Importance of Pharmacovigilance for a Biotechnology company<br />Vivek Ahuja, MD<br />Director, Asia Pacific – Pharmacovig...
2<br />Risks and Benefits<br />Show me a drug without side effects and I <br />shall show you a drug that does not work .<...
3<br />Drugs Withdrawn Post Marketing<br />
4<br />Drugs Withdrawn Post- Marketing<br />
5<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />Abacavirsulphate/ Lamivudine Tabs<br...
6<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />31.Busulfan Inj <br />32. Calcium-Ir...
7<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />61. Divalproex Sodium Capsules<br />...
8<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />91.  Fluticasone propionate and Salm...
9<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />121.     Mechlorethamine HCl Inj<br ...
10<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />151. Oxymetholone Tabs<br />152. Pa...
11<br />Drugs with  a  Black Box warning  <br />(Physicians Drug Reference -2006)<br />181. Salmeterolxinafoate Inhalation...
12<br />Pharmacovigilance<br />Is the safety profile of a drug fully known <br />             at the time of  its launch ?...
13<br />CLINICAL DEVELOPMENT<br />Numbers of humans  tested<br />50-100<br />100-300<br />1500-3000<br />> 10000<br />
Required sample size for detecting a rare adverse drug reaction<br />
15<br />            Evolution of the Indications for Diazepam<br />1974<br />1968<br />1967<br />Year of Introduction<br /...
16<br />Limitations of pre-marketing clinical trials<br />
17<br />Pharmacovigilance<br />The ADR profiles of drugs  and their Risk- Benefit<br />balance  need to be continuously mo...
Traditional small molecule drugs vs. Biopharmaceuticals<br />Complex production process<br />Limited predictability of pre...
Difficulties in causality assessment <br />Biopharmaceuticals, are often indicated to treat severe and/or life-threatening...
Spontaneous data vs. Registries<br />Since biopharmaceuticals are often used in a specialized hospital setting, it is expe...
Pooled Data from RCTs<br />In addition to registries, pooling of data from randomized controlled clinical trials has also ...
ADRs peculiar to Biopharmaceuticals<br />Occurrence of tuberculosis with the use of (TNF)-alphainhibitors, especially Infl...
Safety data from Clinical Studies<br />Full safety profile of a drug is limited at the point of marketing due to the limit...
Post Marketing follow up<br />Changes in the complex production and purification processes of biopharmaceuticals can lead ...
25<br />
Factors affecting the scale of operations<br />26<br />
Regulatory agencies<br />
Consequences of ineffective Pharmacovigilance…..<br />
Consequences for the company…..<br />
Consequences for the company…..<br />
Querying / Data Mining<br />Regulatory Reporting<br />Operational / Risk reporting<br />Aggregate Assessment <br />Medical...
Workflow
Coding</li></ul>Quality Checks<br />Expedited<br />Reporting<br />Medical Review<br />Listedness<br />Case Receipt<br />Sa...
