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Pharmacovigilance

by Dr. Vishal Pawar
MD Pharmacology
a complete and comprehensive view of Pharmacovigilance around the world and in india

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Pharmacovigilance

  1. 1. BY DR. VISHAL PAWAR JR II DEPT. OF PHARMACOLOGY 1
  2. 2. • Pharmacovigilance (PV) Etymological roots : pharmakon (Greek) means drug and vigilare (Latin) means to keep awake or alert, to keep watch WHO Definition Science, activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug related problems Side Effect Any unintended effect of a pharmaceutical product occurring at doses normally used in man which is related to the pharmacological properties of the drug e.g. sedation with anti histaminics Adverse Event / Adverse Experience Any untoward medical occurrence that may present during treatment with a pharmaceutical product at the same time, does not necessarily have a causal relationship with this treatment 2
  3. 3. Adverse Reaction (ADR) A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function Active surveillance system Collection of case safety information as continuous pre-organized process Spontaneous reporting System whereby case reports of adverse drug events are voluntarily submitted from health professionals and pharmaceutical manufacturers to the national regulatory authority Signal Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously 3
  4. 4. 4 Adverse Event Intensity •Mild •Moderate •Severe Seriousness •Non Serious •Serious •Expected •Unexpected CausalityExpectation •Related •Un-related
  5. 5. 5 Poor knowledge of Pharmacology, adverse effects of drugs Irrational use of drugs, poor prescribing patterns Promotional activities by pharmaceutical company detailers Lack of authentic sources of information Liberal drug outlets and unhealthy pharmaceutical practices Liberal OTC and self medication practices Ignorant, illiterate public
  6. 6. Pharmacological classification by Rawling and Thompson: 6 Type A (Augmented) Type B (Bizarre) Type C (Chronic) Type D (Delayed) Type E (End of use) Type F (Failure)
  7. 7. Type A (Augmented) (dose related) • Related to exaggerated pharmacological effects of drug • Eg. Hypoglycemia with Insulin, hypotension by beta blockers, NSAID’s induced gastric ulcers Type B (Bizzarre) • Unexpected, unpredictable, related to patient factors like genetic predisposition • Eg. Penicillin hypersensitivity, malignant hyperthermia Type C (Chronic) • Uncommon, irreversible, unexpected, unpredictable • Due to long term use of drugs • Eg. Hypothalamic pituitary adrenal axis suppression by corticosteroids Type D ( Delayed) • Time related • Eg. Teratogenesis, Carcinogenesis like clear cell cancer of female reproductive tract 7
  8. 8. Type E (End of use/ withdrawal) • Occurs due to sudden discontinuation of the drug after long term therapy • Eg. Adrenocortical insufficiency due to sudden withdrawal of corticosteroids, MI due to beta blocker withdrawal Type F (Failure of therapy) • Common, Dose related • Often caused by drug interactions • Eg. Inadequate dosage of an oral contraceptive particularly when used with specific enzyme inducers • FDA monitors safety of human and veterinary drugs, biologics, medical devices, foods, cosmetics, & other products • Centre for Drug Evaluation and Research (CDER) regulates prescription drugs 8
  9. 9. • Encourage active surveillance • Consider special activities and expertise required for the detection of safety concerns related to vaccines, biologicals, herbal medicines, biotechnology products and investigational drugs • Improve signal detection systems by facilitating availability of ADR data • Revisit definitions of terms used within field of PV including definitions of specific ADRs to ensure reliability and universal understanding of data obtained through ADR reporting systems • Develop and implement ADR detection systems 9
  10. 10. PREVENTION • Improve access to reliable, unbiased drug information at all levels of healthcare • Improve access to safer and more effective medicines for neglected diseases prevalent in developing communities • Encourage awareness of drug safety and rational drug use among health professionals and the public • Integrate PV activities into national drug policies e.g. standard treatment guidelines, essential drugs lists and clinical practice • Improve regulation and PV of traditional and herbal medicines • Develop systems which assess the impact of preventive actions taken in response to drug safety problems 10
