Genéricos y biosimilares en la práctica médica

Mauricio Lema Medina MD

Clínica de Oncología Astorga / Clínica SOMA - Medellín, ColombiaBogotá – 08/2016

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Mauricio Lema: Conflicto de interés

Honorarios por conferencias (2015): Roche, Novartis, MSD, Aztra-Zeneca, AMGEN, Pfizer, Boheringer-Ingelheim

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

Precios de los agentes nuevosMedicamento 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_1http://www.medscape.com/viewarticle/836879http://www.pharmacytimes.com/publications/health-system-edition/2015/march2015/cyramza-by-eli-lilly-and-companyhttp://www.medscape.com/viewarticle/831150http://www.medscape.com/viewarticle/830145http://www.medscape.com/viewarticle/830145http://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

Precios de los agentes nuevosMedicamento 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_1http://www.medscape.com/viewarticle/836879http://www.pharmacytimes.com/publications/health-system-edition/2015/march2015/cyramza-by-eli-lilly-and-companyhttp://www.medscape.com/viewarticle/831150http://www.medscape.com/viewarticle/830145http://www.medscape.com/viewarticle/830145http://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

Genéricos

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

Generics can cost as much as 80–85% less than the original compound

Generic Drug Market: Growing and Merging. Lancet Oncol, 2015

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

Prescription Share in the USRelative cost

2. El problema no es sólo económico, sino que se vuelve también un problema médico. 

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

InnovadorGenérico A

Genérico BBiod

ispon

ibili

dad

acep

tabl

e

FenitoínaCarbamazepinaÁcido valproico

LamotriginaLevetiracetam

Topiramato

LevodopaClopidogrel

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

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’sEmax sigmoid model that could be interpreted as pharmacodynamic nonequivalence

Rodríguez CE, PLoS One, 2016

Generic Vancomycin Enriches Resistant Subpopulations ofStaphylococcus 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.

Rodríguez CE, Amtimicrob Agents Chemother, 2012

Resistance Frequencies with innovator and generics

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

Generic ImatinibA 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

The Introduction of Generic Aromatase Inhibitors and Treatment Adherence

Among Medicare D EnrolleesLIS: 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

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

Sé que algunos son aceptables, pero no tengo manera de saber cuáles…

Conclusiones preliminares

• La adopción de medicamentos genéricos puede traer beneficios económicos y en adherencia.

• Algunos medicamentos genéricos 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

Biosimilares

Front Pharmacol. 2016 Jun 29;7:193.

Oportunidades de los

biosimilares

Alterntiva terapéutica

Expansión del uso de

biológicos

Mejor acceso para los

pacientes

Libera recursos en salud para

otros menesteres

Ahorros y eficiencias en el costo en salud

Front Pharmacol. 2016 Jun 29;7:193.

INN Reference Exclusivityexpiration 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

3. Los medicamentos biológicos no son copiables.

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

Trastuzumab + Paclitaxel.

2001

Phase III

Trastuzumab + Docetaxel

2005

Lapatinib + Capecitabine

2006Phase 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, 2012Verma, et al. NEJM, 2012

1st-line

Current 1st- and 2nd-line therapies in Her2+ MBC

Pertuzumab +Trastuzumab +

Docetaxel2012

T-DM12012

2nd--line

Phase IIICLEOPATRA

Phase IIIEMILIA

Puede el biosimilar de trastuzumab combinarse con el pertuzumab?

35

Genentech Confidential—Internal Use Only

Anatomy of an Antibody-Drug Conjugate (ADC)

Antibody targeted to tumor

Very potentchemotherapeutic 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

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

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

En Colombia se exige más que en otros

países para registrar medicamentos

innovadores

En Colombia se exige menos que en otros países para registrar

medicamentos genéricos / biosimilares

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

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.

“Una conferencia consiste en un combate cuerpo a cuerpo

con los minutos”

José Ortega y Gasset, Vives, 1940

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