This document discusses the importance of pharmacovigilance for biotechnology companies. It notes that the full safety profile of a drug is not known at launch due to limitations of clinical trials. Post-marketing surveillance is needed to continuously monitor a drug's safety profile. It highlights specific challenges for biopharmaceuticals like immunogenicity and difficulties in causality assessment. The document emphasizes the role of registries and pooled clinical trial data in pharmacovigilance for biologics. It also lists some adverse drug reactions peculiar to biopharmaceuticals. Finally, it discusses factors that can affect the scale of pharmacovigilance operations and the consequences of ineffective pharmacovigilance.

1. Importance of Pharmacovigilance for a Biotechnology companyVivek Ahuja, MDDirector, Asia Pacific – PharmacovigilanceBaxter Healthcare –Asia Pacific

2. 2Risks and BenefitsShow me a drug without side effects and I shall show you a drug that does not work . - Anon

3. 3Drugs Withdrawn Post Marketing

4. 4Drugs Withdrawn Post- Marketing

5. 5Drugs with a Black Box warning (Physicians Drug Reference -2006)Abacavirsulphate/ Lamivudine TabsAbacavirsulphate/ Lamivudine/ Zidovudine TabsAbacavirsuphateAcitretin CapsulesActinomycin D InjAdalimumabAdefovirdipivoxil TabletsAdriamycin/Doxorubicin HCL injAldesleukinInjAlemtuzumabAlosetrolHCl TabsAltretamine CapsulesAmilorideHCl TabsAminobenzoate potassium USPAmiodaroneHCl TabsAmlodipinebesylate and BenazeprilHCl Combination CapsulesAmprenavir Oral SolutionAntihemophilic Factor (Human) Arsenic Trioxide InjAsparaginaseAtenolol IV injAtenolol tabsAzathioprine TabsBasiliximabInjBenazeprilHCl and HCTZ tabsBevacizumabInjBexarotene CapsulesBismuth subsalicylateBosentan TabsBupropionHCl SR/ ER Tabs

6. 6Drugs with a Black Box warning (Physicians Drug Reference -2006)31.Busulfan Inj 32. Calcium-Iron Multivitamin33. Calcium-Iron-Zinc Multivitamin34. Candesartan Cilexetil Tabs35. Candesartan Cilexetil/Hydrochlorthiazide Tabs36. Capecitabine Tabs37. Capreomycin Inj38. Captopril Tabs39. Carabamezepine ER Tabs and Caps40. Celecoxib capsules41. Cenestin (Conjugated estrogens) Tabs42. Cetuximab 43. Divalproex Sodium Delayed Release Tabs44. Divalproex Sodium Extended Release Tabs45. Docetaxel Inj46. Doxorubicin HCl liposome Inj47. Drospirone and Ethylestradiol Tabs48. Duloxetine Delayed Release Capsules49. Edetate disodium Inj50. Emtricitabine and Tenofovir disoproxil fumarate tablets51. Emtricitabine capsules 52. Enalapril maleate/HCTZ Tabs53. Enalapril Maleate-Feldopine ER tabs54. Entacavir Solution55. Eprosartan mesylate56. Eprosartan mesylate/ HCTZ57. Escitalopram oxalate 58. Diflunisal Tabs59. Dihydroergotamine mesylate USP Nasal Spray60. Disulphiram Tabs

7. 7Drugs with a Black Box warning (Physicians Drug Reference -2006)61. Divalproex Sodium Capsules62. Divalproex Sodium Delayed Release Tabs63. Divalproex Sodium Extended Release Tabs64. Docetaxel Inj65. Doxorubicin HCl liposome Inj66. Drospirone and Ethylestradiol Tabs67 Duloxetine Delayed Release Capsules68. Edetate disodium Inj69. Emtricitabine and Tenofovir disoproxil fumarate tablets70. Emtricitabine capsules 71. Enalapril maleate/HCTZ Tabs72. Enalapril Maleate-Feldopine ER tabs73. Entacavir Solution74. Eprosartan mesylate75. Eprosartan mesylate/ HCTZ76. Escitalopram oxalate 77.Esterified Estrogens and Methyltestosterone Tabs78. Estradiol – Norgestimate79. Estradiol Gel80. Estradiol Transdermal System81. Estradiol Vaginal Tabs82. Estradiol/ Norehindrone acetate Transdermal83. Estradiol/Levonorgestrel Transdermal system84. Etonogestrel/ Ethinyl estradiol vaginal ring85. Fentanyl Citrate Transmucosal86. Fentanyl TDS87. Ferrous bis-glycinate chelate and Polysaccharide iron complex88. Flecainide acetate Tabs89. Fluoxetine HCl90. Flutamibe Caps

