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Médicaments biologiques: Critères d’enregistrement et de developpement
Prof. Jean Marc NABHOLTZ
Director ,Division of Clinical Research,
Jean Perrin Comprehensive Cancer Center of Auvergne, Clermont-Ferrand, FRANCE
Professor and Former Director, Cancer Therapy Development Program
University of California at Los Angeles (UCLA), CA, USA
Founder and Past Chairman, Breast Cancer International Research Group (BCIRG)
Jean Perrin Comprehensive Cancer Center of Auvergne
Clermont-Ferrand - France .
Breast Cancer Drug Development
NEW SINGLE AGENT
2nd LINE M+
1st LINE M+
ADJUVANT
NEW COMBINATIONS M
+
Nabholtz et al. SABCS 1994.
Trial design • The quality of a clinical trial
depends upon its design • A good quality trial should
– ask a good question – Define the proper patient population
Analysis of trial findings • Main analysis specified by the Statistical
Plan (SAP) – Scientific Hypothesis – Sample size – Patient population à Nb of Events
• Intent to Treat+++ • Evaluable
• Use hazard ratio/confidence intervals in preference to p-values
SAP, statistical analysis plan
• Use appropriate key endpoint(s) to determine the answer: – PFS – TTF – Response – Clinical benefit (Hormonotherapy/
targeted therapies…) – Overall survival
• Concept of Therapeutic Index • Quality of life
Analysis of trial findings
6 « Document réservé à l’usage exclusif des médecins régionaux/centres investigateurs »
Scénarios critère principal
X Pivot et al, ESMO 2012, LBA5_PR
Équivalent
Supérieur
Non Inférieur
Inférieur
A
B
C
D
E 0,85 1 1,15 1,3 1,45 1,6
HR Pivot X. et al. SABCS 2012
7 « Document réservé à l’usage exclusif des médecins régionaux/centres investigateurs »
Equivalence
7
Traitement Expérimental (CT-‐P6) Absence d’effet
ORR
Equivalence Non
équivalence
Traitement de Référence (T)
-‐15 15 Non équivalence
On accepte que C fasse un peu moins bien ou un peu mieux que T de 15% en ORR
H0 : |T – C| ≥ M vs. H1 : |T – C| < M
0
8 « Document réservé à l’usage exclusif des médecins régionaux/centres investigateurs »
Non Inferiority
8
Experimental Therapy No effect
Non Inferiority
Reference rherapy)
Inferiority
0
Unilateral SituaJon
13 December 2012 EMA/CHMP/205/95/Rev.4/ Guidelines on the evaluaEon
of anEcancer medicinal products in man
1. Significant clinical benefit based on improved efficacy Efficacy greater than that of an authorised medicinal product should be assessed using clinically meaningful endpoint(s) in adequate and well-‐controlled clinical trials.
2. Significant clinical benefit based on improved safety Non inferiority on efficacy and robust improved safety.
3. Significant clinical benefit based on major contribuJon to paJent care A new mode of administraEon could be considered a clinical benefit.
13 December 2012 EMA/CHMP/205/95/Rev.4 Oncology Guidelines on the evaluaEon
of anEcancer medicinal products in man
• Acceptable primary endpoints include cure rate, OS and PFS/DFS.
• If PFS/DFS is the selected primary endpoint, OS should be reported as a secondary and vice versa.
FDA Approvals of Oncology Drugs: 1990–2002
� A review of FDA approvals has shown that during the period 1990–2002
� only 32% of the regular marketing authorizations used OS as the basis for approval
� progression-based and ORR endpoints were the dominant clinical endpoints used to support marketing authorizations
� In first-line mBC, 100% of all regular marketing authorizations were based on progression-based or ORR endpoints
Johnson, et al. JCO 2003
Recommended Clinical Endpoints Vary Between Regulatory Bodies: FDA
• United States Food and Drug Administration (FDA)
– recommends OS as the primary trial endpoint in oncology
FDA guidance for industry 2009
“The analysis of overall survival may be confounded by cross-over and/or subsequent therapies. PFS, measured prior to the introduction of other therapies, may more accurately depict a treatment’s therapeutic effect.”
FDA Oncology Head Richard Pazdur “PFS can reflect tumor growth and be assessed before the determination of a survival benefit. Its determination is not confounded by subsequent therapy.”
FDA guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics
Primary Endpoint of MBC Trials (by time)
Verma et al Oncologist 2011
Only 12% of all MBC trials have shown an improvement in OS
Verma et al Oncologist 2011 PFS, progression-free survival; OS, overall survival; TTP, time-to-progression NR – Not Reported
Median TTP, mo 7.4 4.6 .0001
Response Rate, % 50 32 .0001
Median duration 9.1 6.1 .0001 of response, mo
Median TTF, mo 6.6 4.5 .0001
Chemotherapy ± Herceptin as First-Line Therapy (H0648g): Summary of Benefits
H + CT (n = 235)
CT (n = 234)
Slamon et al. N Eng J Med, 2001.
