

next• What is Risk management• Components of an RMP

Introduction• Populations exposed to any drug during post

marketing period vary vastly than those studied during the development of the compound

• In daily practice – real world situation- Patients are not selected- Diverse patient populations- large patient population- Polypharmacy- Several underlying disease factors and concomitant medications

Introduction

• New information on the benefits and risks of any drug may be generated at any time after marketing

• Continuously monitor the safety of the compound/drug throughout the life cycle product

• Continuously assess the benefit risk profile in order to guarantee patient safety

What is a Signal?• Reported information on a possible causal

relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. WHO Definition

• Hypothesis generating• Does not establish any causal relationship

between the drug and the event• Suggests further studies• Should be quick and credible

Other Definitions of Signal

• Early identification of suspected signals with subsequent generation of hypothesis

• Hypothesis of a signal can be generated by identification of:- unexpected SAE (also non-serious) or change in its severity- Increases in reporting frequency of an expected event- AEs experienced in special population groups (i.e. Paediatric, elderly, hepato-renal compromised patients etc)

SIGNAL:

New Safety Information• A new Signal

- Unidentified- Unlabelled

• New information from an existing signal- Change in frequency- Change in severity

• Information on risk factors

Sources of Signals• Premarketing Trials Database• Spontaneous Reports of ADRs

- Individual company database- AERS database- WHO-UMC- EMEA- National & Regional RA database

• Published Literature• Epidemiology/Registries• Automated Databases

- GPRD- IMS- Medicaid- Kaiser Permanante

• Others- PEM- MEMO

Signal Detection Process Flow

Detection of a Signal

Generation of Hypothesis

Verification

Decision to be taken Information

Factors to Consider in Signal Detection

Considerations for when a Drug-Event Pair is a Signal

Patient Characteristics

Trends

Pharmacological Plausibility

ClassEffect

Drug Event Pair

Related SimilarEvents

DPAOver Time

DPA Score

Commonly drug-Related event

SIGNAL

Evaluating Signals Using Evidence Hierarchy

Signal Detection Process

Signal Identified

Information Gathering

Clinical TrialData

(ISS, ISO)

Epidemiology Literature

Spontaneous Data

IncludingDPA Info

Pre-Clinical animal

Toxicology &Pharmacology

Other Databases

(AERS, WHO)

Methodologies in Signal Detection

• Several methodologies are used and available for the purpose of signal detection activities

• Quantitative• Qualitative• RA, Drug monitoring Centres and Pharmaceutical

Companies have developed computerised data mining methods for the purpose of early identification of safety signals in spontaneous reporting databases

• To date there is no guideline or standard method for performing signal detection activities

Data Quality

• Data Quality of all case reports entered into the safety database is essential in order to retrieve and extract the correct safety information

• Completeness and correctness of the ICSR information is the key to good signal detection

• Quality check of entered data

How Signal detection is done?

• Qualitative Analysis: - Signal case/multiple report evaluation

Combined with or without

• Qualitative Analysis- Automated identification of signals

Qualitative Analysis• Case by case review and thorough assessment by

medically qualified persons• Systematic review of multiple case reports

- review of cummulative data- review of frequency trends over time and frequency rates to specific PTs and/or SMQs and/or HLTs or even SOCs with combined retrospective analysis using computerised tools

• Pre-clinical data, scientific support documentation, characteristics of patient population exposed, pharmacological plausibility etc are evaluated in detail

Quantitative Analysis

• Various automated statistical methods used in analysis of safety data

• Most commonly used are;- Proportional reporting Ratio (PRR): MHRA- Reporting Odd’s Ratio (ROR): LAREB- Multi-item Gama Poisson Shrinker (MGPS): FDA- Bayesian Confidence Propogation Neural Network (BCPNN): UMC

Quantitative analysis

• The key main concept of such statistical method is “Disproportion or more than what is Expected”.

