evaluación de fármacos en oncología de oncólogos para ... · cancer de mama zoledronic acid 4...
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Evaluación de fármacos en oncología
De oncólogos para farmacéuticos
Miguel Martin
Instituto de Investigación Sanitaria Gregorio Marañón
Universidad Complutense
Madrid
•Criterios de eficacia
•Generalización de resultados
•Valor de las Guias Clínicas
•El problema del coste de los fármacos
•Papel de la Academia en la generación de evidencia
práctica
Del ensayo clínico a la práctica real:
problemas de interpretación
•Criterios de eficacia
•Generalización de resultados
•Valor de las Guias Clínicas
•El problema del coste de los fármacos
•Papel de la Academia en la generación de evidencia
práctica
Del ensayo clínico a la práctica real:
problemas de interpretación
Trasladando los avances científicos a la
práctica diaria
Práctica clínica
Avances en
investigación
básica
Ensayos
clínicos Diseño de
nuevos
fármacos
Criterios de eficacia de los
medicamentos oncológicos
TRATAMIENTO
Prevención
de complicaciones Alivio de
síntomas
Cura
Aumento de
Supervivencia
Mejoría de la
Calidad de vida
Aumento del tiempo
de control de la
enfermedad (THP)
Objetivos del tratamiento del cáncer
Jerarquía de objetivos terapéuticos en
cáncer
CURA
AUMENTO DE SUPERVIVENCIA
AUMENTO DE THP
TASA DE RESPUESTA TUMORAL
AUMENTO DE CALIDAD DE VIDA
REDUCCION DE COMPLICACIONES
MEJORIA DE LOS SINTOMAS
Gianni L et al Lancet Oncol 12:236, 2011
Sorensen S et al, Intl. J. Techn. Assess. Health Care 28:12, 2012
Jerarquía de objetivos terapéuticos en
cáncer
CURA
AUMENTO DE SUPERVIVENCIA
AUMENTO DE THP
TASA DE RESPUESTA TUMORAL
AUMENTO DE CALIDAD DE VIDA
REDUCCION DE COMPLICACIONES
MEJORIA DE LOS SINTOMAS
Fizari K et al, Lancet Oncol, online 2012 http://dx.doi.org/10.1016/S1470-2045(12)70379-0
Ipilimumab Conveys Long-Term Survival in Pooled
Analysis of Metastatic Melanoma Patients
http://www.ascopost.com/issues/november-15,-2013/ipilimumab-conveys-long-term-survival-in-pooled-analysis-of-metastatic-melanoma-
patients.aspx
Jerarquía de objetivos terapéuticos en
cáncer
CURA
AUMENTO DE SUPERVIVENCIA
AUMENTO DE THP
TASA DE RESPUESTA TUMORAL
AUMENTO DE CALIDAD DE VIDA
REDUCCION DE COMPLICACIONES
MEJORIA DE LOS SINTOMAS
Optional
second-line chemotherapy +
bevacizumab (AVADO and
RIBBON-1 only)
Chemotherapy +
bevacizumab
Treat until PD
RA
ND
OM
IZE
Previously untreated
mBC
RIBBON-1 Capecitabine,
taxane, or
anthracycline
AVADO Docetaxel
E2100 Paclitaxel
Chemotherapy + no
bevacizumab
O’Shaughnessy J et al, SABCS 2010
Meta-Analysis of Bevacizumab trials in MBC
O’Shaughnessy J et al, SABCS 2010
Meta-Analysis of Bevacizumab trials in MBC: PFS
Non-BV
(n=1008)
BV
(n=1439)
Median, mo 6.7 9.2
HR (95% CI) 0.64 (0.57–0.71)
Standard first-line
treatment
Second, third and successive
lines of chemotherapy
Months from the start of first-line therapy
8 24
1/3 2/3
Disease progression Death
Chronology of MBC
Chronology of MBC:
randomized trials without cross-over
Standard first-line
treatment
Disease progression
8 24
Experimental first-line
treatment