8. 8Drugs with a Black Box warning (Physicians Drug Reference -2006)91. Fluticasone propionate and Salmeterol inhalation92. Fondaparinux sodium inj93. Ganciclovir Sodium Inj94. GemtuzumabozogamicinInj95. Hematinic + Vitamins, Calcium and Folic acid dietry supplement96. HeminInj97. HydrocodoneBitartarate and Acetaminophen Oral Solution98. IbretumomabTiuxeten99. Imipraminepamoate100. Immunoglobulin IV human products101. Infliximab102. Irbesartan and Hydrochlorthiazide Tabs103. Irbesartan Tabs104. Irbesartan-HCTZ Tabs105. Irinotecan HCL inj106. Iron DextranInj, USP107. Isotretinoin Capsules108. Lamivudine solution109. Lamivudine Tabs 110. Lamivudine/ Zidovudine111. Lamotrigine Tabs112. Levonorgestral and Ethinylestradiol Tabs113. Levothyroxine sodium 114. Levothyroxine Sodium USP 115. Levothyroxine Sodium, USP Tabs116. Liasinopril/HCTZ Tabs117. Liothyronine sodium Tabs118. Lisinopril119. LisinoprilHydrochlorthiazide120. Losartan potassium/ HCTZ Tabs

9. 9Drugs with a Black Box warning (Physicians Drug Reference -2006)121. Mechlorethamine HCl Inj122. Medroxyprogesterone Acetate InjMelphalan TabsMetformin hydrochloride ER TabsMethohexital sodium InjMethoxsalen CapsMethyldopa/ CTZ TabsMethyldopa/ HCTZ TabsMethylphenidate HCl ER TabsMethylphenidate SR & ER TabsMetoprolol Succinate ER tabsMidodrine HCl TabsMitoxantrone InjMoexipril HCl TabsMorphine sulphate ER TabsMorphine Sulphate SR TabsMuromonab CD3 InjMycophenolate mofetil Caps/ TabsMycophenolic acid Delayed release TabsNadolol TabsNevirapineNorelgestromin / Ethinyl estradiol TDS Norgestimate Ethinyl estradiol TabsNorgestrel and Ethinyl estradiol TabsOlanzapine Olanzapine/ Fluoxetine CapsulesOlmesartan medoxomil-HCTZ tabsOlmesartan TabsOxaliplatin InjOxycodone HCl Controlled Release tabs

10. 10Drugs with a Black Box warning (Physicians Drug Reference -2006)151. Oxymetholone Tabs152. Paroxetine HCl CR Tabs153. Peginterferon alfa-2a interferons154. Peginterferon alpha-2b Inj155. Penicillamine 156. Pentosan Polysulphate sodium capsules157. Pentostatin Inj158. Perindopril erbumine Tabs159. Phospho-Soda Oral Saline160. Phytonadione Aqueous Colloidal Solution160.Pramipexole Dihydrochloride161.Pramlinitide Acetate Injection162.Prenatal vitamins and Minerals163.Procarbazine HCl Caps164.Progesterone USP Caps165.Promethazine HCl Tabs and Suppositories166. Propafenone HCl ER Caps167. Propoxyphene napsylate and acetaminophen Tabs168. Propranolol HCl Long Acting Caps169. Protryptyline HCl170. Queitiapine Fumarate 171. Quinupristin and Dalphopristine Inj172.Rabies Immune Globulin (Human)173. Ramipril174. Rasburicase175. Ribavarin for Inhalation Solution176. Ribavarin USP Caps and Interferon alpha-2b Inj177. Ribavarin USP Caps and Oral Solution178. Risperidone 179. Ritonavir Capsules180. Rituxinab

11. 11Drugs with a Black Box warning (Physicians Drug Reference -2006)181. Salmeterolxinafoate Inhalation powder182. Saquinavirmesylate Caps and Tabs183. Sirolimus Oral Solution and Tabs184. Stavudine185. Sulindac186. Tacrolimus Caps187. Telmisartan and Hydrochlorthiazide Tabs188. Teriparatide (r-DNA) Inj189. Thalidomide190. ThioridazineHCl Tabs191. TiclopidineHCl Tabs192. TimololMaleate/ HCTZ Tabs193. Timololnmaleate Tabs194. Tinidazole Tabs195. Tipranavir196. Tolcapone Tabs197. TopotecanHCl198. Trandolapril/VeerapamilHCl ER199. Tranylcyprominesulphate Tablets200. Trastuzumab201. Tretinoin Caps202. Triamterene + HCTZ Tabs203. Triamterene USP Caps204. Triimipraminemaleate205. ValganciclovirHCl tabs206. Valproate Sodium Injection207. Valsartan / HCTZ Tabs208. Valsartan Tabs209. VenlafaxineHCl Tabs and ER Tabs210. VinorelbinetartarteInj211. Vitamins Iron, Calcium, Folic acid 212. Zidovudine213. ZiprasidoneHCl Caps

12. 12PharmacovigilanceIs the safety profile of a drug fully known at the time of its launch ?No !