P value
5 15 25 35 45 Months
0.2
0
0.4
0.6
0.8
1.0
Herceptin + CT CT
Prob
abili
ty A
live
Overall Survival
RR = .80 p = .046
20.3 mo 25.1 mo
65 % of CT group crossed over to Herceptin
Comparative Study H0648g
Slamon et al. N Eng J Med, 2001.
0 10 20 30 40 50 Months
0.0
0.2
0.4
0.6
0.8
1.0 Herceptin +Chemo (n = 169) Chemo Alone (n = 176)
Risk ratio = 0.70 p=0.007 95% Cl = 0.54, 0.91
Survival Chemotherapy +/- Herceptin, 1st line MBC
Clinical Outcomes Analysis
FISH - FISH+
Pro
babi
lity
0 10 20 30 40 50 Months
0.0
0.2
0.4
0.6
0.8
1.0 Herceptin + Chemo (n = 50)
Chemo Alone (n = 56)
Risk ratio = 1.13 p=ns 95% Cl = 0.72, 1.79
Nabholtz et al. Semin Oncol, 2000.
Breast Cancer Drug Development
NEW SINGLE AGENT
2nd LINE M+
1st LINE M+
ADJUVANT
NEW COMBINATIONS M
+
Updated Nabholtz et al. SABCS 1994. NEOADJUVANT
pCR CORRELATES WITH BETTER EFS IN SUBSETS OF BC INCLUDING HER2+ BC
A FDA led Meta-‐analysis (N=11,955 paJents / 1,989 HER2+)
Cortazar; Lancet 2014 (in press)
San Antonio Breast Cancer Symposium -‐ Cancer Therapy and Research Center at UT Health Science Center – December 10-‐14, 2013
This presentaEon is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute
Trastuzumab
No Trastuzumab pCR rates (%)
Lum A Lum B/HER2- Lum B/HER2+
non lum/ HER2+ TN all pCR
pCR to predict breast cancer outcome?
von Minckwitz et al. JCO 2012
SUBPOPULATION DEFINITION REGIMEN N MEDIAN FU
(MONTHS)
DFS p-‐value pCR vs non-‐
pCR
OS p-‐value pCR vs non-‐pCR HR 95% CI HR 95% CI
HER2 SUBGROUP
HER2+ -‐ CT with Trastuzumab -‐ CT without Trastuzumab
665 662 46.3 2.85
2.10 [1.69-‐4.83] [1.27-‐3.48]
<0 .001 0.04
14.11 2.05
[1.93-‐103.03] [1.03-‐4.10]
0.009** 0.04*
Luminal HER2+ Pure HER2+
-‐ CT with Trastuzumab -‐ CT without Trastuzumab -‐ CT with Trastuzumab -‐ CT without Trastuzumab
356 395 298 239
46.3
1.227 1.180 8.738 3.953
[0.63-‐2.37] [0.59-‐2.36] [3.17-‐24.12] [1.89-‐8.28]
n.s. n.s.
< 0.001** < 0.001**
29.72 0.94 13.80 4.91
[0.63-‐>1.000] [0.37-‐2.41] [1.87-‐102] [1.75-‐13.77]
n.s. n.s.
0.01** 0.002**
TRIPLE NEGATIVE SUBGROUP
HR-‐/HER2-‐
-‐ Anthracyclines/Taxanes or, -‐ Taxanes/AnJmetabolites or, -‐Anthracylines/Taxanes/AlkylaJng agents
911 46.3 6.020 [3.92-‐9.25] <0.001** 12.41 [5.82-‐26.49] <0.001**
von Minckwitz G, et al, J Clin Oncol 2012
pCR to predict breast cancer outcome?