  11. 11. COMMUNICATION • Improve communication, collaboration between key partners in PV • Principles of good communications practice in PV and drug regulation should be encouraged • Different solutions are likely to be developed in different countries and • regions, and the experience should be shared • Develop better understanding of patients, their expectations of medicines and their perception of risk, in order to facilitate programmes that will inform public on benefit and harm associated with medicine • Develop sustained, active relationships with media 11
  12. 12. Post-marketing monitoring or PV or Phase IV clinical studies • Provides information about long-term safety of drug • Safety in extremes of age, special population like pregnant and nursing women • Information about Type B ADR’s, rare ADR’s • In India, mandatory to submit Post Marketing Surveillance (PMS) Report within 2 years of marketing drug 12
  13. 13. • Limited value of animal experiments, Clinical trials • ADRs constituting enormous burden on society • Cost of drug related morbidity, mortality exceeding that of drug itself • 30-50% of ADRs are preventable • Early detection and prevention can help make drug therapy lot safer • Rare or delayed serious reactions are likely to remain unnoticed 13
  14. 14. • 1881  systemic recording of illnesses associated with pharmacotherapy started much later and a book in this regard was published by L. Lewin. • 1937  Unexplained death of hundreds of children. Elixir of sulfanilamide dissolved in diethylene glycol killing 107 children • 1938  Stimulus for food and drug Act (drug safety) for stringent action regarding safety requirement and testing of a new drug before marketing. • Thalidomide disaster in 1962 • 1968  WHO established a system for collecting reports of ADR 14
  15. 15. NEWER CHALLENGES FACED TODAY • Illegal sale of medicines and drugs of abuse over Internet • Increasing self-medication practices • Widespread manufacture and sale of counterfeit and sub standard medicines • Increasing use of traditional medicines outside confines of traditional culture Recently, PV concerns have been widened to include: • Herbals • Traditional and complementary medicines • Blood products • Biologicals • Medical devices • Vaccines 15
  16. 16. 16 Rational and safe use of medical drugs Encourage their safe, rational, more effective, cost effective use Educating and informing patients Assessment and communication of risks and benefits of drug Promote understanding, education and clinical training in PV and its effective communication to the public Improve patient and public healthcare and safety in relation to use of medicines Contribute to regulatory assessment of benefit, harm, effectiveness and risk of medicines
  17. 17. • Established in 1968 • As of October 2008, 89 countries had joined • It consists of a network of the i. National Centres ii. WHO Headquarters iii. Uppsala Monitoring Centre 17
  18. 18. 18 Identification and analysis of new adverse reaction signal Provision of the WHO database Information exchange between WHO and National Centres mainly through Vigiflow Publication of periodical newsletters, guidelines, books Provision of training and consultancy support to National Centres
  19. 19. • Located in Uppsala, Sweden, World Health Organisation Collaborating Centre for International Drug Monitoring • Principal function  manage international database of ADR reports received from National Centres • Works by collecting, assessing and communicating information from member countries' national PV programs in regards to benefits, harm, effectiveness and risks of drugs • Annual meetings for representatives of National Centres • Producing WHO Drug Dictionary and WHO Adverse Reaction Terminology 19
  20. 20. 1. Pharmacovigilance Specification 2. Pharmacovigilance Plan 3. Pharmacovigilance Methods 20
  21. 21. Pre Clinical Studies • Toxicity tests • General pharmacology • Effect of hepatic and renal dysfunction, • Drug interactions, and • Other toxicity-related information or data Animal Tests - Acute toxicity - Kinetics - Carcinogenicity - Organ damage - Mutagenicity - Species specificity - Teratogenicity - Dose dependence 21
  22. 22. Clinical Studies • Adverse events (AEs) / Adverse drug reactions • Identified and potential interactions, including food-drug and drug- drug interactions • Epidemiology of indication(s) and important adverse events • Pharmacological class effects • Limitations of the human safety database 22
  23. 23. 23 Monitoring center Investigator Global HQ Sponsor’s Safety Officer Death and life-threatening, Associated (by Investigator) Cases Immediately or within 24 hours to entry site immediately or within 24 hours immediately or within 24 hours immediately or within 24 hours
  24. 24. 24 Patient Health Professional Regional Centre Manufacturer Hospital National Centre