13. 13CLINICAL DEVELOPMENTNumbers of humans tested50-100100-3001500-3000> 10000

14. Required sample size for detecting a rare adverse drug reaction

15. 15 Evolution of the Indications for Diazepam197419681967Year of Introduction1966196519641963Dermatology GI disordersObstetricsCor.throm.Relief of anxietySedationSurgeryAlcoholismStress Thy.disorders.AnaesthesiaRheumatism.UrologyPoisoningAsthma TetanusConvulsions Narcotic poisoning

16. 16Limitations of pre-marketing clinical trials

17. 17PharmacovigilanceThe ADR profiles of drugs and their Risk- Benefitbalance need to be continuously monitored during their development (Investigational Product Pharmacovigilance) and for their lifetime post-launch(Marketed Product Pharmacovigilance)

18. Traditional small molecule drugs vs. BiopharmaceuticalsComplex production processLimited predictability of preclinical to clinical data – hence the need for enhanced PharmacovigilanceA high potential for immunogenicityAdverse events can often be related to an exaggerated pharmacology

19. Difficulties in causality assessment 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

20. Spontaneous data vs. RegistriesSince biopharmaceuticals are often used in a specialized hospital setting, it is expected that large population-based databases will contain limited information on biopharmaceuticals. Registries have therefore been shown to be an important tool to obtain Pharmacovigilance data.

21. Pooled Data from RCTsIn addition to registries, pooling of data from randomized controlled clinical trials has also been shown to serve as a valuable tool 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

22. ADRs peculiar to BiopharmaceuticalsOccurrence of tuberculosis with the use of (TNF)-alphainhibitors, especially Infliximab (role in immune response to mycobacteria)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)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)Hamilton CD. Infectious complications of treatment with biologic agents. CurrOpinRheumatol 2004 Jul; 16 (4):393-8ImperatoAK, Smiles S, Abramson SB. Long-term risks associated with biologic response modifiers used in rheumaticdiseases. CurrOpinRheumatol 2004 May; 16 (3): 199-205Schellekens H. Immunologic mechanisms of EPO associated pure red cell aplasia. Best Pract Res ClinHaematol 2005 Sep; 18 (3): 473-80Suntharalingam 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

23. Safety data from Clinical StudiesFull 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 populationFor biopharmaceuticals - further complicated due to limited data available from animal studiesPost marketing safety data therefore offers a valuable and necessary complement to the clinical trialsAdditional pharmacovigilance (Post-Authorization Safety Studies [PASS] is the recommendation

24. Post Marketing follow upChanges in the complex production and purification processes of biopharmaceuticals can lead to serious health problems. 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.

25. 25

26. Factors affecting the scale of operations26

27. Regulatory agencies

28. Consequences of ineffective Pharmacovigilance…..

29. Consequences for the company…..

30. Consequences for the company…..

31. Querying / Data MiningRegulatory ReportingOperational / Risk reportingAggregate Assessment Medical review / Data Mining / Alert detectionCase Management Single Case AssessmentCase IntakePharmacovigilanceCase AssessmentAlert Generation & Signal WorkupEnhanced Data AcquisitionRisk CommunicationSignal DetectionAnalyticsMIS ReportsSummary ReportingWorkflow AssignmentSingle case ReportCase processingData Entry

32. Workflow

33. CodingQuality ChecksExpeditedReportingMedical ReviewListednessCase ReceiptSafety DatabasePeriodic ReportingAuthoring & Review WorkflowPSURsPSUR SubmissionLine Listings

34. Complex Systems & Processes

35. Lack of Harmonization

36. Knowledge & Man Power Intensive

37. Changing Regulations, getting more demanding

39. Risk- Benefit Trade OffONE WAY TO CONSIDER DRUG RISKS IS TO BAN ALL DRUGS !

40. Ending all drug induced harm would add 37 minutes to your life expectancyEnding all drug related benefits would subtract 15 years from your Life expectancy and also end the improvement in life quality drugs give - Prof. William Inman, Former Head of MHRA

41. Questions?“Knowing is not enough; we must applyWilling is not enough: we must do” -Goethe