Second, third and successive
lines of chemotherapy
11 26
Death
R
Months from the start of first-line therapy
Second, third and successive
lines of chemotherapy
Chronology of MBC:
randomized trials without cross-over
Standard first-line
treatment
Disease progression
8 24
Experimental first-line
treatment
Second, third and successive
lines of chemotherapy
11 26
Death
R
Months from the start of first-line therapy
Second, third and successive
lines of chemotherapy
SAMPLE SIZE FOR PFS
n=300–1,000 patients
Chronology of MBC:
randomized trials without cross-over
Standard first-line
treatment
Disease progression
8 24
Experimental first-line
treatment
Second, third and successive
lines of chemotherapy
11 26
Death
R
Months from the start of first-line therapy
Second, third and successive
lines of chemotherapy
SAMPLE SIZE FOR PFS
n=300–1,000 patients
SAMPLE SIZE FOR OS
n=3,000–5,000 patients
Broglio, Berry. JNCI 2009 PPS = post-progression survival
The chance of obtaining a significant OS improvement depends on
the length of time that patients live after progression (PPS)
If PPS is longer than 12 months, there is a less than 30% chance
that a trial will report a significant OS, even after reporting 9 months
PFS improvement at a high level of significance (p<0.001)
The influence of PPS means that a lack of statistical significance in
OS does not imply lack of improvement in OS
“OS is a reasonable primary endpoint when median PPS is short,
but is too high a bar when median PPS is longer than 12 months”
Significant OS improvements are more difficult
to measure as patients survive longer after
progression
Patients with heavily
pretreated advanced
breast cancer (N = 762)
Eribulin Mesylate
1.4 mg/m2 2-5 min IV on Days 1, 8
q3w
(n = 508)
Treatment of Physician’s Choice (TPC)
Any monotherapy approved for cancer treatment
(chemotherapeutic, hormonal, or biological),*
or supportive care only†
(n = 254)
•Stratified by geographic region,
previous capecitabine treatment,
HER2/neu status
•Randomized 2:1
*FDA approved for the treatment of cancer. †Palliative treatment or radiotherapy according to local practice.
96% of patients in TPC arm received chemotherapy
Cortes J et al. Lancet Oncol 377:914, 2011
Overall survival (months)
0.0
0.2
0.4
0.6
0.8
1.0
0 28 26 24 22 20 18 16 14 12 10 8 6 4 2
Su
rviv
al
pro
bab
ilit
y
EMBRACE: Overall survival
Eribulin
Median 13.12 months
TPC
Median 10.65 months
HR* 0.81 (95% CI 0.66, 0.99)
p value†=0.041
2.47 months
Cortes J et al, Lancet Oncol 377: 914, 2011
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.
Unstratified HR=0.521 (P<0.0001).
198 120 62 28 13 6 1 0
404 334 241 114 66 27 12 0
TPC
T-DM1
No. at risk: Time (months)
14 12 10 8 6 4 2
0.0
0.2
0.4
0.6
0.8
1.0
0
Pro
po
rtio
n p
rog
ress
ion
-fre
e
TPC
(n=198)
T-DM1
(n=404)
Median (months) 3.3 6.2
No. of events 129 219
Stratified HR=0.528 (95% CI, 0.422, 0.661)
P<0.0001
TH3RESA: PFS
TH3RESA: OS
198
404
169
381
125
316
80
207
51
127
30
65
9
30
0
0
TPC
T-DM1
No. at risk:
3
7
Time (months)
44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.
Unstratified HR=0.57 (P=0.004).
