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 company Vivek Ahuja, MD Director, Asia Pacific – Pharmacovigilance Baxter Healthcare –Asia Pacific

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

3. 3 Drugs Withdrawn Post Marketing

4. 4 Drugs Withdrawn Post- Marketing

5. 5 Drugs with a Black Box warning (Physicians Drug Reference -2006) Abacavirsulphate/ Lamivudine Tabs Abacavirsulphate/ Lamivudine/ Zidovudine Tabs Abacavirsuphate Acitretin Capsules Actinomycin D Inj Adalimumab Adefovirdipivoxil Tablets Adriamycin/Doxorubicin HCL inj AldesleukinInj Alemtuzumab AlosetrolHCl Tabs Altretamine Capsules AmilorideHCl Tabs Aminobenzoate potassium USP AmiodaroneHCl Tabs Amlodipinebesylate and BenazeprilHCl Combination Capsules Amprenavir Oral Solution Antihemophilic Factor (Human) Arsenic Trioxide Inj Asparaginase Atenolol IV inj Atenolol tabs Azathioprine Tabs BasiliximabInj BenazeprilHCl and HCTZ tabs BevacizumabInj Bexarotene Capsules Bismuth subsalicylate Bosentan Tabs BupropionHCl SR/ ER Tabs

6. 6 Drugs with a Black Box warning (Physicians Drug Reference -2006) 31.Busulfan Inj 32. Calcium-Iron Multivitamin 33. Calcium-Iron-Zinc Multivitamin 34. Candesartan Cilexetil Tabs 35. Candesartan Cilexetil/Hydrochlorthiazide Tabs 36. Capecitabine Tabs 37. Capreomycin Inj 38. Captopril Tabs 39. Carabamezepine ER Tabs and Caps 40. Celecoxib capsules 41. Cenestin (Conjugated estrogens) Tabs 42. Cetuximab 43. Divalproex Sodium Delayed Release Tabs 44. Divalproex Sodium Extended Release Tabs 45. Docetaxel Inj 46. Doxorubicin HCl liposome Inj 47. Drospirone and Ethylestradiol Tabs 48. Duloxetine Delayed Release Capsules 49. Edetate disodium Inj 50. Emtricitabine and Tenofovir disoproxil fumarate tablets 51. Emtricitabine capsules 52. Enalapril maleate/HCTZ Tabs 53. Enalapril Maleate-Feldopine ER tabs 54. Entacavir Solution 55. Eprosartan mesylate 56. Eprosartan mesylate/ HCTZ 57. Escitalopram oxalate 58. Diflunisal Tabs 59. Dihydroergotamine mesylate USP Nasal Spray 60. Disulphiram Tabs

7. 7 Drugs with a Black Box warning (Physicians Drug Reference -2006) 61. Divalproex Sodium Capsules 62. Divalproex Sodium Delayed Release Tabs 63. Divalproex Sodium Extended Release Tabs 64. Docetaxel Inj 65. Doxorubicin HCl liposome Inj 66. Drospirone and Ethylestradiol Tabs 67 Duloxetine Delayed Release Capsules 68. Edetate disodium Inj 69. Emtricitabine and Tenofovir disoproxil fumarate tablets 70. Emtricitabine capsules 71. Enalapril maleate/HCTZ Tabs 72. Enalapril Maleate-Feldopine ER tabs 73. Entacavir Solution 74. Eprosartan mesylate 75. Eprosartan mesylate/ HCTZ 76. Escitalopram oxalate 77.Esterified Estrogens and Methyltestosterone Tabs 78. Estradiol – Norgestimate 79. Estradiol Gel 80. Estradiol Transdermal System 81. Estradiol Vaginal Tabs 82. Estradiol/ Norehindrone acetate Transdermal 83. Estradiol/Levonorgestrel Transdermal system 84. Etonogestrel/ Ethinyl estradiol vaginal ring 85. Fentanyl Citrate Transmucosal 86. Fentanyl TDS 87. Ferrous bis-glycinate chelate and Polysaccharide iron complex 88. Flecainide acetate Tabs 89. Fluoxetine HCl 90. Flutamibe Caps

8. 8 Drugs with a Black Box warning (Physicians Drug Reference -2006) 91. Fluticasone propionate and Salmeterol inhalation 92. Fondaparinux sodium inj 93. Ganciclovir Sodium Inj 94. GemtuzumabozogamicinInj 95. Hematinic + Vitamins, Calcium and Folic acid dietry supplement 96. HeminInj 97. HydrocodoneBitartarate and Acetaminophen Oral Solution 98. IbretumomabTiuxeten 99. Imipraminepamoate 100. Immunoglobulin IV human products 101. Infliximab 102. Irbesartan and Hydrochlorthiazide Tabs 103. Irbesartan Tabs 104. Irbesartan-HCTZ Tabs 105. Irinotecan HCL inj 106. Iron DextranInj, USP 107. Isotretinoin Capsules 108. Lamivudine solution 109. Lamivudine Tabs 110. Lamivudine/ Zidovudine 111. Lamotrigine Tabs 112. Levonorgestral and Ethinylestradiol Tabs 113. Levothyroxine sodium 114. Levothyroxine Sodium USP 115. Levothyroxine Sodium, USP Tabs 116. Liasinopril/HCTZ Tabs 117. Liothyronine sodium Tabs 118. Lisinopril 119. LisinoprilHydrochlorthiazide 120. Losartan potassium/ HCTZ Tabs

