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

2. 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

3. 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

4. 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

5. 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

6. 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)

7. 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

8. 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

9. Signal Detection Process Flow Detection of a Signal Generation of Hypothesis Verification Decision to be takenInformation

10. Factors to Consider in Signal Detection Considerations for when a Drug-Event Pair is a Signal Patient Characteristics Trends Pharmacological Plausibility Class Effect Drug Event Pair Related Similar Events DPA Over Time DPA Score Commonly drug- Related event SIGNAL

11. Evaluating Signals Using Evidence Hierarchy Signal Detection Process Signal Identified Information Gathering Clinical Trial Data (ISS, ISO) EpidemiologyLiterature Spontaneous Data Including DPA Info Pre-Clinical animal Toxicology & Pharmacology Other Databases (AERS, WHO)

12. 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

13. 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

14. How Signal detection is done? Qualitative Analysis: - Signal case/multiple report evaluation Combined with or without Qualitative Analysis - Automated identification of signals

15. 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 Odd’s Ratio (ROR): LAREB - Multi-item Gama Poisson Shrinker (MGPS): FDA - Bayesian Confidence Propogation Neural Network (BCPNN): UMC

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

18. 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)

19. 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)ABA+B All other medicinal Products CDC+D TOTALA+CB+DN=A+B+ C+D

20. 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.

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

22. 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

23. 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”

24. 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)

25. What does the MAH do when a signal has be confirmed and strengthened? Variation of CCSI/SPC/PIL PASS Further 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

26. Principles of Risk Management in Pharmacovigilance

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30. 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.”throatjust in Hrithik also revealed later that a delay of about 15-minute would make the condition fatal.delay He complained of temperature, headache, backache, muslce pain and tiredness earlier.temperatureheadache Family members of the star are quite shocked and also scared over his condition Familythe star

31. 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)

32. 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

33. 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

34. 34 Enhanced PMS/ Communication activities Active influence on safe use in the market place Assessment of RM programme effectiveness Pre-marketing Risk Assessment ISSApprovalRisk 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

35. 35 Overall Objectives of Risk Management Planning Benefit - Risk Optimization

36. 36 Optimizing Benefit Risk Benefit Risk Manageable Risk Unacceptable Risk Acceptable Risk Low High Low

37. 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”

38. Risk Management Definition Risk Management = Risk Assessment + Risk Minimization

39. 39 b Safety Specification Summary 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 Minimization Activities 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

40. 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

41. 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

42. 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.

43. Safety Specification Content Non-clinical and Clinical Part of the Safety Specification Limitations of the Human Safety Database Populations not studied in the Pre-Authorisation Phase Adverse Events/Adverse Reactions Identified risks that require further evaluation Potential risks that require further evaluation Presentation of risk data Identified and Potential Interactions Epidemiology Pharmacological Class Effects Additional EU Requirements Potential for overdose Potential for transmission of infectious agents Potential for misuse for illegal purposes Potential for off-label use Potential for off-label paediatric use

44. 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

45. 45 Limitations of human safety database Table x: Exposure by baseline disease No of patients Total ( male/female ) Diabetic nephropathy Hypertensive nephropathy Glomerulonephritis Other 246 (140/106) 207 (143/64) 71 ( 47/24) 65 (39/26) Table y: Special population exposure Population Number of patients Ethnic origin CaucasianCaucasian otherother 584 5 Genetic polymorphism Relevant co-morbidities Hepatic impairmentHepatic impairment Cardiac diseaseCardiac disease Not applicable Elderly (>75 years) 14 Children (<12 years) None Pregnant or lactating women None 57 243 ….

46. 46 Toxic Epidermal Necrolysis (TEN) Clearly a serious and important risk

47. 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

48. 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

49. 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

50. 50 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

51. 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

52. 52 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

53. Thank You! pippa@symogenlimited.com pipasha.biswas@gmail.com www.symogenlimited.com pippa@symogenlimited.com