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  3.  PHARMACOVIGILANCE The World Health Organization (WHO) defines Pharmacovigilance as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.”  ADVERSE DRUG REACTION According to WHO “ADR is a response to a drug which is noxious and unintended, and which occurs at doses normally 3
  4. HISTORY OF PHARMACOVIGILANCE  1848 The Lancet started collecting notifications of side effects caused by use of anaesthesia.  1906 US Federal and Food Act was implemented stating that pharmaceuticals should be ‘pure’ & free from ‘contamination’.  1937 In USA 107 lethal cases were reported after diethylene glycol was mistakenly used as solvent for sulphanilamides. 4
  5.  1959-61 Reports of foetal abnormalities after the use of drug thalidomide.  1962 USA revised law requiring to prove safety and efficacy of drug before issuing marketing authorization.  1967 WHO’s International Drug Monitoring programme was launched. 5
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  7. WHAT IS GPV (Good Pharmacovigilance Practices) Good Pharmacovigilance practices (GVP) are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU). GVP apply to marketing-authorisation holders, the European Medicines Agency and medicines regulatory authorities in EU Member States.  Our knowledge of a drug’s adverse reactions can be increased by various means, including spontaneous reporting, intensive monitoring and database studies. 7
  8. METHODS 1) CLINICAL TRIAL DATA COLLECTION  Main method currently used to gather information on a drug in the pre-marketing phase.  Pre-marketing clinical trials can be divided into three phases.  These are considered to be the most rigorous approach to determining whether a cause-effect relationship exists between a treatment and an outcome. 8
  9.  This study design is not optimal due to the limited number of patients participating, it is generally not possible to identify ADRs that occur only rarely.  Moreover short duration of clinical trials makes it difficult to detect ADRs with a long latency.  Another limitation of clinical trials is the population in which a drug is tested i.e characteristics of the participants do not always correspond to the characteristics of the population in which it will later be used; consequently, it may be difficult to extrapolate the results obtained from clinical trials to the population at a larger scale. 9
  10. 2)SPOTANEOUS REPORTING  In 1961, a letter from the Australian physician WG McBride was published in Lancet. In this letter, he shared his observation that babies whose mothers had used thalidomide during pregnancy were born with congenital abnormalities more often than babies who had not been exposed to thalidomide in utero.  In the years to come it became evident that thousands of babies had been born with limb malformations due to the maternal use of thalidomide. 10
  11.  In order to prevent a similar disaster from occurring, systems were set up all over the world with the aim of regulating and monitoring the safety of drugs.  Thus, Spontaneous reporting systems (SRS) were created and these have become the primary method of collecting post-marketing information on the safety of drugs. 11
  12.  This system enables physicians and, increasingly more often, pharmacists and patients to report suspected ADRs to a pharmacovigilance centre.  The task of the pharmacovigilance centre is to collect and analyse the reports and to inform stakeholders of the potential risk when signals of new ADRs arise.  Also used by various industries for reporting of their drugs.  Possible to monitor all drugs on the market throughout their entire life cycle at a relatively low cost.  The main criticism of this approach is the potential for selective reporting and underreporting 12
  13. 3 DATA MINING IN SPONTANEOUS REPORTING  The term ‘data mining’ refers to the principle of analysing data from different perspectives and extracting the relevant information.  Approaches of data mining are currently in use are Proportional reporting ratios (PPRs), compare the proportion of reports for a specific ADR reported for a drug with the proportion for that ADR in all other drugs.  The Bayesian confidence propagation neural network (BCPNN) method is used to highlight dependencies in a data set. This approach uses Bayesian statistics implemented in a neural network architecture to 13
  14.  WHO Collaborating Centre for International Drug Monitoring uses this method for data mining.  A related approach is the Multi-Item Gamma Poisson Shrinker (MGPS) used by the FDA for data mining of their spontaneous report’s database. The MGPS algorithm computes signal scores for pairs, and for higher-order (e.g. triplet, quadruplet) combinations of drugs and events that are significantly more frequent than their pair-wise associations would predict 14
  15. 4)INTENSIVE MONITORING  In the late 1970s and early 1980s a new form of active surveillance was developed in New Zealand (Intensive Medicines Monitoring Programme) and the UK (Prescription Event Monitoring).  These intensive monitoring systems use prescription data to identify users of a certain drug.  The prescriber of the drug is asked about any adverse event occurring during the use of the drug being monitored. These data are collected and analysed for new signals. 15
  16.  It is unaffected by the kind of selection and exclusion criteria that characterise clinical trials, thereby eliminating selection bias.  Another strength of this methodology is that it is based upon event monitoring and is therefore capable of identifying signals for events that were not necessarily suspected as being ADRs of the drug being studied. 16
  17. This approach, however, also hasThis approach, however, also has recognised limitations :-recognised limitations :- a)a) The proportion of adverse effects thatThe proportion of adverse effects that go unreported is unknown.go unreported is unknown. b)b) It produces reported event ratesIt produces reported event rates rather than true incident ratesrather than true incident rates c)c) The true background incidence forThe true background incidence for events is not is not known.  In European commission consultationIn European commission consultation ‘Strategy to better protect public‘Strategy to better protect public health by strengthening andhealth by strengthening and rationalising EU pharmacovigilance’rationalising EU pharmacovigilance’ intensive monitoring is mentioned asintensive monitoring is mentioned as 17
