Principles of Signal Detection

1
Principles of Signal Detection Risk Management
in Pharmacovigilance

• Dr Pipasha Biswas
• MD MFPM DM MRQA
• Principal Consultant Director
• Symogen Limited, UK.
• ISPRT SOPI Conference, Lady Hardinge Medical
  College, New Delhi
• 26 28 November 2010

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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

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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

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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

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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

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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)

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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

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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

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Signal Detection Process Flow
Detection of a Signal
Generation of Hypothesis
Verification
Decision to be taken
Information
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Factors to Consider in Signal Detection

• Considerations for when a Drug-Event Pair is a
  Signal

Patient Characteristics Trends
Pharmacological Plausibility
Class Effect
SIGNAL
Drug Event Pair
Commonly drug- Related event
Related Similar Events
DPA Over Time
DPA Score
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Evaluating Signals Using Evidence Hierarchy
Signal Detection Process
Signal Identified
Other Databases (AERS, WHO)
Clinical Trial Data (ISS, ISO)
Information Gathering
Pre-Clinical animal Toxicology Pharmacology
Spontaneous Data Including DPA Info
Epidemiology
Literature
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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

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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

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How Signal detection is done?

• Qualitative Analysis
• - Signal case/multiple report evaluation
• Combined with or without
• Qualitative Analysis
• - Automated identification of signals

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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

16
Quantitative Analysis

• Various automated statistical methods used in
  analysis of safety data
• Most commonly used are
• - Proportional reporting Ratio (PRR) MHRA
• - Reporting Odds Ratio (ROR) LAREB
• - Multi-item Gama Poisson Shrinker (MGPS) FDA
• - Bayesian Confidence Propogation Neural Network
  (BCPNN) UMC

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Quantitative analysis

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

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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)

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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 AB
All other medicinal Products C D CD
TOTAL AC BD NABCD
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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 gt 1 - positive quantitative association
  between the drug and the event of interest.

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Multi-Item Gamma Poison Shrinker (MGPS)
Adjusted relative Reporting ratio (After
modelling)
Reporting Ratio
Modified Reporting Ratio
Stratification (e.g. gender, Age, year)
Bayesian shrinkage To address small cell sizes
Empiric Bayesian Geometric Mean
EB05
EB95
EBGM
DuMouchel 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.
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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

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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

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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)

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What does the MAH do when a signal has be
confirmed and strengthened?
Variation of CCSI/SPC/PIL
Provision of the safety information to HCP and/or
patients
PASS Further to validate a signal
Update of Risk management Plan
Presentation of the Signal in the PSUR with
planned future actions
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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 timeAll cool now. Im under
  observationIt was an allergic reaction to the
  antibiotics I was taking. Lungs and throat went
  into spasm. I reached hospital just in timeAll
  cool now. Im 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

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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)

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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 products
  risks throughout its life cycle in order to
  optimise that products risk/benefit balance

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Why Manage Risk Proactively?

• Regulatory Expectation
• - US, Europe, ICH E2E
• Company Perspective
• - to understand the risk profile
• - to protect the companys 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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Risk Management A Shift in Emphasis
New Model
Modify in the light of new safety data
Pre-marketingRisk Assessment
ISS
Approval
Risk Management Implementation
Safety Specification Pharmacovigilance Plan
Risk Minimization Plan/ Risk Map

• Enhanced PMS/ Communication activities
• Active influence on safe use in the market place
• Assessment of RM programme effectiveness

• Traditional analyses plus
• Anticipated conditions of use
• Intrinsic/extrinsic risks (identified and
  potential)
• Epidemiology of disease
• Benefit risk assessment

New data
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Overall Objectives of Risk Management Planning
Benefit - Risk Optimization
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Optimizing Benefit Risk
High
Unacceptable Risk
Risk
Manageable Risk
Acceptable Risk
Low
Low
High
Benefit
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Risk Management Strategy

• Product Risk Management Plan
• Plan 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 elements
• Pharmacovigilance specification
• Pharmacovigilance Plan
• Risk Minimisation toolkit

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Risk Management Definition

• Risk Management
• Risk Assessment
• Risk Minimization

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Basic Components of a Risk Management Plan
b
Risk Management Plan
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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

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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

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Safety Specification Purpose

• The 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.

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Safety Specification Content

• Non-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

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Risk Management Plan

• Purpose
• 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 disease
No of patients Total ( male/female )
Diabetic nephropathy
65 (39/26)
Hypertensive nephropathy
71 ( 47/24)
Glomerulonephritis
207 (143/64)
Other
246 (140/106)
Table y Special population exposure
Number of patients
Population
Children (lt12 years)
None
Elderly (gt75 years)
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Pregnant or lactating women
None

• Relevant co-morbidities
• Hepatic impairment
• Cardiac disease

57 243 .
Genetic polymorphism
Not applicable

• Ethnic origin
• Caucasian
• other

584 5
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Toxic Epidermal Necrolysis (TEN) Clearly a
serious and important risk
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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

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Risk Mitigation

• How 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

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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
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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
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Thank You!pippa_at_symogenlimited.compipasha.biswas
_at_gmail.comwww.symogenlimited.com