Complex Systems & Processes<br />
Lack of Harmonization<br />
Knowledge & Man Power Intensive<br />
Changing Regulations, getting  more demanding<br />
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Importance of Pharmacovigilance for a Biotechnology company

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Importance of Pharmacovigilance for a Biotechnology company
By Vivek Ahuja, MD
Director, Asia Pacific – Pharmacovigilance
Baxter Healthcare –Asia Pacific

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Importance of Pharmacovigilance for a Biotechnology company

  1. 1. Importance of Pharmacovigilance for a Biotechnology company<br />Vivek Ahuja, MD<br />Director, Asia Pacific – Pharmacovigilance<br />Baxter Healthcare –Asia Pacific<br />
  2. 2. 2<br />Risks and Benefits<br />Show me a drug without side effects and I <br />shall show you a drug that does not work .<br /> - Anon<br />
  3. 3. 3<br />Drugs Withdrawn Post Marketing<br />
  4. 4. 4<br />Drugs Withdrawn Post- Marketing<br />
  5. 5. 5<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />Abacavirsulphate/ Lamivudine Tabs<br />Abacavirsulphate/ Lamivudine/ Zidovudine Tabs<br />Abacavirsuphate<br />Acitretin Capsules<br />Actinomycin D Inj<br />Adalimumab<br />Adefovirdipivoxil Tablets<br />Adriamycin/Doxorubicin HCL inj<br />AldesleukinInj<br />Alemtuzumab<br />AlosetrolHCl Tabs<br />Altretamine Capsules<br />AmilorideHCl Tabs<br />Aminobenzoate potassium USP<br />AmiodaroneHCl Tabs<br />Amlodipinebesylate and BenazeprilHCl Combination Capsules<br />Amprenavir Oral Solution<br />Antihemophilic Factor (Human) <br />Arsenic Trioxide Inj<br />Asparaginase<br />Atenolol IV inj<br />Atenolol tabs<br />Azathioprine Tabs<br />BasiliximabInj<br />BenazeprilHCl and HCTZ tabs<br />BevacizumabInj<br />Bexarotene Capsules<br />Bismuth subsalicylate<br />Bosentan Tabs<br />BupropionHCl SR/ ER Tabs<br />
  6. 6. 6<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />31.Busulfan Inj <br />32. Calcium-Iron Multivitamin<br />33. Calcium-Iron-Zinc Multivitamin<br />34. Candesartan Cilexetil Tabs<br />35. Candesartan Cilexetil/Hydrochlorthiazide Tabs<br />36. Capecitabine Tabs<br />37. Capreomycin Inj<br />38. Captopril Tabs<br />39. Carabamezepine ER Tabs and Caps<br />40. Celecoxib capsules<br />41. Cenestin (Conjugated estrogens) Tabs<br />42. Cetuximab <br />43. Divalproex Sodium Delayed Release Tabs<br />44. Divalproex Sodium Extended Release Tabs<br />45. Docetaxel Inj<br />46. Doxorubicin HCl liposome Inj<br />47. Drospirone and Ethylestradiol Tabs<br />48. Duloxetine Delayed Release Capsules<br />49. Edetate disodium Inj<br />50. Emtricitabine and Tenofovir disoproxil fumarate tablets<br />51. Emtricitabine capsules <br />52. Enalapril maleate/HCTZ Tabs<br />53. Enalapril Maleate-Feldopine ER tabs<br />54. Entacavir Solution<br />55. Eprosartan mesylate<br />56. Eprosartan mesylate/ HCTZ<br />57. Escitalopram oxalate <br />58. Diflunisal Tabs<br />59. Dihydroergotamine mesylate USP Nasal Spray<br />60. Disulphiram Tabs<br />
  7. 7. 7<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />61. Divalproex Sodium Capsules<br />62. Divalproex Sodium Delayed Release Tabs<br />63. Divalproex Sodium Extended Release Tabs<br />64. Docetaxel Inj<br />65. Doxorubicin HCl liposome Inj<br />66. Drospirone and Ethylestradiol Tabs<br />67 Duloxetine Delayed Release Capsules<br />68. Edetate disodium Inj<br />69. Emtricitabine and Tenofovir disoproxil fumarate tablets<br />70. Emtricitabine capsules <br />71. Enalapril maleate/HCTZ Tabs<br />72. Enalapril Maleate-Feldopine ER tabs<br />73. Entacavir Solution<br />74. Eprosartan mesylate<br />75. Eprosartan mesylate/ HCTZ<br />76. Escitalopram oxalate <br />77.Esterified Estrogens and Methyltestosterone Tabs<br />78. Estradiol – Norgestimate<br />79. Estradiol Gel<br />80. Estradiol Transdermal System<br />81. Estradiol Vaginal Tabs<br />82. Estradiol/ Norehindrone acetate Transdermal<br />83. Estradiol/Levonorgestrel Transdermal system<br />84. Etonogestrel/ Ethinyl estradiol vaginal ring<br />85. Fentanyl Citrate Transmucosal<br />86. Fentanyl TDS<br />87. Ferrous bis-glycinate chelate and Polysaccharide iron complex<br />88. Flecainide acetate Tabs<br />89. Fluoxetine HCl<br />90. Flutamibe Caps<br />
