PHARMACOVIGILANCE, ADR assessment and reporting

Pharmacovigilance

1. PHARMACOVIGILANCE & PvPI Dr. Ankita Rao JR2, Dept. of Pharmacology T.N.M.C., Mumbai 02/02/2023

2. OVERVIEW 2

3. PHARMACOVIGILANCE WHAT IS PHARMACOVIGILANCE ? 3

4. WHAT IS PHARMACOVIGILANCE ? PHARMACOVIGILANCE 4

5. WHAT IS PHARMACOVIGILANCE ? PHARMACOVIGILANCE 5 Pharmakon Vigilare Drug To keep awake or alert/ to keep watch

6. DEFINITION 6 PHARMACOVIGILANCE “The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug related problems.” – WHO

7. AE ADR TERMINOLOGIES 7

8. 8 TERMINOLOGIES SERIOUS ADVERSE EVENT OR REACTION (SAE/SAR) Any untoward medical occurrence that at any dose: • Results in death, • Is life-threatening, • Requires inpatient hospitalization or prolongation of existing hospitalization, • Results in persistent or significant disability/ incapacity, • Is a congenital anomaly/birth defect, • Is an important medical event or reaction, that may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed above.

9. The scope of pharmacovigilance has widened to include: 9

10. EVOLUTION OF PHARMACOVIGILANCE ACTIVITIES

11. 1848: Hannah’s death by Chloroform 1848 1937 1938 1961 1962 1964 1968 1978 1997 11 Sir James Simpson had discovered – chloroform was a safer & powerful anaesthetic. Hannah Greener died after receiving chloroform anesthetic before removal of an infected toenail.

12. 12 1937: Sulfanilamide disaster 2011 1937 1938 1961 1962 1964 1968 1978 1997 1848 A small Tennessee company prepared an elixir of sulfanilamide by dissolving the drug in diethylene glycol. 107 deaths in USA

13. 13 1938: Federal Food, Drug and Cosmetic Act 1848 1937 1938 1961 1962 1964 1968 1978 1997 Federal Food, Drug and Cosmetic Act was established in 1938. The new law foresaw that the safety of drugs should be demonstrated before their market approval & introduced the possibility of conducting factory inspections.

14. 14 1961: Thalidomide disaster 1848 1937 1938 1961 1962 1964 1968 1978 1997 McBride’s letter about thalidomide tragedy. Dr. Lenz from Germany discussed similar association during a paediatric conference. Over 12000 cases of malformation were recorded.

15. 15 1962: Kefauver – Harris amendment 2011 1937 1938 1961 1962 1964 1968 1978 1997 1848 Dr. Frances Oldham Kelsey blocked the registration for thalidomide in USA. Led to Kefauver-Harris amendment. It reinforced and made compulsory the scientific evidences of efficacy & safety of drugs before marketing in humans.

16. 16 1964 & 1965: Development in UK & Europe 1848 1937 1938 1961 1962 1964 1968 1978 1997 In 1964: The “Yellow Card” was structured in UK In 1965: European legislation was developed (EC Directive 65/65)

17. 17 1968: WHO PIDM 2011 1937 1938 1961 1962 1964 1968 1978 1997 1848 In 1968: WHO Programme for International Drug Monitoring was instituted with headquarters at Geneva. Initially 10 members had participated.

18. 18 1978: WHO – UMC 2011 1937 1938 1961 1962 1964 1968 1978 1997 1848 WHO Collaborating centre was shifted from Geneva to Uppsala, Sweden as a part of agreement between WHO and Swedish Government.

19. 19 1997: India Joins 1848 1937 1938 1961 1962 1964 1968 1978 1997 In 1997: India joined the WHO ADR monitoring programme, based in Uppsala, Sweden.