  25. 25. • Relationship between the drug treatment and occurrence of an adverse event • Defined: structured and standardised assessment of individual patients/case reports of the likelihood of involvement of suspected drug in causing particular event in a given patientWHO assessment scale • Methods 25 Naranjo's scale European ABO system Karch and Lasagna's scale Kramer scale Bayesian Neural network Yale algorithm
  26. 26. • Data collection & Data management • Signal detection • Risk assessment and quantification • Benefit/ Risk assessment • Actions to reduce risk or increase benefit • Communication of risks or interventions • Audit 26
  27. 27. • Passive surveillance a) Spontaneous reporting b) Case series c) Large linked administrative database d) Electronic medical records • Intensified reporting • Active Surveillance • Comparative Observational Studies • Targeted Clinical Investigations • Descriptive studies 27
  28. 28. Spontaneous reporting • Identification of safety signals once a drug is marketed • Is voluntary for health professionals • Most useful where reaction is unusual and unexpected • And where ADRs occur in close temporal relation with start of treatment or increase in dose • Provide important information on at-risk groups, risk factors, and clinical features of known serious ADRs 28
  29. 29. Reports for regulatory authorities are in form of • Expedited adverse drug reaction (ADR) reports • Periodic Safety Update Reports (PSURs) • Underreporting is an important limitation • Causes being lack of awareness of time, ill filled report forms, misconception that the medicine caused the event • Reporting rates cannot be used to reliably estimate incidence rates 29
  30. 30. Case series • Provide evidence of association between drug and adverse event • More useful for generating hypotheses than for verifying an association between drug exposure and outcome • Reports of events like SJS, Anaphylaxis should undergo detail and rapid follow up Large linked administrative database • Eg. Medicaid in USA and Ontario provincial database • Contain data on millions of subjects • Completeness of details, such as diagnoses, are questionable in many circumstances • May not be representative of the whole population Electronic medical record • Large number and detail of variables are available like use of tobacco products and nonprescription drugs, symptoms and signs, • Can be combined to generate new diagnoses or adverse events, • Hypotheses which are not restricted to existing diagnoses, can be explored 30
  31. 31. • To encourage and facilitate reporting for new products, methods used are • Onine reporting of adverse events • Systematic stimulation of reporting of adverse events based on a pre-designed method ACTIVE MONITORING • Patients might be identified from electronic prescription data or automated health insurance claims • A follow-up questionnaire can then be sent to each prescribing physician or patient to obtain outcome information • More detailed information can be collected • Limitation - poor response rates 31
  32. 32. • A registry is a list of patients presenting with the same characteristics • Used as information gathering and hypothesis generating tool • Particularly on drug exposure during pregnancy and for orphan drugs • Can act as population basis for linkage studies COMPARATIVE OBSERVATIONAL STUDIES • Are key component in evaluation of adverse events • Cross- sectional studies - primarily used to gather data for surveys or for ecological analyses • Case-control studies - used to investigate whether there is an association between a drug (or drugs) and one specific rare adverse event, as well as to identify risk factors for adverse events • Cohort studies - incidence rates of adverse events in addition to the relative risks of adverse events are calculated 32
  33. 33. • Evaluate MOA for adverse reaction • Pharmacodynamic and pharmacokinetic studies • Investigate potential drug-drug interactions and food-drug interactions DESCRIPTIVE STUDIES • These are primarily used to obtain background rate of outcome events • Establish prevalence of use of drugs in specified populations 33
  34. 34. • Reported information on a possible causal relationship between an adverse event and a drug • Relationship being unknown or incompletely documented previously • Usually more than a single report is required to generate a signal • Depending upon seriousness of event and quality of the information • Describes the first alert of a problem with a drug • Cannot be regarded as definitive • Indicates the need for further enquiry or action • The automated systems used to generate signal is called as data mining 34
