Foro de genéricos y biosimilares

Ponencia en la academia nacional de medicina

1. Gen éricos y biosimilares en la práctica médica Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia Bogot á – 08/ 2016 @ Onconerd

2. @onconerd

3. Mauricio Lema: Conflicto de interés Honorarios por conferencias (2015): Roche, Novartis , MSD, Aztra-Zeneca , AMGEN, Pfizer, Boheringer-Ingelheim

4. 1. No estaríamos hoy aquí si los medicamentos innovadores fueran baratos

5. Precios de los agentes nuevos Medicamento Dosis Precio/mg (US$) Costo mediano (US$) Nivolumab 3 mg/kg 28.78 103.220 (Melanoma) Pembrolizumab 2 mg/kg - 150.000 (Melanoma) Ipilimumab 3 mg/kg 156.46 158.282 (Melanoma) Palbociclib 125 qd x21/28d 3.75 118.090 (Mama) Blinatumomab 28 mcg /kg/d 9000 178.000 (ALL) Ramucirumab 8 mg/kg q15d 10.2 159.000 (Colon) http:// www.medscape.com/viewarticle/845707 - http :// www.medscape.com/viewarticle/839171#vp_1 http:// www.medscape.com/viewarticle/836879 http://www.pharmacytimes.com/publications/health-system-edition/2015/march2015/cyramza-by-eli-lilly-and-company http :// www.medscape.com/viewarticle/831150 http:// www.medscape.com/viewarticle/830145 http://www.medscape.com/viewarticle/830145 http://www.medscape.com/viewarticle/828882 Oro: US$ 0.036/mg Medicamento Dosis Precio mes ($US) Costo mediano (US$) Crizotinib 250 mg bid 11.500 138.000/año Ceritinib 750 mg/d 13.200 158.000 /año

6. Precios de los agentes nuevos Medicamento Dosis Precio/mg (US$) Costo mediano (US$) Nivolumab 3 mg/kg 28.78 103.220 (Melanoma) Pembrolizumab 2 mg/kg - 150.000 (Melanoma) Ipilimumab 3 mg/kg 156.46 158.282 (Melanoma) Palbociclib 125 qd x21/28d 3.75 118.090 (Mama) Blinatumomab 28 mcg /kg/d 9000 178.000 (ALL) Ramucirumab 8 mg/kg q15d 10.2 159.000 (Colon) http:// www.medscape.com/viewarticle/845707 - http :// www.medscape.com/viewarticle/839171#vp_1 http:// www.medscape.com/viewarticle/836879 http://www.pharmacytimes.com/publications/health-system-edition/2015/march2015/cyramza-by-eli-lilly-and-company http :// www.medscape.com/viewarticle/831150 http:// www.medscape.com/viewarticle/830145 http://www.medscape.com/viewarticle/830145 http://www.medscape.com/viewarticle/828882 Aprobado en Colombia Medicamento Dosis Precio mes ($US) Costo mediano (US$) Crizotinib 250 mg bid 11.500 138.000/año Ceritinib 750 mg/d 13.200 158.000 /año

7. Gen éricos

8. A generic medicinal product is a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product ( the innovator ), and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies , thus supporting equivalent efficacy , unless the requirements for a Biowaiver have been satisfactorily fulfilled Committee for Medicinal Products for Human Use, EMA, 2012

9. G enerics can cost as much as 80–85% less than the original compound Generic Drug Market : Growing and Merging . Lancet Oncol , 2015

10. According to IMS Health , in the US alone unbranded generic drugs accounted for 80% of prescriptions dispensed during the 2013 fiscal year Generic Drug Market : Growing and Merging . Lancet Oncol , 2015

11. Prescription Share in the US Relative cost

12. 2. E l problema no es sólo económico, sino que se vuelve también un problema médico. 

13. The extensive experience from bringing generic products to the market over the last decades allows the conclusion that they are well-accepted and provide a useful alternative option for cost-effective pharmacotherapy . Borg JJ, Sci Pharm , 2014

14. Innovador Gen érico A Gen érico B Biodisponibilidad aceptable Fenito ína Carbamazepina Ácido valproico Lamotrigina Levetiracetam Topiramato Levodopa Clopidogrel   Burkhardt RT   Neurology . 2004;63:1494–1496. Armstrong TS  J Neurooncol . 2010;98:137–141.  Gidal BE   Curr Neurol Neurosci Rep. 2009;9:333–337.  Berg MJ   Neurology . 2008;71:525–530. Bautista RE   Epilepsy Res. 2011;95:158–167. Andermann F  Epilepsia. 2007;48:464–469.  LeLorier J   Neurology . 2008;70:2179–2186. Makus KG   Clin Ther . 2007;29:334–341. Talati R Pharmacotherapy . 2012;32:314–322.  Duh MS Neurology . 2009;72:2122–2129.  Gasser UE BMC Pharmacol Toxicol . 2013;14: 24

15. Impact on Bacterial Resistance of Therapeutically Nonequivalent Generics : The Case of Piperacillin-Tazobactam We studied a generic product of piperacillin-tazobactam characterized by pharmaceutical and pharmacokinetic equivalence but a faulty fit of Hill’sE max   sigmoid model that could be interpreted as pharmacodynamic nonequivalence Rodr íguez CE, PLoS One , 2016

16. Generic Vancomycin Enriches Resistant Subpopulations of Staphylococcus aureus   after Exposure in a Neutropenic Mouse Thigh Infection Model The great capacity of generic vancomycin to select for less susceptible organisms raises concerns about the role of therapeutic inequivalence of any antimicrobial on the epidemiology of resistance worldwide . Rodr íguez CE, Amtimicrob Agents Chemother , 2012 Resistance Frequencies with innovator and generics