20. NEED FOR PHARMACOVIGILANCE 20

21. NEED FOR PHARMACOVIGILANCE 21

22. 22 AIMS OF PHARMACOVIGILANCE

23. WHO PROGRAMME FOR INTERNATIONAL DRUG MONITORING 23 WHO Headquarters Uppsala Monitoring Centre National PV Centres

24. 24 PHARMACOVIGILANCE PROCESS

25. 25 DATA COLLECTION & MANAGEMENT Passive surveillance Active surveillance Comparative observational studies Targeted clinical investigations Descriptive studies a. Spontaneous reporting b. Case series c. Stimulated reporting a. Sentinel sites b. Drug event monitoring c. Registries a. Cross-sectional study b. Case-control study c. Cohort study a. Natural history of disease b. Drug Utilization study

26. SPONTANEOUS REPORTING 26 Spontaneous Reports Healthcare professionals Consumers Unsolicited communication by to Company, regulatory authority or other organization (e.g., WHO, Regional centres, Poison control centre) One or more adverse drug reactions Study or any organized data collection scheme Identification of safety signals once a drug is marketed Describes Not derived from Play a major role in DATA COLLECTION & MANAGEMENT

27. 27 In India for healthcare professionals - “Suspected adverse drug reaction reporting form” for patients – “Medicines side effect reporting form” In UK “Yellow Card” In US “Med Watch” forms are used. Form FDA 3500 – Voluntary reporting (for healthcare professionals) Form FDA 3500A – Mandatory reporting (for manufacturers, distributors, importers) Form FDA 3500B – Voluntary reporting (for patients)

28. HEALTHCARE PROFESSIONALS PATIENTS

29. HEALTHCARE PROFESSIONALS

30. HEALTHCARE PROFESSIONALS

31. ADVERSE EVENT FOLLOWING IMMUNIZATION 37 Reporter AMC NCC- PvPI National level AEFI committee Local AEFI team FIR/PIR/DIR Causality assessment REPORTING FORMS:

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34. ADVERSE EVENT FOLLOWING IMMUNIZATION 40 Reporter AMC NCC- PvPI National level AEFI committee Local AEFI team FIR/PIR/DIR Causality assessment REPORTING FORMS:

35. CASE SERIES 41 Series of case reports Can provide evidence of Drug Adverse event Association between More useful Hypothesis Detailed and rapid follow up Anaphylaxis, aplastic anaemia, TEN, Stevens-Johnson syndrome DATA COLLECTION & MANAGEMENT

36. STIMULATED REPORTING 42 Healthcare professionals Product launched Pharma companies Provide safety information May ask Spontaneous Reports Data obtained from stimulated reporting cannot be used to generate accurate incidence rates, but can be used to estimate reporting rates. DATA COLLECTION & MANAGEMENT

37. SENTINEL SITES 43 Complete & accurate data Adverse event Required Community or geographical area Data from specific patient subgroups Most efficient for those drugs used mainly in institutional settings Problems with selection bias Small number of patients Increased costs DATA COLLECTION & MANAGEMENT

38. DRUG EVENT MONITORING 44 STRENGTH: Detailed information on adverse events from a large number of physicians and/or patients might be collected. LIMITATION: Poor physician and patient response rates. DATA COLLECTION & MANAGEMENT

39. REGISTRIES 45 Presenting with the same characteristics Disease registry Drug registry Observational methods Data on drug exposure related to a clinical condition To gather Populations exposed to drug of interest addresses Specific populations (e.g. Pregnant women) List of patients Very valuable when examining the safety of an orphan drug indicated for a specific condition DATA COLLECTION & MANAGEMENT

40. COMPARATIVE OBSERVATIONAL STUDIES 46 DATA COLLECTION & MANAGEMENT

41. TARGETED CLINICAL INVESTIGATIONS 47 Identified from Pre-clinical approval trials Clinical studies might be required to evaluate mechanism of action for the adverse reaction Further DATA COLLECTION & MANAGEMENT

42. DESCRIPTIVE STUDIES 48 Not used for the detection or verification of adverse events associated with drug exposures. Used to obtain – a. Background rate of outcome events and/or b. Establish the prevalence of the use of drugs in specified populations. Natural History of disease Drug Utilization Study Specific aspects of adverse events – incidence rate or risk factors How a drug is marketed, prescribed & used in a population & how these factors influence clinical, social and economic outcomes examines describes DATA COLLECTION & MANAGEMENT

43. 49 PHARMACOVIGILANCE PROCESS

44. SIGNAL MANAGEMENT PROCESS 50 What is a ‘signal’? WHO has defined a pharmacovigilance “signal” as “reported information on a possible causal association between an adverse event and a drug, the relationship being unclear or incompletely documented previously” A signal is not a confirmatory finding but it is a hypothesis generating situation that must be validated or disapproved.

