Ponencia en la academia nacional de medicina

1. Genéricos y biosimilares en la práctica
médica
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA - Medellín, Colombia
Bogotá – 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. Genéricos

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. Generics 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 USRelative cost

12. 2. El 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
Genérico A
Genérico B
Biodisponibilidad
aceptable
Fenitoína
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’sEmax sigmoid
model that could be interpreted as
pharmacodynamic nonequivalence
Rodríguez CE, PLoS One, 2016

16. 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

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

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

24. 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

25. Biosimilares

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

27. 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

29. 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

30. 3. Los medicamentos
biológicos no son copiables.

31. 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

33. 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

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

36. Genentech Confidential—Internal Use Only
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

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

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

39. 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

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

41. 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.

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