17. Pharmacodynamics of nine generic products of amikacin compared with the innovator in the neutropenic mouse thigh infection model As we demonstrated previously with other antibiotics such as vancomycin , gentamicin and oxacillin , the generic products of amikacin failed the in vivo efficacy testing . The therapeutic equivalence should be assessed in vivo before clinical approval of generic products . Zuluaga A, BMC Res Notes, 2015

18. Generic Imatinib A Multi-centric Bioequivalence Trial in Ph + Chronic Myeloid Leukemia Patients to Assess Bioequivalence and Safety Evaluation of Generic Imatinib Mesylate 400 mg Tablets Both formulations were well tolerated after oral administration of IMPs . Failure of copy Imatib (CIPLA, India) to maintain hematologic and cytogenetic responses in chronic myeloid leukemia in chronic phase . This case report suggests a difference in clinical efficacy between the authorized form of imatinib ( Glivec ) and the copy version of the drug ( Imatib ) Arora R, Cancer Res Treat . 2016 Mattar M Int J Hematol , 2010

19. The Introduction of Generic Aromatase Inhibitors and Treatment Adherence Among Medicare D Enrollees LIS: Lower-income subsidy The introduction of generic medications attenuated the decline in adherence to AIs over three years of treatment among breast cancer survivors not receiving low-income subsidies Neuner J, JNCI, 2015

20. The extensive experience from bringing generic products to the market over the last decades allows the conclusion that they are well-accepted and provide a useful alternative option for cost-effective pharmacotherapy . Borg JJ, Sci Pharm , 2014

21. S é que algunos son aceptables, pero no tengo manera de saber cuáles…

22. Conclusiones preliminares La adopci ón de medicamentos genéricos puede traer beneficios económicos y en adherencia. Algunos medicamentos gen éricos son eficaces y seguros. Otros no. En Colombia existen DEMASIADOS que no lo son. No tenemos herramientas confiables para separar los unos de los otros. Existe un clima de desconfianza e incertidumbre que afecta la credibilidad de todos los involucrados

23. Biosimilares

24. Front Pharmacol . 2016 Jun 29;7:193.

25. Oportunidades de los biosimilares Alterntiva terap éutica Expansi ón del uso de biológicos Mejor acceso para los pacientes Libera recursos en salud para otros menesteres Ahorros y eficiencias en el costo en salud

26. Front Pharmacol . 2016 Jun 29;7:193. INN Reference Exclusivity expiration EU Biosimilar Year of EMA approval Infliximab Remicade 2015 1999 Inflectra 2013 Remsima 2013 Adalimumab Humira 2018 2003 Etanercept Enbrel 2015 2016 Benepali 2016 Rituximab Rituxan 2013 1998 Trastuzumab Herceptin 2014 2000 Bevacizumab Avastatin 2022 2005 Cetuximab Erbitux 2014 2004 Ranibizumab Lucentis 2022 2007

27. 3. Los medicamentos biol ógicos no son copiables.

28. Pure Red-Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Erythropoietin Casadevall N, NEJM, 2002 Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin

29. Trastuzumab + Paclitaxel. 2001 Phase III Trastuzumab + Docetaxel 2005 Lapatinib + Capecitabine 2006 Phase III Slamon  DJ, et al. (2001) N Engl J Med   344 :783–792. Marti M, et al. J Clin Oncol   23 :4265–4274. Geyer , et al. NEJM, 2006 Baselga , et al. NEJM, 2012 Verma , et al. NEJM, 2012 1st-line Current 1st- and 2nd-line therapies in Her2+ MBC Pertuzumab + Trastuzumab + Docetaxel 2012 T-DM1 2012 2nd--line Phase III CLEOPATRA Phase III EMILIA

30. Puede el biosimilar de trastuzumab combinarse con el pertuzumab ? 35

31. Anatomy of an Antibody-Drug Conjugate (ADC) Antibody targeted to tumor Very potent chemotherapeutic drug Tubulin polymerization inhibitors Maytansines (DM1, DM4) Auristatins (MMAE, MMAF) DNA damaging agents Calicheamicins Duocarmycins Anthracyclines (doxorubicin) Humanized monoclonal Ab (IgG1) mAb with Fc modifications (modulate ADCC, CDC activity) Other mAb fragments 36 Linker stable in circulation Linker biochemistry Acid labile (hydrazone) Enzyme dipeptides (cleavable) Thioether (uncleavable) Hindered disulfide (uncleavable) Site of conjugation Fc, HC, LC

32. 4. Los biosimilares pueden ser adoptados siempre y cuando cumplan todos los pasos que demuestren su eficacia y seguridad

33. “Innovar” en la forma de evaluar la eficacia y seguridad de biosimilares puede ser potencialmente fatal para los pacientes…

34. En Colombia se exige m ás que en otros países para registrar medicamentos innovadores En Colombia se exige meno s que en otros países para registrar medicamentos genéricos / biosimilares

35. En mi pa ís no dejan entrar las drogas innovadoras, pero piensan admitir biosimilares con estándares no aceptables en países civilizados…

36. Conclusiones Los medicamentos genéricos y biosimilares pueden ser alternativas de tratamiento cuando se demuestra que tienen eficacia y seguridad comparables con los innovadores. Las entidades regulatorias deben ser al menos tan exigentes con estos medicamentos no-innovadores a como lo son con los innovadores, y no al revés como se viene practicando. Las soluciones inmediatistas del problema económico que se suscita del avance de la medicina implican que algunos pacientes no van a tener acceso a medicamentos de buena calidad o innovadores, y ambas situaciones inaceptables para un país que se jacta de cuidar a sus ciudadanos, y son inaceptables como médico.

37. “ Una conferencia consiste en un combate cuerpo a cuerpo con los minutos” José Ortega y Gasset , Vives , 1940 @ Onconerd