45. 51 SIGNAL MANAGEMENT PROCESS Traditional methods Statistical methodology Bayesian Confidence Propagation Neural Network (BCPNN) Multi Item Gamma Poisson Shrinker (MGPS) Reporting Odds Ratio (ROR) Proportional Reporting Ratio (PRR) WHO-UMC US FDA PvPI Measurement of Disproportionality

46. 52 SIGNAL MANAGEMENT PROCESS Severity and outcome of the adverse reaction Patient exposure in vulnerable populations Consequences of treatment discontinuation on the disease under treatment and the availability of other therapeutic options Whether the signal is likely to apply to other substances of the same class of medicinal products.

47. 53 SIGNAL MANAGEMENT PROCESS Every confirmed signal is assessed in terms of : Causality Frequency Seriousness Preventability

48. EVALUATION AND INVESTIGATION 54 CAUSALITY ASSESSMENT Causality Assessment is method by which the extent of relationship between a drug and a suspected reaction is established AMC is responsible for performing causality assessment of reports which shall be reviewed at NCC

49. METHODS OF CAUSALITY ASSESSMENT: 55 WHO-UMC Causality Assessment Scale Naranjo Scale Kramer method Australian method Probabilistic or Bayesian approaches European ABO system Yale Algorithm

50. WHO-UMC CAUSALITY ASSESSMENT SCALE 56 Assessment is based on following 4 criteria: Time relationships between the drug use and the adverse event Absence of other competing causes (medications, disease process itself) Response to dechallenge Response to rechallenge CERTAIN : a,b,c,d met PROBABLE : a,b and c met POSSIBLE : Only a is met UNLIKELY : when a & b are not met

51. TERMINOLOGIES: 57 Dechallenge :   This term is use when the suspect drug was discontinued or withdrawn or dose reduced due to adverse event. Positive de-challenge: This refers to the adverse event disappearing after the stopping of the drug. Negative de-challenge: This refers to the adverse event not disappearing  after the stopping of the drug. Rechallenge:  This term is use when the suspect drug was  restarted after dechallenge and it only applicable after positive dechallenge . Positive re-challenge : refers to the adverse event recurring  after restarting the drug. For this, the adverse event had to previously disappeared after de-challenge in order for it to restart. Negative re-challenge : This is the case where the adverse event does not recur  after the drug is restarted.

52. 58 Applied when more data is needed & such data is being sought or is already under examination Finally when the information in a report is incomplete or contradictory and cannot be verified

53. CASE STUDY 59 Female, 60 years Complaints: Fever, bodyache , headache, generalized weakness Suspect drug: Risedronate 35 mg/week for osteoporosis Concomitant-medication: Omeprazole Complaints approximately lasted for 5 days. After next intake same complaints appeared. Switch to risedronate 5 mg once daily - no effect on any of the symptoms Medication changed into alendronate 70 mg/week - no complaints anymore. Assessment? PROBABLE

54. NARANJO SCALE 60 Definite: ≥ 9 Probable: 5-8 Possible: 1-4 Doubtful: ≤ 0 LIMITATION: Method explains causality of only one drug; not when multiple drugs are involved or in presence of drug interactions

55. 61 CASE STUDY Score: 6 5-8: Probable PROBABLE

56. Modified Hartwig Siegel ADR severity scale 62 EVALUATION AND INVESTIGATION SEVERITY ASSESSMENT

57. ACTIONS 63

58. COMMUNICATIONS 64 Newsletters Social media Uppsala reports UMC’s Podcast Scientific Journals Social media campaign

59. PHARMACOVIGILANce in india

60. PHARMACOVIGILANCE PROGRAMME OF INDIA (PVPI) 66 Headquarters National Co-ordinating Centre (NCC) WHO Collaborating centre for International drug monitoring

61. 67 PVPI INTEGRATION WITH PUBLIC HEALTH PROGRAMMES

62. 1986 1997 2005 2010 MILESTONES

63. 1986 1997 2005 2010 1986 – 1 st ADR monitoring system was proposed (12 regional centres – 50 million each) 1989 – 6 regional centres were set up Mumbai New Delhi Kolkata Lucknow Pondicherry Chandigarh

64. 1986 1997 2005 2010 In 1997, India joined WHO Adverse Drug Reaction Monitoring Programme Uppsala, Sweden.

