Pharmacovigilance in Focus by Dr.Prashant, Cipla

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Pharmacovigilance in Focus by Dr.Prashant, Cipla

  1. 1. In focus ! Pharmacovigilance
  2. 2. Medicine Safety <ul><li>To undergo treatment you have to be very healthy, because apart from your sickness you have to stand the medicine. </li></ul>World Health Organization
  3. 3. Why health damage through drug use? <ul><ul><li>Sub-standard drugs </li></ul></ul><ul><ul><ul><li>Adulteration, piracy </li></ul></ul></ul><ul><ul><li>Misuse and abuse of drugs </li></ul></ul><ul><ul><ul><li>for pleasure or addiction </li></ul></ul></ul><ul><ul><ul><li>Compensation for life style </li></ul></ul></ul><ul><ul><li>Human error </li></ul></ul><ul><ul><ul><li>Prescription errors/Unknown interactions and contra-indications </li></ul></ul></ul><ul><ul><ul><li>Inappropriate off-label use/Patient non-compliance </li></ul></ul></ul><ul><ul><li>Inherent safety issues of drugs </li></ul></ul>
  4. 4. Impact of ADRs <ul><li>Since 1995, costs with DRPs – doubled & given the economic and medical burdens </li></ul><ul><li>DRP are common in females than males. </li></ul><ul><li>UK Study : Drug related admissions 10.1 % (Bhalla et al. 2003) </li></ul><ul><li>French study : 10.3 % prevalence of ADRs (Imbs et al. 1999) </li></ul>
  5. 5. Economic impact <ul><li>Cohort study- 4108 admission - total of 190 ADEs </li></ul><ul><ul><ul><li>60 ADE were preventable. </li></ul></ul></ul><ul><li>The additional length of stay associated with an ADE was 2.2 days. </li></ul><ul><li>The cost increased to $ 2595 for all ADEs and $ 4685 for preventable ADEs </li></ul><ul><li>Annual costs for 700 bed hospital </li></ul><ul><ul><ul><li>All ADEs 5.6 million $ </li></ul></ul></ul><ul><ul><ul><li>preventable ADEs 2.8 million $. </li></ul></ul></ul>David & Nathan,1997
  6. 6. Economic impact <ul><li>Overall, the cost of drug-related morbidity and mortality exceeded $177.4 billion in 2000. </li></ul><ul><li>Hospital admissions accounted - 70% ($121.5 billion) long-term-care admissions -18% ($32.8 billion). </li></ul><ul><li>$ 847 m/y in UK(2006, BMJ) </li></ul><ul><li>> 70% are preventable (Pirmohamed et al, BMJ; 2006) </li></ul>
  7. 7. Birth of Vigilance <ul><li>Thalidomide was sold from 1956 to 1962 in almost 50 countries </li></ul><ul><li>Prescribed to pregnant women, as an antiemetic </li></ul><ul><li>From 1956 to 1962 ≈ 5,000 in Germany and 10,000 children in Europe, Australia & US were born with severe malformations. </li></ul><ul><li>50% survived. </li></ul>
  8. 8. Thalidomide <ul><li>1998-FDA approved for lesion associated –Erythema nodosum leprosum. </li></ul><ul><li>2006- Multiple myeloma </li></ul><ul><li>2007- approved for leprosy </li></ul><ul><li>504 million $ Sales. </li></ul>
  9. 9. Vioxx safety data manipulated In Sep 2004 Merck publicly announced its voluntary withdrawal of the drug vioxx a 2.5 billion $ seller from the market worldwide. Drug companies has been found to have suppressed and manipulated certain critical data that misled the regulatory body — U.S.FDA. Journal of the American Medical Association confirms that the Merck was well aware of its dangers even before it withdrew the drug in 2004
  10. 10. MERCK ORDERED TO PAY COMPENSATION TO VIOXX USER <ul><li>FDA analysts estimated 139,000 heart attacks, 30 to 40 % fatal (marketted 5 years). </li></ul><ul><li>>16, 000 cases relating to Vioxx are scheduled in federal Courts in the US. </li></ul><ul><li>A Texas jury -- liable for the death of a man who took the painkiller Vioxx, $253.4 million in damages. </li></ul><ul><li>2007 Nov, reached $ 4.85 billion settlement . </li></ul>
  11. 11. <ul><li>FDA panel concluded (Feb 05) Vioxx, Celebrex and Bextra ( April 2005 Pfizer withdrew ) all pose heart risks but should be available to consumers. </li></ul><ul><li>Should carry a so- called ''black box'' warning label about cardiovascular risk. </li></ul><ul><li>Merck & Co wins Vioxx court case, dismisses meta-analysis claim 24 November 2009 </li></ul>Vioxx- FDA