Statistical Tools Used for Signal Detection

• All measures are calculated from a 2x2 table- Proportional Rate Ratio (PRR)- Reporting Odds Ratio (ROR)- Relative Reporting Ratio (RRR)- Information Component (IC; Bayesian)

Statistical Tools Used for Signal Detection

• All measures are calculated from a 2x2 table- Proportional Rate Ratio (PRR)- Reporting Odds Ratio (ROR)- Relative Reporting Ratio (RRR)- Information Component (IC; Bayesian)

Event

(R)

All Other Events

TOTAL

Medicinal Product (P) A B A+B

All other medicinal Products

C D C+D

TOTAL A+C B+D N=A+B+C+D

PRR

• PRR is the ratio of the number of reports of:• Event of interest for drug of interest Event of

interest for all other drugs/All events for drug of interest All events for all other drugs

• PRR > 1 - positive quantitative association between the drug and the event of interest.

Multi-Item Gamma Poison Shrinker (MGPS)

Reporting RatioModified Reporting

Ratio

Adjusted relativeReporting ratio

(After modelling)

Empiric Bayesian Geometric Mean

Bayesian shrinkageTo address small cell sizes

Stratification(e.g. gender,Age, year)

EB05 EBGM EB95DuMouchel W, Pregibon D. Emperical bayes screening for multi-item associations. Proceedings of the Conference on knowledge discovery and data; 2001 Aug 26-29; San Diego (CA): ACM Press: 67-76.

Empirical Bayes Geometric Mean (EBGM)

• EBGM is an Observed/Expected score that is the output of the MGPS method

• EB05 and EB95 are the lower and upper limits of the 2-sided 90% CI around EBGM

• Interpretation:- If EBGM = 7.2 for paracetamol-hepatic failure, then this drug-event combination occurred in the data set 7.2 times more frequently than expected- If EB05 + 4, then the drug-event occurred at least 4 times more frequently in the data set than expected

• Thresholds used for Data Mining:- EB05 ≥ 2 will flag drug-event combinations that occur at least twice as often expected

Measures Used for Signal Detection

• All measures of SDR are basically calculations of Observed/Expected event/drug reports

• Since Expected Data originates from the same pool as the Observed Data – cannot use a PRR as an RR nor a ROR as a OR

• Expected Data in epidemiology comes from sources other than the Observed

• Expected Data in PV also referred to as “Background”

Measures Used for Signal Detection

• Since the calculation is O/E, the relationship between background and statistic of interest is inversely related- As background increases resulting statistic decreases (large E results in small PRR)- As background decreases resulting statistic increases (Small E results in large PRR)

What does the MAH do when a signal has be confirmed and strengthened?

Variation of CCSI/SPC/PIL

PASSFurther to validate a signal

Update of Risk management Plan

Presentation of the Signal in the PSUR with planned future actions

Provision of the safety information to HCP and/or

patients

Principles of Risk Management in Pharmacovigilance

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Hrithik Roshan Suffered Drug Allergy• By SUNIL Sonkar November 22 — Bollywood actor Hrithik Roshan was

hospitalised on Sunday to Kokilaben Dhirubhai Ambani Hospital in Mumbai after his lungs practically collapsed. Hrithik was unable to breathe and his lips became ten times bigger and face was also swollen. The problem started when he took an antibiotic after complain of chest infection, which led to strong allergy. He took the tablet on Saturday. Though he was discharged in the evening, but was kept under observation. He said, “It was an allergic reaction to the antibiotics I was taking. Lungs and throat went into spasm. I reached hospital just in time…All cool now. I’m under observationIt was an allergic reaction to the antibiotics I was taking. Lungs and throat went into spasm. I reached hospital just in time…All cool now. I’m under observation.”

• Hrithik also revealed later that a delay of about 15-minute would make the condition fatal.

• He complained of temperature, headache, backache, muslce pain and tiredness earlier.