65. 1986 1997 2005 2010 NATIONAL PHARMACOVIGILANCE PROGRAMME (NPP) 1 st January 2005 – 2009 WHO-sponsored and World Bank-funded CDSCO SW NE National PV centre National PV Advisory Committee Zonal PV centre KEM hospital, Mumbai AIIMS, New Delhi Regional PV Centre Peripheral PV centre

66. 1986 1997 2005 2010 PHARMACOVIGILANCE PROGRAMME OF INDIA (PVPI) NPP renamed as PVPI Operational since: 14 th July 2010 National Coordination Centre (NCC) [old] : AIIMS, New Delhi 22 ADR monitoring centres IPC, Ghaziabad (current NCC) NCC 15 th April 2011 652 ADR Monitoring centres (AMC)

67. PVPI: MISSION & VISION 73 MISSION To safeguard the health of Indian population by ensuring that the benefits of use of medicine outweigh the risks associated with its use. VISION To improve patient safety and welfare of Indian population by monitoring safety of medicines , thereby reducing the risk associated with their use.

68. PVPI: OBJECTIVES 74 Create a nation-wide system for patient-safety by ensuring drug-safety Identify and analyse new signals from the reported cases Analyse the benefit-risk ratio of marketed medications Generate evidence-based information on safety of medicines Communicate safety information on use of medicines to various stakeholders for preventing/minimizing the risk

69. PVPI: OBJECTIVES 75 Support regulatory agencies in the decision-making process on use of medications Emerge as a National Centre of Excellence for Pharmacovigilance Activities Collaborate with other national Centres for exchange of information and data management Provide training and consultancy support to other National Pharmacovigilance Centres across the globe Promote rational use of medicines

70. COMMUNICATION SYSYTEM OF PVPI 76

71. CDSCO ZONAL OFFICES 77 North zone, Ghaziabad East zone, Kolkata Zonal office, Hyderabad South zone, Chennai Zonal office, Ahmedabad West zone, Mumbai

72. FUNCTIONS OF THE STAKEHOLDERS 78

73. PV ACTIVITY IN INDIA: OVERVIEW 79 Drug Patient Reporting ADR AMC- Data entry in Vigiflow Communication Drug ban/ withdrawal of drug NCC – PVPI Various PV centres Regulatory Authority: CDSCO/ WHO-UMC Signal detection Consumed by Quality assessment Experiences Patient safety Impact of PV Invalid/ incomplete ICSR Revert to AMC

74. REPORTING ADR s 80 What to report? Who can report? When to report? Where to report? How to report?

75. WHAT TO REPORT? 81 All types of suspected ADRs: Known or unknown Serious or non-serious Frequent or rare ADRs by: Medical devices Biologicals including vaccines Herbal drugs/ Nutraceuticals etc Reactions to any other drugs which are suspected of significantly affecting a patient’s management , including reactions suspected of causing: Death Life-threatening (real risk of dying) Hospitalization (initial or prolonged) Disability (significant, persistent or permanent) Congenital anomaly Required intervention to prevent permanent impairment or damage

76. WHO CAN REPORT? 82 Healthcare professionals Consumers Pharmacists Nurses Pharmaceutical companies ADR monitoring centres

77. WHEN TO REPORT? 83 All spontaneous case – within 10 days All suspected ADRs – as soon as possible Death event – as soon as possible All serious ADR/event – within 7 days and non-serious cases – within 30 days WHERE TO REPORT? ADR monitoring centres

78. HOW TO REPORT? 84 ADR reporting forms Available on IPC website ( www.ipc.gov.in ) or CDSCO site ( www.cdsco.nic.in ) 2. Toll-free helpline number (launched on 11 th October 2013) 3. e-Reporting of ADRs: Mobile app