16 12 10 8 6 4 2
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n s
urv
ivin
g
0 14
Observed 21% of targeted events
TPC
(n=198)
T-DM1
(n=404)
Median (months) 14.9 NE
No. of events 44 61
Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034
Efficacy stopping boundary HR<0.363 or P<0.0000013
O’Shaughnessy J et al, SABCS 2010
Meta-Analysis of Bevacizumab trials in MBC: OS
Non-BV
(n=1008)
BV
(n=1439)
Median, mo 26.4 26.7
HR (95% CI) 0.97 (0.86–1.08)
PFS as main endpoint
•The value of PFS as main endpoint for drug approval in
MBC is under debate
•Prolonging disease control could be good enough by itself
•An increase in PFS is usually translated into an increase on
OS, although of inferior magnitude
•Demonstrating an OS advantage in first-line is difficult,
except for very effective drugs
•If we require an OS benefit for approval, we can miss drugs
of moderate efficacy in MBC
Beluga S et al, Annals of Oncology 23: 2977–2982, 2012
Jerarquía de objetivos terapéuticos en
cáncer
CURA
AUMENTO DE SUPERVIVENCIA
AUMENTO DE THP
TASA DE RESPUESTA TUMORAL
AUMENTO DE CALIDAD DE VIDA
REDUCCION DE COMPLICACIONES
MEJORIA DE LOS SINTOMAS
Progression-based endpoints are dominant
in randomized MBC trials
Progression-based primary endpoints are now used much more
frequently in mBC randomized trials (62%) than OS (2%)
The use of OS as a primary endpoint in breast cancer clinical trials
is uncommon
Saad, et al. Ann Oncol 2009
36 of 58 randomized trials in leading journals used progression-based
primary endpoints
62%
PFS/TTP/TTF
36%
RR
2%
OS
Palliative effect of chemotherapy: objective
tumor response is associated with symptom
improvement
Geels et al, JCO 18:2395, 2000
0
50
100
Pain Mood
CR/PR SD PD
Proportion of patients with symptom response
according to response to chemotherapy
SOB Depression
%
Fármacos antitumorales aprobados en
base a estudios fase II
Paclitaxel (década de los 90):
• cáncer de ovario (refractario a
cisplatino)
• cáncer de mama refractario a
antraciclinas
Capecitabina (2000):
• cáncer colorectal
• cáncer de mama refractario a
taxanos y antraciclinas
Jerarquía de objetivos terapéuticos en
cáncer
CURA
AUMENTO DE SUPERVIVENCIA
AUMENTO DE THP
TASA DE RESPUESTA TUMORAL
AUMENTO DE CALIDAD DE VIDA
REDUCCION DE COMPLICACIONES
MEJORIA DE LOS SINTOMAS
Círculo vicioso de la destrucción ósea
RANK
RANKL
Bone
resorption
Osteoclast
Cancer cells in bone
Growth factors
(TGF-β, IGFs, FGFs,
PDGFs, BMPs)
Cytokines and growth factors (IL-
6, IL-8, IL-1β, PGE-2,
TNFα, CSF-1, PTHrP) R
AN
KL
Direct effects
on tumor?
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
1.McClung MR et al. New Engl J Med 2006;354:821–31;
2. Prolia® (Denosumab) Summary of product characteristics, Amgen.
Anticuerpo monoclonal humanizado dirigido contra el ligando
de RANK, de gran afinidad y especificidad specificity1
Denosumab
Consecuencias de las metástasis óseas
METASTASIS
OSEAS
HIPERCALCEMIA
COMPRESION
MEDULAR
FRACTURAS
DOLOR
PERDIDA DE
ATONOMIA
INCREMENTO DE
COSTO
SANITARIO
REDUCCION DE
SUPERVIVENCIA
CIRUGIA
RADIOTERAPIA
Denosumab frente a acido zoledronico en
cancer de mama
Zoledronic acid 4 mg IV
(N = 1020)
Denosumab 120 mg SC
(N = 1026)
Supplemento de calcio y vitamina D
Criterios de inclusión
Adultos con cáncer de
mama y metástasis óseas
Criteripos de exclusión
Previos bifosfonatos
Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.
Denosumab frente a ácido zoledrónico
en cáncer de mama
Martin M et al, Clinical Cancer Research, 18:4841-4849, 2012.
Denosumab frente a ácido zoledrónico en
cáncer de mama
Martin M et al, Clinical Cancer Research, 18:4841-4849, 2012.