Generated 27NOV13 17:07 by F_EFS4LandmarkHR_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)
'
Generated 27NOV13 17:07 by F_EFS4Landmark_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)
'
LANDMARK ANALYSIS: EFS BY PCR
All paJents
This presentaEon is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute
San Antonio Breast Cancer Symposium -‐ Cancer Therapy and Research Center at UT Health Science Center – December 10-‐14, 2013
Tests for interacJon: pCR x HR p=0.34
Generated 27NOV13 17:07 by F_EFS4LandmarkHR_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)
'
Tests for interacJon: Lap + Tras vs. Tras x pCR, p=0.42 Lap vs. Tras x pCR, p=0.94
LANDMARK POPULATION BY ARM: EFS BY PCR
This presentaEon is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute
San Antonio Breast Cancer Symposium -‐ Cancer Therapy and Research Center at UT Health Science Center – December 10-‐14, 2013
Generated 27NOV13 17:08 by F_EFS4LandmarkTrt_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)
'
Generated 27NOV13 17:08 by F_EFS4LandmarkTrt_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)
'
Generated 27NOV13 17:08 by F_EFS4LandmarkTrt_slide.sas (r3892) from data as of 13-NOV-2013 11:21 (UTC)
'
Generated 27NOV13 17:08 by F_OS4Landmark_slide.sas (r3893) from data as of 13-NOV-2013 11:21 (UTC)
'
Generated 27NOV13 17:23 by F_OS4LandmarkHR_slide.sas (r3897) from data as of 13-NOV-2013 11:21 (UTC)
'
Generated 27NOV13 17:23 by F_OS4LandmarkHR_slide.sas (r3897) from data as of 13-NOV-2013 11:21 (UTC)
Generated 27NOV13 17:08 by F_OS4Landmark_slide.sas (r3893) from data as of 13-NOV-2013 11:21 (UTC)
'
LANDMARK ANALYSIS: OS BY PCR
All paJents
This presentaEon is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute
San Antonio Breast Cancer Symposium -‐ Cancer Therapy and Research Center at UT Health Science Center – December 10-‐14, 2013
Tests for interacJon: pCR x HR p=0.36
pCR en Europe The note for guidance does not address the possible use of pathological complete remission (pCR) as primary endpoint in neoadjuvant trials for high-‐risk early-‐stage breast cancer Currently, there is liqle regulatory experience with this endpoint and the published data are limited. Further experience and robust prospecJve clinical data are warranted before firm recommendaJons can be made.
27 November 2012 EMA/768937/2012 Answers from the CHMP ScienEfic Advisory Group (SAG) for Oncology for Revision of the anEcancer guideline hep://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformaEon/Guidances/UCM30550 1.pdf)
13 December 2012 EMA/CHMP/205/95/Rev.4/ Guidelines on the evaluaEon
of anEcancer medicinal products in man
1. Significant clinical benefit based on improved efficacy Efficacy greater than that of an authorised medicinal product should be assessed using clinically meaningful endpoint(s) in adequate and well-‐controlled clinical trials.
2. Significant clinical benefit based on improved safety Non inferiority on efficacy and robust improved safety.
3. Significant clinical benefit based on major contribuJon to paJent care A new mode of administraEon could be considered a clinical benefit.
Phase III, non-inferiority trial
Stratification factors
Breast cancer type (operable vs. locally advanced vs. inflammatory)
Oestrogen receptor status (positive vs. negative vs. unknown)
Secondary endpoints
PK: Observed Ctrough at pre-dose cycle 13; predicted Ctrough for pre-dose Cycle 8 and 13
Efficacy: tpCR (pCR in breast and axilla); overall response rate and time to response; event-free and overall survival
Safety (including immunogenicity)
HER2+ EBC (N=596)
A trastuzumab
B trastuzumab
surgery
Follo
w-‐up: 24 mo
pCR
18 cycles/ 1year
Docetaxel 75 mg/m2
FEC 500/75/500
Neo-‐adjuvant Adjuvant
R
1 :1
HannaH: Both co-‐primary endpoints met
PK Efficacy
Difference in pCR rate: 4.7%† (95% CI: –4.0, 13.4)
Geometric mean ratio: 1.33* (90% CI: 1.24, 1.44)
Seru
m C
trou
gh le
vels
pCR
in th
e br
east
Trastuzumab SC (n = 234)
Trastuzumab IV (n = 235)
Trastuzumab SC (n = 260)
Trastuzumab IV (n = 263)
51.8 µg/mL
69.0 µg/mL
45.4% 40.7%
100
75
50
25
0
100
75
50
25
0
Trastuzumab SC demonstrated a comparable efficacy and PK profile to the IV formulation
* Non-inferiority margin for the ratio between groups of 0.80 † Non-inferiority margin for the difference between groups of –12.5% CI, confidence interval Ismael G, et al. Lancet Oncol 2012; 13:869–878.
PrefHer: PaEents overwhelmingly preferred trastuzumab SC over IV
SC preferred (exact binomial): Overall = 91.5% (95% CI 87.2% to 94.7%) Pivot X, et al. Lancet Oncol 2013; 14:962–970.
IV No pref
6.8% n = 16
n = 4 1.7%
3.5% n = 11
94.7% n = 54
1.8% n = 1
7.8% n = 14
1.7% n = 3
90.5% n = 162
91.5% n = 216
SC
CONCLUSION
• Analysis of the compound – Define the appropriate quesEon
• Define the type of trial – Superiority, Equivalence, Non-‐inferiority… – Non-‐inferiority trials become more and more common
• Define the endpoints – Primary endpoint – Secondary endpoints
CONCLUSION
• Follow the guidelines of regulatory agencies • Learn to interpret the results within the defined quesEon
• Define the impacy for clinical pracEce