  12. 12. Real Lesson from Vioxx <ul><li>Decision Making </li></ul><ul><ul><li>There is always a need to link evidence to decision and decision to action. </li></ul></ul><ul><ul><li>E.g. the signal indicating that Rofecoxib is associated with MI could be confounded by the age group or concomitant illnesses of patients treated. </li></ul></ul><ul><li>Regulatory Decision </li></ul><ul><ul><li>The decision to take action should be based upon the level of certainty of the signal and its seriousness. </li></ul></ul><ul><ul><li>In the rofecoxib situation a limited warning was quickly given. The kind of regulatory decision should obviously be based on what is reliably known at the time </li></ul></ul>
  13. 13. Real Lesson from Vioxx <ul><li>Communication of Decisions </li></ul><ul><ul><ul><li>The information should be ethically and effectively communicated. </li></ul></ul></ul><ul><ul><ul><li>Education in the appropriate use of drugs, including interpretation of safety information is essential for the public. </li></ul></ul></ul><ul><ul><ul><li>All the evidence needed to assess and understand risks and benefits must be openly available. </li></ul></ul></ul><ul><li>The Vioxx situation was not a failure of regulation itself, neither was it an issue of data collection ( data manipulation ), nor of the quality of studies performed. It was and is a complex decision-making/communication challenge in which improvements are possible. </li></ul>Ralf. E drug safety 2005
  14. 14. rofecoxib Rimonabant Astemizole EPO Rosiglitazone Vildagliptin Desvenlafaxine Lumiracoxib
  15. 15. <ul><li>Rimonabant helps 60 million obese and with a revenue of $4 b. </li></ul><ul><li>Rosiglitazone in diabetics, FDA issued alert(2.8b$) </li></ul><ul><li>Vildagliptin not approved in US (2b$) </li></ul><ul><li>Desvenlafaxine - FDA approved the drug for antidepressant in Feb 2008, EMEA- benefit-risk is not positive. with special warning----Suicidal thinking & behavior </li></ul>Rosiglitazone Vildagliptin Desvenlafaxine Rimonabant Advantage
  16. 16. The World's Best-Selling Drugs <ul><li>Lipitor-Pfizer (Atorvastatin)- 13.7 b$ </li></ul><ul><li>Plavix-Bristol-Myers (Clopidogrel)-8.6 b$ </li></ul><ul><li>Nexium-Sanofi(Esomeprezole)-7.8b$ </li></ul><ul><li>Advair-GSK (Salmeterol/fluticasone) 7.7b$ </li></ul><ul><li>Enbrel- Amgen(Etanercept) 5.7 b$ </li></ul>
  17. 17. Lipitor Safety Questioned in Lawsuit <ul><li>June 2006 – Lawsuits filed that drug-maker Pfizer has failed to warn doctors and patients about serious possible side effects . </li></ul><ul><ul><ul><ul><li>debilitating muscle and nerve problems -- including memory loss. </li></ul></ul></ul></ul><ul><ul><li>It is the most studied drug in the world,&quot; Haskins&quot; </li></ul></ul><ul><ul><li>It has been studied in over 400 clinical trials with 80,000 patients. </li></ul></ul><ul><ul><li>More than 20 million patients have taken the drug since it entered the market about a decade ago. </li></ul></ul><ul><ul><li>Any potential side effects, any significant adverse events are on the drug's label. </li></ul></ul>
  18. 18. Black Box Warning Issued for Etanercept Regarding Infections, March 2008 <ul><li>Clinical studies enrolling > 20,000 patients </li></ul><ul><ul><ul><ul><li>cases of tuberculosis in approximately 0.01% of patients treated with Etanercept. </li></ul></ul></ul></ul>FDA Safety Warning The new warning highlights screening and monitoring patients for tuberculosis, including patients who tested negative for latent tuberculosis infection
  19. 19. Non-compliance with Pharmacovigilance regulatory obligations <ul><li>Under EU legislation, when non-compliance with PV regulatory obligations is detected, the necessary action will be judged on a case-by case basis. </li></ul><ul><li>What action is taken will depend on the potential negative public health impact of non-compliance </li></ul>CPMP/PhVWP/1618/01
  20. 20. REGULATORY ACTION <ul><li>Education & facilitation </li></ul><ul><li>Inspection (to determine the extent of non-compliance) </li></ul><ul><li>Warning (from competent authority) </li></ul><ul><li>Naming non-compliant MAH (making public) </li></ul><ul><li>Prosecution </li></ul><ul><ul><ul><li>Cases of serious or persistent non-compliance may be prosecuted. Action may be also taken against directors, managers or QPPV. </li></ul></ul></ul>CPMP/PhVWP/1618/01
  21. 21. Financial penalties for infringement of certain obligations <ul><ul><li>Inaccurate submissions to EMEA (art. 1(1)) </li></ul></ul><ul><ul><li>Breach of post-marketing obligations </li></ul></ul><ul><ul><li>Infringements of PhVig rules (art. 1(12) to 1(17)) </li></ul></ul><ul><ul><ul><li>e.g. recording suspected/serious adverse reactions </li></ul></ul></ul>COMMISSION REGULATION (EC) No 658/2007