  8. 8. 8<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />91. Fluticasone propionate and Salmeterol inhalation<br />92. Fondaparinux sodium inj<br />93. Ganciclovir Sodium Inj<br />94. GemtuzumabozogamicinInj<br />95. Hematinic + Vitamins, Calcium and Folic acid dietry supplement<br />96. HeminInj<br />97. HydrocodoneBitartarate and Acetaminophen Oral Solution<br />98. IbretumomabTiuxeten<br />99. Imipraminepamoate<br />100. Immunoglobulin IV human products<br />101. Infliximab<br />102. Irbesartan and Hydrochlorthiazide Tabs<br />103. Irbesartan Tabs<br />104. Irbesartan-HCTZ Tabs<br />105. Irinotecan HCL inj<br />106. Iron DextranInj, USP<br />107. Isotretinoin Capsules<br />108. Lamivudine solution<br />109. Lamivudine Tabs <br />110. Lamivudine/ Zidovudine<br />111. Lamotrigine Tabs<br />112. Levonorgestral and Ethinylestradiol Tabs<br />113. Levothyroxine sodium <br />114. Levothyroxine Sodium USP <br />115. Levothyroxine Sodium, USP Tabs<br />116. Liasinopril/HCTZ Tabs<br />117. Liothyronine sodium Tabs<br />118. Lisinopril<br />119. LisinoprilHydrochlorthiazide<br />120. Losartan potassium/ HCTZ Tabs<br />
  9. 9. 9<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />121. Mechlorethamine HCl Inj<br />122. Medroxyprogesterone Acetate Inj<br />Melphalan Tabs<br />Metformin hydrochloride ER Tabs<br />Methohexital sodium Inj<br />Methoxsalen Caps<br />Methyldopa/ CTZ Tabs<br />Methyldopa/ HCTZ Tabs<br />Methylphenidate HCl ER Tabs<br />Methylphenidate SR & ER Tabs<br />Metoprolol Succinate ER tabs<br />Midodrine HCl Tabs<br />Mitoxantrone Inj<br />Moexipril HCl Tabs<br />Morphine sulphate ER Tabs<br />Morphine Sulphate SR Tabs<br />Muromonab CD3 Inj<br />Mycophenolate mofetil Caps/ Tabs<br />Mycophenolic acid Delayed release Tabs<br />Nadolol Tabs<br />Nevirapine<br />Norelgestromin / Ethinyl estradiol TDS <br />Norgestimate Ethinyl estradiol Tabs<br />Norgestrel and Ethinyl estradiol Tabs<br />Olanzapine <br />Olanzapine/ Fluoxetine Capsules<br />Olmesartan medoxomil-HCTZ tabs<br />Olmesartan Tabs<br />Oxaliplatin Inj<br />Oxycodone HCl Controlled Release tabs<br />
  10. 10. 10<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />151. Oxymetholone Tabs<br />152. Paroxetine HCl CR Tabs<br />153. Peginterferon alfa-2a interferons<br />154. Peginterferon alpha-2b Inj<br />155. Penicillamine <br />156. Pentosan Polysulphate sodium capsules<br />157. Pentostatin Inj<br />158. Perindopril erbumine Tabs<br />159. Phospho-Soda Oral Saline<br />160. Phytonadione Aqueous Colloidal Solution<br />160.Pramipexole Dihydrochloride<br />161.Pramlinitide Acetate Injection<br />162.Prenatal vitamins and Minerals<br />163.Procarbazine HCl Caps<br />164.Progesterone USP Caps<br />165.Promethazine HCl Tabs and Suppositories<br />166. Propafenone HCl ER Caps<br />167. Propoxyphene napsylate and acetaminophen Tabs<br />168. Propranolol HCl Long Acting Caps<br />169. Protryptyline HCl<br />170. Queitiapine Fumarate <br />171. Quinupristin and Dalphopristine Inj<br />172.Rabies Immune Globulin (Human)<br />173. Ramipril<br />174. Rasburicase<br />175. Ribavarin for Inhalation Solution<br />176. Ribavarin USP Caps and Interferon alpha-2b Inj<br />177. Ribavarin USP Caps and Oral Solution<br />178. Risperidone <br />179. Ritonavir Capsules<br />180. Rituxinab <br />