79. MODES OF COMMUNICATION IN PVPI 85 Official Website Newsletters – 3 issues every year Posters & Pamphlets

80. 86 MODES OF COMMUNICATION IN PVPI Various social media

81. PVPI RECOMMENDATIONS TO CDSCO 87 Drug Alert Updating Package Insert Signal 71 24 05

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85. ADRs REPORTING STATUS OF AMC s 91 IPC updates ADR reporting status on its website Available – Yearwise and monthwise Latest report as on December 2022 – Total 12066 ICSRs were reported AMC/ ART/ RNTCP/ NTEP 7606 MAH (Marketing Authorization Holders) 4460 Initial 2732 Follow-up 1728

86. 92 TOOLS FOR PHARMACOVIGILANCE VigiFlow VigiBase VigiLyze VigiMed WHODrug Global VigiMobile

87. TOOLS FOR PHARMACOVIGILANCE 93 1. VIGIFLOW Web-based ICSR data management system Used by NCC, pharmaceutical companies, CROs Compatible with updated international standards [ICH-E2B (R3)] Direct access to VigiLyze Standardized terminologies in VigiFlow: MedDRA (Medical Dictionary for Regulatory Activities): It can be used to add adverse reactions, drug indication, medical history, cause of death, test names and diagnosis WHODrug : Dictionary for finding drug names or active substances. (WHO-ART [WHO Adverse Reaction Terminology]: Disapproved since 2015; available on request for limited specific purposes.)

88. ICH GUIDELINES: PHARMACOVIGILANCE 94 E2A – E2F: Pharmacovigilance E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2B(R3) Clinical Safety Data Management: Data Elements for Transmission of ICSRs E2C(R2) Periodic Benefit-Risk Evaluation Report E2D Post-approval Safety Data Management: Definitions and Standards for Expedited Reporting E2E Pharmacovigilance Planning E2F Development Safety Update Report

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90. 2. VIGIBASE 101 WHO global ICSR database Previously known as ‘International Drug Information Centre (INTDIS)’ Largest, most comprehensive data resource Updated on a continuous basis Developed & maintained by UMC Access allowed to all National Centres Linked Databases - WHO Drug Dictionary, WHO-ART, MedDRA, ICD TOOLS FOR PHARMACOVIGILANCE

91. 3. VIGILYZE 102 VigiLyze is a signal detection and signal management tool that provides a global context for national data through its close integration with Vigibase . It provides overview graphs, tables and disproportionality calculations for national data. 4. VIGIMED Vigimed is a worldwide email discussion group maintained by the UMC. Vigimed allows rapid exchange of information and opinions on drug safety matters between NPCs around the world as well as the UMC. Membership is restricted to persons connected to NPCs or drug regulatory agencies in participating countries, including ‘associate member countries’. TOOLS FOR PHARMACOVIGILANCE

92. 5. WHODrug Global 103 International reference for medicinal product information maintained by the Uppsala monitoring centre. Each medicine has a unique drug code . It helps to identify drug names, including active ingredients and products’ anatomical & therapeutic classification. Covers both conventional medicines ( prescription-only products, over-the-counter (OTC), biotech and blood products, diagnostic substances and contrast media) and herbal remedies . The data is continuously updated with new releases twice a year, on 1 st March & 1 st September Easy search & analysis of drug safety data Available in English and Chinese TOOLS FOR PHARMACOVIGILANCE

93. 6. VIGIMOBILE 104 VigiMobile is a new offline app developed by UMC for national immunisation programmes as a part of VigiFlow for AEFI. With the app, immunisation field workers can quickly and accurately report AEFI on their smartphones or other mobile devices regardless of internet access.  It is based on the WHO Standard AEFI reporting form and a ll reports are sent directly to VigiFlow for AEFI. TOOLS FOR PHARMACOVIGILANCE

94. VIGIMOBILE: KEY BENEFITS 105 Can be installed on smartphone, laptop or tablet Structured reporting – saves time and effort Structured geographic data capture makes it possible to locate and investigate clusters of adverse events at district, provincial and national level. Easy to use, have to fill it only once .  Mobile friendly reporting form, drop-down menus with prequalified vaccine lists Included in VigiFlow for AEFI at no extra cost