9. 9 Drugs with a Black Box warning (Physicians Drug Reference -2006) 121. Mechlorethamine HCl Inj 122. Medroxyprogesterone Acetate Inj Melphalan Tabs Metformin hydrochloride ER Tabs Methohexital sodium Inj Methoxsalen Caps Methyldopa/ CTZ Tabs Methyldopa/ HCTZ Tabs Methylphenidate HCl ER Tabs Methylphenidate SR & ER Tabs Metoprolol Succinate ER tabs Midodrine HCl Tabs Mitoxantrone Inj Moexipril HCl Tabs Morphine sulphate ER Tabs Morphine Sulphate SR Tabs Muromonab CD3 Inj Mycophenolate mofetil Caps/ Tabs Mycophenolic acid Delayed release Tabs Nadolol Tabs Nevirapine Norelgestromin / Ethinyl estradiol TDS Norgestimate Ethinyl estradiol Tabs Norgestrel and Ethinyl estradiol Tabs Olanzapine Olanzapine/ Fluoxetine Capsules Olmesartan medoxomil-HCTZ tabs Olmesartan Tabs Oxaliplatin Inj Oxycodone HCl Controlled Release tabs

10. 10 Drugs with a Black Box warning (Physicians Drug Reference -2006) 151. Oxymetholone Tabs 152. Paroxetine HCl CR Tabs 153. Peginterferon alfa-2a interferons 154. Peginterferon alpha-2b Inj 155. Penicillamine 156. Pentosan Polysulphate sodium capsules 157. Pentostatin Inj 158. Perindopril erbumine Tabs 159. Phospho-Soda Oral Saline 160. Phytonadione Aqueous Colloidal Solution 160.Pramipexole Dihydrochloride 161.Pramlinitide Acetate Injection 162.Prenatal vitamins and Minerals 163.Procarbazine HCl Caps 164.Progesterone USP Caps 165.Promethazine HCl Tabs and Suppositories 166. Propafenone HCl ER Caps 167. Propoxyphene napsylate and acetaminophen Tabs 168. Propranolol HCl Long Acting Caps 169. Protryptyline HCl 170. Queitiapine Fumarate 171. Quinupristin and Dalphopristine Inj 172.Rabies Immune Globulin (Human) 173. Ramipril 174. Rasburicase 175. Ribavarin for Inhalation Solution 176. Ribavarin USP Caps and Interferon alpha-2b Inj 177. Ribavarin USP Caps and Oral Solution 178. Risperidone 179. Ritonavir Capsules 180. Rituxinab

11. 11 Drugs with a Black Box warning (Physicians Drug Reference -2006) 181. Salmeterolxinafoate Inhalation powder 182. Saquinavirmesylate Caps and Tabs 183. Sirolimus Oral Solution and Tabs 184. Stavudine 185. Sulindac 186. Tacrolimus Caps 187. Telmisartan and Hydrochlorthiazide Tabs 188. Teriparatide (r-DNA) Inj 189. Thalidomide 190. ThioridazineHCl Tabs 191. TiclopidineHCl Tabs 192. TimololMaleate/ HCTZ Tabs 193. Timololnmaleate Tabs 194. Tinidazole Tabs 195. Tipranavir 196. Tolcapone Tabs 197. TopotecanHCl 198. Trandolapril/VeerapamilHCl ER 199. Tranylcyprominesulphate Tablets 200. Trastuzumab 201. Tretinoin Caps 202. Triamterene + HCTZ Tabs 203. Triamterene USP Caps 204. Triimipraminemaleate 205. ValganciclovirHCl tabs 206. Valproate Sodium Injection 207. Valsartan / HCTZ Tabs 208. Valsartan Tabs 209. VenlafaxineHCl Tabs and ER Tabs 210. VinorelbinetartarteInj 211. Vitamins Iron, Calcium, Folic acid 212. Zidovudine 213. ZiprasidoneHCl Caps

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

13. 13 CLINICAL DEVELOPMENT Numbers of humans tested 50-100 100-300 1500-3000 > 10000

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

15. 15 Evolution of the Indications for Diazepam 1974 1968 1967 Year of Introduction 1966 1965 1964 1963 Dermatology GI disorders Obstetrics Cor.throm. Relief of anxiety Sedation Surgery Alcoholism Stress Thy.disorders. Anaesthesia Rheumatism. Urology Poisoning Asthma Tetanus Convulsions Narcotic poisoning

16. 16 Limitations of pre-marketing clinical trials

17. 17 Pharmacovigilance The ADR profiles of drugs and their Risk- Benefit balance 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. Biopharmaceuticals Complex production process Limited predictability of preclinical to clinical data – hence the need for enhanced Pharmacovigilance A high potential for immunogenicity Adverse 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. Registries Since 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 RCTs In 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 Biopharmaceuticals Occurrence 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):393-8 ImperatoAK, Smiles S, Abramson SB. Long-term risks associated with biologic response modifiers used in rheumatic diseases. CurrOpinRheumatol 2004 May; 16 (3): 199-205 Schellekens H. Immunologic mechanisms of EPO associated pure red cell aplasia. Best Pract Res ClinHaematol 2005 Sep; 18 (3): 473-80 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

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

24. Post Marketing follow up Changes 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 operations 26

27. Regulatory agencies

28. Consequences of ineffective Pharmacovigilance…..

29. Consequences for the company…..

30. Consequences for the company…..

32. Workflow

33. CodingQuality Checks Expedited Reporting Medical Review Listedness Case Receipt Safety Database Periodic Reporting Authoring & Review Workflow PSURs PSUR Submission Line Listings

34. Complex Systems & Processes

35. Lack of Harmonization

36. Knowledge & Man Power Intensive

37. Changing Regulations, getting more demanding

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