•Criterios de eficacia
•Generalización de resultados
•Valor de las Guias Clínicas
•El problema del coste de los fármacos
•Papel de la Academia en la generación de evidencia
práctica
Del ensayo clínico a la práctica real:
problemas de interpretación
Eficacia frente a eficiencia
•relative efficacy can be defined as the extent to which an
intervention does more good than harm, under ideal
circumstances, compared to one or more alternative
interventions
•relative effectiveness can be defined as the extent to
which an intervention does more good than harm
compared to one or more alternatives for achieving the
desired results when provided under the usual
circumstances of health care practice
Efficacy vs effectiveness: definitions of
the EFPIA
EUROPEAN FEDERATION OF PHARMACEUTICAL INDUSTRIES AND ASSOCIATIONS, 2010
From clinical trials to clinical practice:
Generalization
Clinical
trials
Daily
practice
From clinical trials to clinical practice:
Generalization
Clinical trials Daily practice
Incertidumbres en la aplicación práctica de
los resultados de los EECC
La mayoría de los EECC actuales son promovidos por la industria, con
registro de fármaco como objetivo final
El diseño de los estudios se adapta esencialmente a este objetivo
En publicaciones, la eficacia es a menudo sobre-enfatizada y la toxicidad
minimizada
Los pacientes son seleccionados en base a criterios de buen pronóstico y
no representan necesariamente a la población general
Los estudios se centran en un nicho terapéutico (por ejemplo, enfermos
refractarios a una terapia estándar) en lugar de analizar el manejo global
de la enfermedad
Clin Pharmacol & Ther 87: 398, 2010
Niraula S et al, J Clin Oncol 30:3012,2012
Niraula S et al, J Clin Oncol 30:3012,2012
Uncertainty in medical
treatment of cancer
Mullins CD, et al, The Oncologist 15(suppl 1):58, 2010
Significant evidentiary uncertainty to establish the
greatest level of benefit possible at a given level of cost
Significant gaps in real-world evidence exist
“Pragmatic” trials should be encouraged
•Criterios de eficacia
•Generalización de resultados
•Valor de las Guías Clínicas
•El problema del coste de los fármacos
•Papel de la Academia en la generación de evidencia
práctica
Del ensayo clínico a la práctica real:
problemas de interpretación
Value of clinical guidelines
NCCN Guidelines are widely recognized and used
as a standard reference for clinical policy in
oncology by clinicans and payors
Categories of evidence and consensus:
Category 1: Based upon high-level evidence, there is uniform NCCN
consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform
NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN
consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN
disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
NCCN GUIDELINES
Poonacha T K , Go R S JCO 2011;29:186-191
Poonacha T K , Go R S JCO 2011;29:186-191
•In 2005 the NCCN estimated that 50% to 75% of drugs
used to treat cancer in the United States was off label
•The supporting evidence base for efficacy or superiority to
other drugs may be limited or nonexistent, and patients are
exposed to potential risks without the associated safeguards
•The accrual to legitimate clinical trials may be undermined
•The cost of unproven use of off label drugs is of concern
Off-label use of oncology drugs: the need
for more data and then some
Pfister DG, JCO 30:584-596, 2012
The problem of off-label uses of drugs should be urgently
addressed and solved positively
Regulatory bodies (EMA) should take some responsibility on the
off-label issue
Pragmatically, lists of drugs with acceptable indications should be
worked out and in the European Union (EU) this might follow the
principle underlying the centralized procedure for approval of new
drugs
New regulatory mechanisms should be searched, by which uses of
drugs could be expanded even beyond the initiative of
pharmaceutical companies
The off-label use of drugs in oncology: a position
paper by the european society for medical oncology
(ESMO)
Casali PG, Ann Oncol 18:1923-1925, 2007
•Criterios de eficacia
•Generalización de resultados
•Valor de las Guias Clínicas
•El problema del coste de los fármacos
•Papel de la Academia en la generación de evidencia
práctica
Del ensayo clínico a la práctica real:
problemas de interpretación
The cost issue
efficacy toxicity
Treatment of metastatic cancer:
efficacy vs toxicity
efficacy toxicity
cost?
Treatment of metastatic cancer:
efficacy vs toxicity
Factors influencing selection of anticancer
treatments
Magnitude of
benefit
Scientific
evidence Cost
Guirgis HM, J Oncol Pract 8:224,2012
Conclusiones (1)
Translating results from clinical trials to everyday practice in
cancer is not always easy
The role of very effective therapies (based on a strong
molecular rationale) is usually easy to establish
The evidence for less effective therapies is often in the grey
zone
This is particularly relevant due to the high cost of the new
drugs
Conclusiones (2)
Significant gaps in real-world evidence
Most trials are aimed at drug approval
Few trials addressing practical issues
Urgent need for academic (“pragmatic”) studies to
bridge the gaps