• Family members of the star are quite shocked and also scared over his condition

The Bar is Being Raised Across the Industry for Formal Risk Management Planning

• While approval times are decreasing, industry has experienced high profile withdrawals in recent times

• Product Safety is under increasing scrutiny- Patients- Prescribers- Regulators- Auditors- Media- Legal

• Industry is moving quickly to design and implement Risk Management processes

• Risk Management Programs can enable challenging products to stay on the market (by supporting the use of appropriate products by appropriate patients)

What is Risk Management?

• The activities and interventions deployed to a drug, in order to manage and mitigate known and possible risks, with the aim of protecting the individual

• Identification and implementation of strategies to reduce risk to individuals & populations

• A continuous process of minimising a product’s risks throughout its life cycle in order to optimise that product’s risk/benefit balance

Why Manage Risk Proactively?

• Regulatory Expectation- US, Europe, ICH E2E

• Company Perspective- to understand the risk profile- to protect the company’s asset

• Patient perception- expect safe and effective drugs- do not fully understand risks

• Need to change prescribing behaviour: labelling not always sufficient

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Enhanced PMS/ Communication activities

Active influence on safe use in the market place

Assessment of RM programme effectiveness

Pre-marketingRisk Assessment

ISS Approval Risk Management Implementation

“New Model”

Safety Specification

Pharmacovigilance Plan

± Risk Minimization Plan/ Risk Map

Modify in the light of new safety data

New data

Traditional analyses plus

Anticipated conditions of use

Intrinsic/extrinsic risks (identified and potential)

Epidemiology of disease

Benefit : risk assessment

Risk Management – A Shift in Emphasis

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Overall Objectives of Risk Management Planning Benefit - Risk Optimization

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Optimizing Benefit Risk

Benefit

Risk

Manageable Risk

Manageable Risk

Unacceptable RiskUnacceptable Risk

Acceptable RiskAcceptable Risk

Low High

High

Low

Risk Management Strategy

• Product Risk Management PlanPlan identifying the risks associated with a medicinal product, methods to further clarify the safety profile and ways to minimise risk to individual patients in clinical use

• Three elementsPharmacovigilance specificationPharmacovigilance PlanRisk Minimisation “toolkit”

Risk Management Definition

Risk Management

=

Risk Assessment

+

Risk Minimization

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b

Safety SpecificationSummary of important identified risks, important potential risks and missing

information (ICH E2E)

Pharmacovigilance Plan

Based on safety specification; Routine PV practices and action plan to investigate specific safety concerns

(ICH E2E)

Risk MinimizationActivities to be taken to minimize the impact of

specific safety concerns on the benefit-risk balance

Risk Management Plan

Basic Components of a Risk Management Plan

RMP Elements• Identified pre-clinical concerns• Missing Pre-clinical data• ADRs in clinical trials (including seriousness and

predictability)• Potential ADRs requiring further evaluation to clarify

a risk hypothesis• Population not studied in the pre-approval phase• Documented interactions• Potential for unidentified interactions that may occur

post-approval• Disease epidemiology• Class effects

Pharmacovigilance Specification

• A structured method of documenting the established risks of a drug and the potential for unidentified risks at the time of marketing authorisation

Safety Specification PurposeThe Safety Specification should be a summary of the

- [important] identified risks of a medicinal product,

- [important] potential risks,

- important missing information.

- populations potentially at risk

- outstanding safety questions which warrant further investigation

- identifies any need for specific data collection

to refine understanding of the benefit-risk profile during the post-authorisation period.

Safety Specification ContentNon-clinical and Clinical Part of the Safety Specification

Limitations of the Human Safety DatabasePopulations not studied in the Pre-Authorisation Phase Adverse Events/Adverse ReactionsIdentified risks that require further evaluationPotential risks that require further evaluationPresentation of risk dataIdentified and Potential Interactions Epidemiology Pharmacological Class Effects

Additional EU Requirements

Potential for overdose Potential for transmission of infectious agentsPotential for misuse for illegal purposesPotential for off-label use Potential for off-label paediatric use

Risk Management PlanPurpose

Assessing risks by focused evaluation to close gaps in knowledge systematically (PM commitments - continued development - targeted populations)

- looking for potential risks (class effects)