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96. PVPI: REGIONAL TRAINING CENTRES 107 Sr. No. Regional Training Centre State/UT under purview 1 PGIMER, Chandigarh J&K, Himachal Pradesh, Punjab, Haryana, Chandigarh & Delhi 2 Seth GS Medical College & KEM Hospital, Mumbai Maharashtra, Goa, Dadra & Nagar Haveli 3 JSS Medical College Hospital, Mysore Karnataka, Kerala, Tamil Nadu, Puducherry and Lakshadweep 4 Institute of Postgraduate Medical Education & Research, Kolkata Andaman Nicobar, West Bengal, Jharkhand, Bihar & Odisha 5 Silchar Medical College & Hospital Assam, Arunachal Pradesh, Nagaland, Manipur, Meghalaya, Mizoram, Tripura, Sikkim 6 AIIMS, Bhopal Madhya Pradesh and Chhattisgarh 7 BJ Medical College, Ahmedabad Gujarat, Rajasthan, Daman & Diu 8 AIIMS, Rishikesh Uttarakhand and Uttar Pradesh 9 Nizam’s Institute of Medical Sciences, Hyderabad Andhra Pradesh and Telangana

97. RECENT PROGRESS OF PVPI 108 NCC- PvPI , IPC was launched as a WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes and Regulatory Services on 30 th October 2017 “ National Strategic Plan for Scale up of Pharmacovigilance in India” & “Pharmacovigilance Guidelines for Stakeholders”

98. ARTIFICIAL INTELLIGENCE IN PHARMACOVIGILENCE 109 BENEFITS OF AI ISSUES WITH AI Relatively new and developing field. Machine learning Natural learning processing

99. ARTIFICIAL INTELLIGENCE IN PHARMACOVIGILENCE 110 BENEFITS OF AI

100. ARTIFICIAL INTELLIGENCE IN PHARMACOVIGILENCE 111 ISSUES WITH AI

101. WHODrug Koda 112 WHODrug Koda is a powerful and fully automated drug coding assistant that uses AI and advanced algorithms for more efficient and consistent drug coding Key features It enables automated coding of drug names (including non-unique names). It provides automated ATC selections according to the latest regulatory expectations. It is possible to integrate WHODrug Koda in existing coding tools or similar via an API. Also available as a web application, it is easily accessible via the  UMC website .

102. CONCLUSION 113 As rightly said by DJP Barker – “There are three actions of a drug: the one you want, the one you don’t want and the one you don’t know about.” ADRs lead to significant morbidity and mortality with considerable social and economic consequences. There is inadequate nationwide awareness and illiteracy about PV, especially among common populations. The issues of underreporting are resolving due to available reporting facilities like toll free dial number, message, mail and ADR form in vernacular languages. The future strategies of drug safety could become more advanced, driven by AI techniques. More researches are needed in the field of AI with respect to PV.

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104. REFERENCES 115 Centre UM. [Internet]. Uppsala Monitoring Centre. [cited 2022Dec]. Available from: https://who-umc.org/ Pharmacovigilance Programme of India ( PvPI ) [Internet]. Pharmacovigilance programme of India. [cited 2022Dec]. Available from: https://www.ipc.gov.in/PvPI/pv_home.html Gupta SK. Textbook of Pharmacovigilance. New Delhi: Jaypee Brothers Medical Publishers; 2011. Amale PN, SA D, YD N, NA A. Pharmacovigilance process in India: An overview. Journal of Pharmacovigilance. 2018;06(02). Guidance document for spontaneous Adverse Drug Reaction Reporting [Internet]. [cited 2023Jan]. Available from: https://ipc.gov.in/PvPI/pub/Guidance%20Document%20for%20spontaneous%20Adverse%20Drug%20Reaction%20Reporting.pdf Fornasier G, Francescon S, Leone R, Baldo P. An historical overview over pharmacovigilance. International Journal of Clinical Pharmacy. 2018;40(4):744–7. Medhi B, Murali K, Kaur S, Prakash A. Artificial Intelligence in Pharmacovigilance: Practical utility. Indian Journal of Pharmacology. 2019;51(6):373.

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