  11. 11. 11<br />Drugs with a Black Box warning <br />(Physicians Drug Reference -2006)<br />181. Salmeterolxinafoate Inhalation powder<br />182. Saquinavirmesylate Caps and Tabs<br />183. Sirolimus Oral Solution and Tabs<br />184. Stavudine<br />185. Sulindac<br />186. Tacrolimus Caps<br />187. Telmisartan and Hydrochlorthiazide Tabs<br />188. Teriparatide (r-DNA) Inj<br />189. Thalidomide<br />190. ThioridazineHCl Tabs<br />191. TiclopidineHCl Tabs<br />192. TimololMaleate/ HCTZ Tabs<br />193. Timololnmaleate Tabs<br />194. Tinidazole Tabs<br />195. Tipranavir<br />196. Tolcapone Tabs<br />197. TopotecanHCl<br />198. Trandolapril/VeerapamilHCl ER<br />199. Tranylcyprominesulphate Tablets<br />200. Trastuzumab<br />201. Tretinoin Caps<br />202. Triamterene + HCTZ Tabs<br />203. Triamterene USP Caps<br />204. Triimipraminemaleate<br />205. ValganciclovirHCl tabs<br />206. Valproate Sodium Injection<br />207. Valsartan / HCTZ Tabs<br />208. Valsartan Tabs<br />209. VenlafaxineHCl Tabs and ER Tabs<br />210. VinorelbinetartarteInj<br />211. Vitamins Iron, Calcium, Folic acid <br />212. Zidovudine<br />213. ZiprasidoneHCl Caps<br />
  12. 12. 12<br />Pharmacovigilance<br />Is the safety profile of a drug fully known <br /> at the time of its launch ?<br />No !<br />
  13. 13. 13<br />CLINICAL DEVELOPMENT<br />Numbers of humans tested<br />50-100<br />100-300<br />1500-3000<br />> 10000<br />
  14. 14. Required sample size for detecting a rare adverse drug reaction<br />
  15. 15. 15<br /> Evolution of the Indications for Diazepam<br />1974<br />1968<br />1967<br />Year of Introduction<br />1966<br />1965<br />1964<br />1963<br />Dermatology <br />GI disorders<br />Obstetrics<br />Cor.throm.<br />Relief of anxiety<br />Sedation<br />Surgery<br />Alcoholism<br />Stress <br />Thy.disorders.<br />Anaesthesia<br />Rheumatism.<br />Urology<br />Poisoning<br />Asthma Tetanus<br />Convulsions Narcotic poisoning<br />
  16. 16. 16<br />Limitations of pre-marketing clinical trials<br />
  17. 17. 17<br />Pharmacovigilance<br />The ADR profiles of drugs and their Risk- Benefit<br />balance need to be continuously monitored <br />during their development <br />(Investigational Product Pharmacovigilance) <br />and <br />for their lifetime post-launch<br />(Marketed Product Pharmacovigilance)<br />
  18. 18. Traditional small molecule drugs vs. Biopharmaceuticals<br />Complex production process<br />Limited predictability of preclinical to clinical data – hence the need for enhanced Pharmacovigilance<br />A high potential for immunogenicity<br />Adverse events can often be related to an exaggerated pharmacology<br />
  19. 19. Difficulties in causality assessment <br />Biopharmaceuticals, are often indicated to treat severe and/or life-threatening diseases in patients who often have other diseases and are treated with concomitant medications<br />
  20. 20. Spontaneous data vs. Registries<br />Since biopharmaceuticals are often used in a specialized hospital setting, it is expected that large population-based databases will contain limited information on biopharmaceuticals. <br />Registries have therefore been shown to be an important tool to obtain Pharmacovigilance data.<br />
  21. 21. Pooled Data from RCTs<br />In addition to registries, pooling of data from randomized controlled clinical trials has also been shown to serve as a valuable tool <br />E.g.observed 3.3-fold increased risk for malignancies and the 2.0-fold increased risk for serious infections in patients treated with TNF antagonists after pooling of clinical trial data<br />