- following observed events

- characterizing outcomes that are mulifactorial

Advance planning and communication of evaluation for new products

Method

Integration of incremental data acquisition starting in development, systemizing postmarketing commitments and new indication projects for the newly released compound

Continued integration of all available data requires start at phase 1

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Limitations of human safety database

Table x: Exposure by baseline diseaseNo of patientsNo of patients

Total ( male/female )Total ( male/female )

Diabetic nephropathyDiabetic nephropathyHypertensiveHypertensive nephropathynephropathy

GlomerulonephritisGlomerulonephritis

OtherOther 246 (140/106)

207 (143/64)

71 ( 47/24)65 (39/26)

Table y: Special population exposure

PopulationPopulation Number of patientsNumber of patients

Ethnic originEthnic origin•CaucasianCaucasian•otherother

584 5

Genetic polymorphismGenetic polymorphism

Relevant co-morbiditiesRelevant co-morbidities•Hepatic impairmentHepatic impairment•Cardiac diseaseCardiac disease

Not applicable

Elderly (>75 years)Elderly (>75 years) 14Children (<12 years)Children (<12 years) None

Pregnant or lactatingPregnant or lactating womenwomen None

57243….

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Toxic Epidermal Necrolysis (TEN)

Clearly a serious and important risk

Risk Minimisation “Tool Kit”

• Based on Specification• Focus on practical ways to reduce risk to the

population- SPC and labelling – population, indication(s), warnings, contradictions and monitoring- Communication to healthcare professionals and the public both pre and post launch, including letters, advertisements and educational programmes- Control of distribution or prescribing- Treatment protocols

Risk MitigationHow to bring the risk profile to the prescriber and the patient • Routine label activities• Outside communication (DDL, Training)• Tests associated with precriptions• Market withdrawal

Drugs can safely stay in the market by targeting the right patient groups through a coordinated safety and marketing strategy where revenue expectations that are consistent with what the safety profile supports

Good decision making in drug lifecycle management must be the objective of strategic pharmacovigilance in implementing the recognized risk/benefit

Risk Management Strategies

• Reduce drug exposure- restrict indication- controlled drug distribution- optimise dosage regimen

• Modify ADR occurrence- screen patients at baseline- monitor precursors (signs & symptoms)- educate prescribers and patients- ask for informed consent- introduce independent patient monitoring- provide hotlines for medical advice

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Safety Communications - A Patient Perspective

“Wonder Pills” Sir, My wife has been prescribed pills. According to the accompanying leaflet,

possible side-effects are: sickness, diarrhoea, indigestion, loss of appetite, belching, vertigo, abdominal cramps, dizziness, stomach ulcers, bleeding from intestine or blood diarrhoea, ulcerative colitis, sore mouth and tongue, constipation, back pains, inflammation of pancreas, mouth ulcers, skin rashes, hair loss, sensitivity to sunlight, drowsiness, tiredness, impaired hearing, difficulty with sleeping, seizures, irritability, anxiety, depression, mood changes, tremor, memory disturbances, disorientation, changes in vision, ringing in ears, bad dreams, taste alteration, allergic reactions, swelling due to water retention, palpitations, impotence or tightness of the chest.

Should she take them?Yours faithfully,A D. O,Hertfordshire.

Letter to the Editor,1996 Information withheld due to data privacy

Conclusion• Signal detection and Risk Management is a fascinating field,

which is now more often used in PV in majority of the MNCs• Databases provide a powerful tool for early detection of

safety signals• ICSR & domain knowledge (epidemiology & natural history of

disease, medical practice, pharmacology of drug) are essential for assessing causality between a drug & an event

• Risk management should start early during clinical drug development process

• Risk Management Plans should be for all drugs and submitted to RA

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Risk Management - Conclusion Embracing Change

“It is not the strongest of the species that survive, nor the most intelligent, but the one most responsive

to change.”

Charles Darwin, 1859

Thank You!pippa@symogenlimited.compipasha.biswas@gmail.comwww.symogenlimited.com