  35. 35. DATA MINING Application of statistical techniques, e.g. predictive modeling, clustering, link analysis, deviation detection and disproportionality measures, to databases to generate signal 35 Formulation of hypothesis of association Method of highlighting potential ADR and safety issues of a drug needing further investigations Signal Generation Assessment of available data Improved knowledge about suspected ADR and indicates need for early warning or intervention Signal strengthening
  36. 36. SNIP criteria Strong signals that are judged to be New, clinically Important, and have potential for Prevention, be given priority for further evaluation Methods of signal detection • Spontaneous reporting system • Hospital based surveillance system • Prescription- event monitoring • Case reports in literature • Epidemiological studies Aim of statistical aids • To provide means of comparing the frequency of a medicine - event combination • With all other such combinations in the database under consideration • With potential for early detection of signals of possible medicine - event association 36
  37. 37. Evaluation of drug safety issue • Causality assessment • Identifying other possible cause • Assessing the risk to individual and public • Benefit/ Risk assessment is continued throughout life of a drug • Guidelines to assess risk/ benefit differ from country to country Key elements • Description of target disease, populations being treated, purpose of intervention • Degree of efficacy, presence of alternative therapy • Type of risk and identification of risk factors • Consideration of all benefits and risks by indication and population 37
  38. 38. Actions to reduce risk or increase benefit and Communication • Contraindicate use of drug in specific group • Reducing maximum authorized dose • Contraindicating concomitant use of interacting drug • Monitoring early warning signs • Educating practitioners and consumers • Withdrawal of drug AUDIT • To evaluate outcomes of the interventions • To plan future activities 38
  39. 39. Other issues relevant include • Substandard medicines • Medication errors • Lack of efficacy reports • Use of medicines for indications that are not approved and for which there is inadequate scientific basis 39
  40. 40. • 1986: ADR monitoring system consisting of 12 regional centres each covering population of 50 million, was proposed for India • 1989: 6 regional centers : Delhi, Mumbai, Calcutta, Pondicherry, Lucknow, Chandigarh • 1997: India joined WHO Monitoring Programme based in Uppsala, Sweden • 2004: The WHO sponsored and World Bank funded National Pharmacovigilance Program (NPP) for India was made operational • NPP was to be overseen by National Pharmacovigilance Advisory Committee 40
  41. 41. • 2009: World bank funding ended and programme was temporarily suspended • Late 2009: workshop org by AIIMS, Dept. of Pharmacology and CDCSO when a framework of new programme was formulated • July, 2010: Recognizing the need for improved ADR monitoring in the country, under the aegis of Health Ministry, a nation-wide revised ADR monitoring programme was launched and named as Pharmacovigilance Programme of India (PvPI) 41
  42. 42. • Provides a system to collect the data and use the inferences • To recommended regulatory interventions, besides communicating risks to healthcare professionals and public • Indian Pharmacopoeia Commission (IPC) under the Ministry of Health and Family Welfare has been functioning as the National Coordination Centre (NCC) for PvPI since April 2011 • Medical colleges and hospitals are cornerstone of PvPI • Under PvPI, ADRs are being identified and spontaneously reported by the healthcare professionals of Adverse Drug Reaction Monitoring Centres (AMC) 42
  43. 43. • Currently, 179 Medical Council of India approved teaching hospitals and corporate hospitals have been identified as AMCs across the country • These AMCs are responsible for collecting adverse event as per Standard Operating Procedure (SOP) • Performing follow up if require for the completeness of ADR reports • Uploading these reports in net- based software used for ADR reporting called as Vigiflow • These drug safety information/Individual Case Safety Reports (ICSRs) are collected in predesigned suspected ADR reporting forms • Broadly consisting of 4 sections i.e., patient’s information, suspected adverse reaction, suspected medication(s), and reporter’s information 43
  44. 44. • Under PvPI, AMC plays a vital role in collection and follow-up of ADR reports from healthcare professionals • At present there are 400 AMCs under this programme and categorized into four zones i.e., North, South, East and West • Making this one of the largest Pharmacovigilance Programme in the world • PvPI have also extended its reach to other National Health Programmes within country • Integrating with Revised National Tuberculosis Control Program, National AIDS Control Organization • Has collaborations with Central Drugs Standard Control Organization (CDSCO) 44