  22. 22. ADRs peculiar to Biopharmaceuticals<br />Occurrence of tuberculosis with the use of (TNF)-alphainhibitors, especially Infliximab (role in immune response to mycobacteria)<br />Dramatically increased incidence of pure red cell aplasia in patients treated with one particular formulation of recombinant human epoetin (immunogenic response to endogenous molecules, which occurred following changes in the manufacturing of epoetinalfa)<br />Cytokine storm occurring in healthy volunteers treated with the superagonist anti-CD28 monoclonal antibody TGN1412 (TeGenero) (cytokine storm had not been seen in the preclinical phases)<br />Hamilton CD. Infectious complications of treatment with biologic agents. CurrOpinRheumatol 2004 Jul; 16 (4):393-8<br />ImperatoAK, Smiles S, Abramson SB. Long-term risks associated with biologic response modifiers used in rheumatic<br />diseases. CurrOpinRheumatol 2004 May; 16 (3): 199-205<br />Schellekens H. Immunologic mechanisms of EPO associated pure red cell aplasia. Best Pract Res ClinHaematol 2005 Sep; 18 (3): 473-80<br />Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006 Sep; 355 (10):1018-28<br />
  23. 23. Safety data from Clinical Studies<br />Full safety profile of a drug is limited at the point of marketing due to the limitations of randomized controlled trials, limited sample size & duration & a homogeneous population<br />For biopharmaceuticals - further complicated due to limited data available from animal studies<br />Post marketing safety data therefore offers a valuable and necessary complement to the clinical trials<br />Additional pharmacovigilance (Post-Authorization Safety Studies [PASS] is the recommendation <br />
  24. 24. Post Marketing follow up<br />Changes in the complex production and purification processes of biopharmaceuticals can lead to serious health problems. <br />To be able to identify this type of problem at an early stage, activities to improve traceability of the biopharmaceutical responsible for the ADR, for example the specific batch, should specifically be taken into account. <br />
  25. 25. 25<br />
  26. 26. Factors affecting the scale of operations<br />26<br />
  27. 27. Regulatory agencies<br />
  28. 28. Consequences of ineffective Pharmacovigilance…..<br />
  29. 29. Consequences for the company…..<br />
  30. 30. Consequences for the company…..<br />
  31. 31. Querying / Data Mining<br />Regulatory Reporting<br />Operational / Risk reporting<br />Aggregate Assessment <br />Medical review / Data Mining / Alert detection<br />Case Management <br />Single Case Assessment<br />Case Intake<br />Pharmacovigilance<br />Case Assessment<br />Alert Generation & Signal Workup<br />Enhanced Data Acquisition<br />Risk Communication<br />Signal Detection<br />Analytics<br />MIS Reports<br />Summary Reporting<br />Workflow Assignment<br />Single case Report<br />Case processing<br /><ul><li>Data Entry
  32. 32. Workflow
  33. 33. Coding</li></ul>Quality Checks<br />Expedited<br />Reporting<br />Medical Review<br />Listedness<br />Case Receipt<br />Safety Database<br />Periodic Reporting<br />Authoring & Review Workflow<br />PSURs<br />PSUR Submission<br />Line Listings<br />
  34. 34. Complex Systems & Processes<br />
  35. 35. Lack of Harmonization<br />
  36. 36. Knowledge & Man Power Intensive<br />
  37. 37. Changing Regulations, getting more demanding<br />
  38. 38.
  39. 39. Risk- Benefit Trade Off<br /><ul><li>ONE WAY TO CONSIDER DRUG RISKS IS TO BAN ALL DRUGS !
  40. 40. Ending all drug induced harm would add 37 minutes to your life</li></ul> expectancy<br /><ul><li>Ending all drug related benefits would subtract 15 years from your Life expectancy and also end the improvement in life quality drugs give </li></ul> - Prof. William Inman, Former Head of MHRA<br />
  41. 41. Questions?<br />“Knowing is not enough; we must apply<br />Willing is not enough: we must do”<br /> -Goethe<br />

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