  18. 5)DATABASE STUDIES  The General Practice Research Database (GPRD) and the PHARMO Record Linkage System are two major European database used for ADR reporting.  GPRD  Virtually all patient care in the UK is coordinated by the general practitioner (GP), and data from this source provide an almost complete picture of a patient, his illnesses and treatment.  In any given year, GPs, who are members of the GPRD, collect data from about 3 million patients and ADR reporting is done.  There have been over 250 publications in peer-reviewed journals using the GPRD. 18
  19.  PHARMO  In the early 1990s, the PHARMO system of record linkage was developed in The Netherlands.  PHARMO links community pharmacy and hospital data within a specific region on the basis of patient birth date, gender and GP code.  The system now includes drug-dispensing records from community pharmacies and hospital discharge records of about 2 million people in the Netherlands. 19
  20.  The data collection is longitudinal and goes back to 1987.  The system has well-defined denominator information that allows incidence and prevalence estimates and is relatively cheap because existing databases are used and linked.  The PHARMO database is used for follow-up studies, case-control studies and other analytical epidemiological studies for evaluating drug-induced effects. 20
  21. 6.PERIODIC SAFETY UPDATE REPORTS(PSUR)  Pre marketing clinical trials may not be sufficient to reflect the product safety profile.  Therefore medically advanced countries impose the “post marketing drug safety monitoring period ” on new drugs. License holders shall proactively collect post marketing safety data, prepare PSUR and submit them to the health authority. 21
  22.  According to the “regulation of medical products under safety monitoring” ,if pharmaceutical companies fail to submit PSUR as required , then the health authority may reassess the safety of the concerned product.  The last PSUR should be submitted before the expiration of the drug safety monitoring period. The “summary bridging report” provides summarized information of the PSURs. 22
  23. NARANJO ALGORITHM For assessing the causality – - Definite = ≥9 - Probable = 5-8 - Possible = 1-4 - Doubtful = ≤ 0 23
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  25. Hartwig and Seigels scale For assessing the severity- 1.Mild ADRs-are self limiting and do not contribute to prolongation of length of hospital stay. 2.Moderate ADRs- require therapeutic intervention or hospital admission or prolonged hospital stay by at least one day . 3.Severe ADRs- life threatening, requiring intensive medical care or produce disability or lead to death. 25
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  27. DEVELOPMENTS IN PV  USA  In February 2007, on the basis of the IOM report, the FDA announced several initiatives designed to improve the safety of prescription. These initiatives fall into four main categories. These are :- i. Increasing the resources for drug safety activities & perceiving the agency as being overly dependent on industry funding. ii. Reform new authority for the FDA. iii. Improvement of post-marketing surveillance. iv. changes in the FDA management practices and safety supervision are necessary 27
  28.  In May 2007, the U.S. senate passed its version of reform for the FDA. The senate proposed that the Prescription Drug User Fee Act, which allows the pharmaceutical industry to pay money directly to the FDA, should increase their payments to the FDA by close to U.S. 400 million dollars.  EUROPE  In 2005, a document was drafted by the Heads of the Medicines Agencies called ‘Implementation of the Action Plan to Further Progress the European Risk Management Strategy’. 28
  29.  The Yellow Card Scheme is the UK system for collecting information on suspected adverse drug reactions (ADRs) to medicines. The scheme allows the safety of the medicines and vaccines that are on the market to be monitored.  Founded in 1964 after the thalidomide disaster, and was developed by Bill Inman.  It is run by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM). Suspected ADRs are collected on all licensed medicines and vaccines, from those issued on prescription to medicines bought over the counter from a pharmacist or supermarket.  The Scheme also includes all herbal preparations and unlicensed medicines. ADRs can be reported by any 29
  30.  The sort of ADRs that should be reported are: i. ADRs that have caused death or a serious illness ii. Any ADR, however minor, if associated with a new medicine or one that is under continued monitoring (highlighted in the British National Formulary (BNF) with a ▼ black triangle) iii. Any ADR, however minor, if associated with a child (under 18 years of age) or in pregnancy  Yellow Cards are available from pharmacies and a few are presented near the back of the BNF as tear-off pages, copies may also be obtained by telephoning +44 (0) 808 100 3352.The scheme provides forms that allow members of the public to report suspected side effects, as well as health professionals. 30
  31.  Officially started on 23 November 2004 at new Delhi.  Pharmaceutical industry in India is valued at 90,000crore and is growing at the rate of 12-14% per annum.  Total export of Pharmacy products is to the extent of 40,000crore.  India is now being recognized as the “global pharmacy of generic drugs” 31
  32. India is also emerging rapidly as a hub of global clinical trials & destination for drug discovery and development. In a vast country like India with a population of over1.2 billion with vast ethnic variability ,different disease prevalence patterns , practice of different systems of medicines, different SES , it is important to have robust Pharmacovigilance and drug safety monitoring programmes. 32
  33.  PVPI is under control of- 1.CDSCO(Central Drugs Standard Control Organization) 2.directorate general of health services 3.Indian Pharmacopeia Commission (Ghaziabad) The programme is conducting by NCC(National Coordinating Centre) . 33
  34. Goals and objectives- Goal- to ensure that the benefits of use of medicine outweighs the risks. Objectives- 1. To monitor ADRs . 2.To create awareness among health care professionals about ADRs. 3. To monitor benefit-risk profile of medicines. 34
  35. 4. Generate independent ,evidence based recommendations. 5. Support the CDSCO. 6. Communicate findings with all stake holders. 7. Create a national centre. 35
  36. PvPI is administered and monitored by the following committees:- 1.Steering Committee 2.Strategic Advisory Committee 36