  45. 45. • Education and Training on PV at Regional Training Centres • India, with a current population of 1.27 billion, is the fourth largest producer of pharmaceuticals in the world • With more than 6000 licensed manufacturers and over 60,000 branded formulations in the market • Over 5 years, has played a significant role in creating awareness among healthcare professionals about reporting ADRs • Having more than 1,49,000 ADRs reported till December 2015 • Currently, the contribution of India to the WHO global Individual Case Safety Reports (ICSRs) database is 3% • Its trying to create sufficient database on ADRs, awareness among healthcare providers of government, corporate hospitals 45
  46. 46. Communications • Website : websites of CDSCO (www.cdsco.nic.in) and NCC (www. ipc.gov.in) are important tools for communication to the stakeholders and public seeking specific information • Media : communicate the findings in national newspapers, electronic media, etc., on regular basis • Newsletter: unique among healthcare professionals because it focuses on the ADRs related information • Scientific Journals • Helpline Facility to Provide Assistance in ADR Reporting • Android Mobile Application for Adverse Drug Reaction Reporting 46
  47. 47. • Co-ordination among clinician, pharmacist, and nurse appears vital in contributing each of their respective expertise and experience to promote the rational use of medicines • The reason for poor reporting may also include financial incentives, ignorance (only serious ADRs are to be reported), apprehension of reporting serious ADRs, and lack of time or over load • In year 2013, India’s contribution to WHO–UMC’s global drug safety database was 2% • India was 7th in position among top 10 counties contributing to global drug safety database • Awareness about the ADR reporting among the healthcare providers can improve the rate of reporting across the country 47
  48. 48. • Wide misconception that ‘natural’ means ‘safe’ • There are examples of traditional and herbal medicines being adulterated or contaminated • With allopathic medicines, chemicals such as corticosteroids, non- steroidal anti-inflammatory agents and heavy metals • Self-medication further aggravates the risk to patients • When used in conjunction with other medicines there is potential of serious adverse drug interactions • These products should be governed by standards of safety, quality and efficacy that are equivalent to those required for other pharmaceutical products 48
  49. 49. • New vaccines for pandemic diseases such as HIV/AIDS and malaria are in the later phases of development • Vaccines and biologicals require modified systems of safety monitoring often administered to healthy children, particularly used within a national immunization programme • The skills and infrastructure to deal with genuine adverse events are essential in preventing or managing misplaced fear • Caused by false or unproven signals from patients and health workers that might adversely affect immunization cover 49
  50. 50. • Eg. concerns about safety of whole-cell Pertussis resulted in dramatic reductions in vaccines coverage and a resurgence of Pertussis in many countries • Contamination of blood and blood products by infectious organisms such as HIV and hepatitis B • Quality of screening and sterilization procedures and appropriate selection of donors are linked to the risks of contamination • Such safety issues related to the use of plasma-derived medicinal products fall under PV programmes 50
  51. 51. • Drug safety monitoring is an essential element for the effective use of medicines and for high quality medical care • PV is a clinical discipline in its own right - one that contributes to an ethos of safety and serves as an indicator of standards of clinical care practised within a country • 3 approaches that might serve to increase awareness and interest in drug safety among clinicians, and to address research issues are • Education, training and access to reliable information • Health professionals are more likely to identify and report important ADRs if they have confidence in their ability to diagnose, manage and prevent such reactions • National PV centres and training institutions play a central role in this by encouraging inclusion of the principles and methods of PV • And the study of iatrogenic disease at UG and PG levels in schools of medicine, pharmacy and nursing 51
