1. 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
.

2. Breast Cancer Drug
Development
NEW SINGLE AGENT
2nd LINE M+
1st LINE M+
ADJUVANT
NEW
COMBINATIONS M
+
Nabholtz et al. SABCS

3. 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

4. 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

5. • 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. 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. 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. 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

9. 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.

10. 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.

11. 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

12. 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

13. Primary Endpoint of MBC Trials
(by time)
Verma et al Oncologist 2011

14. 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

15. 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

16. 5 15 25 35 45
Months
0.2
0
0.4
0.6
0.8
1.0
Herceptin + CT
CT
ProbabilityAlive
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.

17. 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+
Probability
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.

18. Breast Cancer Drug
Development
NEW SINGLE AGENT
2nd LINE M+
1st LINE M+
ADJUVANT
NEW
COMBINATIONS M
+
Updated Nabholtz et al. SABCS 1994.NEOADJUVANT

19. 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
marEne.piccart@bordet.be
for
permission
to
reprint
and/or
distribute
Trastuzumab
No
Trastuzumab
pCR
rates
(%)

20. 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

21. 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?

23. Generated 27NOV13 17:07 by F_EFS4LandmarkHR_slide.sas (r3892) from data as of 13
'
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
marEne.piccart@bordet.be
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-
'

24. 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
marEne.piccart@bordet.be
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 da
'
'

25. Generated 27NOV13 17:23 by F_OS4LandmarkHR_slide.sas (r3897) from data as of 13-N
'
Generated 27NOV13 17:23 by F_OS4LandmarkHR_slide.sas (r3897) from data as of 13-NOV-2013 1
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
marEne.piccart@bordet.be
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

26. 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)

27. 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.

28. 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
Follow-­‐up:
24
mo
pCR
18
cycles/
1year
Docetaxel
75 mg/m2
FEC
500/75/500
Neo-­‐adjuvant
Adjuvant
R
1
:1

29. 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)
SerumCtroughlevels
pCRinthebreast
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.

30. 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

31. 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

32. CONCLUSION
• Follow
the
guidelines
of
regulatory
agencies
• Learn
to
interpret
the
results
within
the
defined
quesEon
• Define
the
impacy
for
clinical
pracEce