  22. 22. Financial penalties for infringement of certain obligations <ul><li>Art. 16: Maximum penalties </li></ul><ul><ul><li>Fine not exceeding 5 % of the MAH’s Community turnover in the preceding year. </li></ul></ul><ul><ul><li>Continuous infringement: daily fine not exceeding 2.5 % of daily Community turnover </li></ul></ul><ul><li>Art. 19: Non-cooperation </li></ul><ul><ul><li>0.5 % of Community annual turnover </li></ul></ul><ul><ul><li>Daily fine of 0.5 % of daily Community turnover in case of continuous non-cooperation. </li></ul></ul>COMMISSION REGULATION (EC) No 658/2007
  23. 23. Penalties <ul><li>Non-compliance with pharmacovigilance requirements by MA-holder </li></ul><ul><ul><ul><li>Fine £5000 and/or imprisonment (max 2yrs) </li></ul></ul></ul>UK Germany Fine max 25000 Euro (QPPV). Netherlands Administrative penalty 4500 Euro Repetition: possibility to prosecute
  24. 24. France <ul><ul><li>Offence: fine 3750 Euro </li></ul></ul><ul><ul><li>Repeated offence: fine 7500 Euro and 3 months imprisonment </li></ul></ul><ul><ul><li>Company fines: Competent court may also order the closing down of the pharmaceutical establishment. </li></ul></ul>
  25. 25. Practical Problems and Challenges <ul><li>Spontaneous reporting </li></ul><ul><ul><li>Spontaneous reporting rates to regulatory agencies < 10% – and ongoing monitoring is passive in many countries. </li></ul></ul><ul><ul><li>Data are usually based on suspicion, preliminary, doubtful or wrong. </li></ul></ul><ul><ul><li>Premature or wrong conclusions may be reached and lead to unbalanced publicity, unnecessary anxiety, patient non-compliance & unwarranted decisions. </li></ul></ul><ul><li>OTC drugs </li></ul><ul><ul><li>Healthcare professionals are often ill-informed with regard to OTC drug </li></ul></ul><ul><ul><li>Adverse effects of OTC drugs are relatively rarely reported. </li></ul></ul><ul><ul><li>OTC drugs may require additional pharmacovigilance activities </li></ul></ul>
  26. 26. Practical Problems and Challenges <ul><li>Non-orthodox drugs (e.g. phytotherapy, traditional remedies) </li></ul><ul><ul><li>Products may contain large numbers of poorly or unidentified drugs, several of which may cause serious adverse effects. </li></ul></ul><ul><ul><li>Additional challenges for pharmacovigilance. </li></ul></ul><ul><li>Monitoring of Drug Promotion </li></ul><ul><ul><li>Modest deviations from the approved indications for use may be commercially attractive. </li></ul></ul><ul><ul><li>Monitoring of the promotional activities of pharmaceutical companies, as regards their compliance with the approved condition. </li></ul></ul>
  27. 27. Practical Problems and Challenges <ul><li>Hospital Pharmacovigilance </li></ul><ul><ul><li>Patients with serious adverse drug reactions are likely to be admitted to hospital. </li></ul></ul><ul><ul><li>Polypharmacy adverse drug reactions and interactions are common in the hospital environment. </li></ul></ul><ul><ul><li>The establishment of pharmacovigilance centres in hospitals </li></ul></ul><ul><ul><ul><ul><li>Will improve the care of patients with drug-induced diseases and </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Qualitatively and quantitatively increases adverse reaction reporting. </li></ul></ul></ul></ul>Meyboom et al., drug safety
  28. 28. Way Forward <ul><li>With respect to Adverse Drug Reactions and PV </li></ul><ul><ul><ul><li>Industry has no interest in losing their marketing authorisation </li></ul></ul></ul><ul><ul><ul><li>Industry has no interest in product liability </li></ul></ul></ul><ul><ul><ul><li>Industry has interest in improving public image </li></ul></ul></ul><ul><li>Even though regulatory requirements with respect to PV are steep and expensive: </li></ul><ul><ul><ul><li>Compliance is natural </li></ul></ul></ul><ul><ul><ul><li>Safety issues are discussed openly and transparently </li></ul></ul></ul><ul><ul><ul><li>(Almost) no serious pharmaceutical company would use Drug Safety spending as an element of cost-cutting </li></ul></ul></ul>
  29. 29. Conclusion <ul><li>Preventing patients from being affected unnecessarily (safety/ethics) </li></ul><ul><li>More safety data (increases sales) </li></ul><ul><li>Unexpected beneficial effects </li></ul><ul><li>Regulatory requirements (avoids penalty) </li></ul>

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