  52. 52. • For all medicines there is a trade-off between benefits and the potential for harm • To minimize the harm, it is necessary that medicines of good quality, safety and efficacy are used rationally, and that the expectations and concerns of the patient are taken into account when therapeutic decisions are made • The discipline of PV has developed considerably since the 1972 WHO technical report, and it remains a dynamic clinical and scientific discipline • It has been essential to meet the challenges of the increasing range and potency of medicines (including vaccines), which carry with them an inevitable and sometimes unpredictable potential for harm • When adverse effects and toxicity appear - particularly when previously unknown in association with the medicine - it is essential that they should be analysed and communicated effectively to an audience that has the knowledge to interpret the information 52
  53. 53. • This is the role of PV. Much has already been achieved • PV activities are expanding around the world • This is reflected in the increasing number of national PV centres that have been established in recent years • There are still many countries where no formal systems for PV are in place • To ensure that the existing centres are effective, their impact on public health and health costs should be measurable and the benefits demonstrable • Only then will widespread support and long term sustainability of PV centres be assured 53
  54. 54. The following is a summary of some of the serious challenges facing PV programmes in the next ten years • Globalization • Web-based sales and information • Broader safety concerns • Public health versus pharmaceutical industry economic growth • Attitudes and perceptions to benefit and harm 54
  55. 55. • Very concept of detection of an ADR can jeopardize their economics • Should realize that ADR monitoring can be a source of revenue generation if a new indication is found for the drug • Can be tackled by giving conditional clearance for marketing of a new drug • Enforcing strict drug regulations • So that Fraudulent and counterfeit drugs do not find a way into the market 55
  56. 56. • Handbook of resolutions and decisions of the World Health Assembly and Executive Board, Clinical and pharmacological Evaluation of Drugs, Vol 11948-1972. Geneva: World Health Organization, 1973. WHA16.36. • WHO Medicines Strategy: Framework for Action in Essential Drugs and Medicines Policy 2000-2003. WHO/EDM/2000.1. • Meyboom RHB, Egberts ACG, Gribnau FWJ, Hekster YA. Pharmacovigilance in perspective. Drug Safety 1999; 21(6): 429-447. • The importance of pharmacovigilance, safety monitoring of medicinal products, WHO. • Lihite R, Lahkar M. An update on the Pharmacovigilance Programme of India. Frontiers in Pharmacology. 2015;6. 56
  57. 57. • Portnoff J, Lewis D. The Enigma of Pharmacovigilance of Patient Support Programs. Therapeutic Innovation & Regulatory Science. 2017;51(4):486-493. • Lihite R, Lahkar M. An update on the Pharmacovigilance Programme of India. Frontiers in Pharmacology. 2015. • Khosla P, Bhati N, Kannan S. Good pharmacovigilance practice: Need of the hour from pharmaceutical companies. Perspectives in Clinical Research. 2015;6(3):171. • Kalaiselvan V, Prakash J, Singh GN. Pharmacovigilance programme of India. Arch Pharm Pract 2012;3:229-32. • Dal Pan G. Ongoing Challenges in Pharmacovigilance. Drug Safety. 2013;37(1):1-8. Davies EC, Green CF, Taylor S, Williamson PR, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital in-patients: A prospective analysis of 3695 patient-episodes. PLoS One 2009;4:e4439. 57
  58. 58. • Preda A. Pharmacovigilance and Beyond. Journal of Pharmacovigilance. 2013;01(04). • Pharmacovigilance guidance document, Indian Pharmacopoeia commission and CDSCO. • Gagnon S, Schueler P. Pharmacovigilance and Risk Management, global clinical trials playbook, chapter 15:142. • Sloane R, Osanlou O, Lewis D, Bollegala D, Maskell S, Pirmohamed M. Social media and pharmacovigilance: A review of the opportunities and challenges. British Journal of Clinical Pharmacology. 2015;80(4):910-920. • Harugeri A, Shastri V, Patel C. Deriving meaningful insights from clinical trial and postmarketing safety data: Perspectives from India. Perspectives in Clinical Research. 2017;8(2):68. • Casadevall N, Edwards I, Felix T, Graze P, Litten J, Strober B et al. Pharmacovigilance and biosimilars: considerations, needs and challenges. Expert Opinion on Biological Therapy. 2013;13(7):1039-1047. • Effective communications in Pharmacovigilance. The Erice Report. International Conference on Developing Effective Communications in Pharmacovigilance, Erice, Sicily, 24-27 September 1997. 58
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