POST MENOPAUSAL

OSTEOPOROSIS
EVOLUTION OF EU GUIDANCE

Eric ABADIE MD, MBA

AFSSAPS, CPMP Vice Chair
 LABELLING
- Treatment of osteoporosis (decrease incident
fractures)
• Both spinal and femoral should be sought
• Indication granted only if antifracture efficacy
demonstrated at one site (no deleterious effect at
the other site)
• Results specified in the labelling

- Prevention of osteoporosis (maintain or increase bone

mass and strength in order to avoid the occurrence of
fractures)
 PRE CLINICAL PACKAGE

– A robust pre clinical package would show:

• No adverse effect on bone quality
• Increase in bone mass and strength

– No impact of the pre clinical package on the

burden of proof required in fracture studies
 CLINICAL TRIALS (Patients)
– Indication « treatment »
• T<-2.5 SD (spine / hip)
• With / without fractures (stratification)
– Indication « prevention »
• 2 populations in phase III (within / more 5
years, same study or 2 studies)
• risk factors : BMD, others
• No BMD requirement in phase II
CLINICAL TRIALS (Endpoints)
– Fractures
• 1st endpoint phase III, indication
« treatment »
• Incidence of patients with new fractures
• Serial X rays (once / year)
– BMD
• 1st endpoint in phase II and in phase III
(indication « prevention »)
• Not an appropriate surrogate for fractures
 Relationship between the Risk of
Vertebral Fracture and Increases in
BMD*
% Reduction in Vert. Fx. Risk

100
Prevalent
80 Vertebral Fx
Calcitonin1 Yes
60 Raloxifene2 Yes
Raloxifene2 No
40 Risedronate3 Yes
Risedronate4 Yes
20 Alendronate5 Yes
Alendronate6 No
0
0 1 2 3 4 5 6 7
% Increase in BMD
†
*Not head-to-head comparison; †vs placebo. Error bars represent 95% confidence intervals.
1
Chesnut CH, et al. Am J Med. 2000;109:267-276; 2Ettinger B, et al. JAMA. 1999;282:637-645; & data on
file, Eli Lilly and Company; 3Harris ST, et al. JAMA. 1999;282:1344-1352; 4Reginster J-Y, et al.
Osteoporosis Int. 2000;11:83-91; 5Black DM, et al. Lancet. 1996;348:1535-1541; 6Cummings SR, et al.
JAMA. 1998;280:2077-2082.
 CLINICAL TRIALS
(Endpoint, cont.)
– Biochemical markers
• Inhibitors of bone resorption (coprimary
endpoint with BMD in phase II)
• Stimulators of bone formation : role unclear
– Criteria of safety
• Serum levels of PTH and 25 0H vit D
• Quantitative bone histomorphometry
dependent on pre clinical testing
 CLINICAL TRIALS
(Design, « treatment »)
– Placebo and / or comparator controlled
– Superiority (placebo) and non inferiority
(comparator)
– Duration : 3 years
– Calcium / Vit D supplementation clearly
documented
– Questions about placebo :
• Is it desirable ?
• Is it feasible ?
ABOUT PLACEBO CONTROLLED TRIALS
– Most efficient tool to assess efficacy / safety
of a test
– Ethical concern is obvious
– Should ethical concern be the same in all
populations ?
ABOUT ACTIVE CONTROLLED TRIALS
– Common requirement in EU
– Advantage : relative B/R compared to other
therapeutic strategies
– Drawback of non inferiority trials : imply
assumptions difficult to verify, choice of delta is
critical
 CLINICAL TRIALS
(design, « prevention »)

- Same formulation, same dose

• Placebo controlled trial
- New dose, new route, new formulation
• 3 arm study (placebo, dose or formulation
effective in reducting incidence of fractures)
- Both situations : BMD first endpoint, 2
year study
 CONCLUSION
• Main difference FDA/CPMP: role of BMD and pre
clinical safety (FDA) vs fracture rate (CPMP) for
initial drug registration.
• Difficulties in the design of confirmatory trials in
« treatment » indication.
• Two alternatives (not mutually exclusive)
– To use placebo in a certain category of patients
– To shorten the duration of confirmatory trials,
and/or modify the endpoint.
FUTURE OF CLINICAL
TRIALS DESIGN

E.ABADIE
 PLACEBO COULD BE
FEASIBLE IN CERTAIN
CIRCUMSTANCES

– Placebo in osteoporosis without fracture?

– Placebo in trials of shorter duration?

– Placebo in add on trials with patients already
treated by an agent of a different class than the
test?
 Incidence of vertebral fractures over 3 years versus
risk profile of patients at baseline
Drug Study Risk profile Nb of Relative risk
Fracture incid.
patients (95 %CI)
randomise Placebo Drug
d
Alendronate FIT 2 Low 4432 3% 2% 0.56
5- 10 mg (0.39-0.8)

Raloxifene MORE 1 Low 3012 5% 2% 0.50

60 mg (0.4-0.8)

Alendronate FIT 1 High 2027 15 % 8% 0.53

5 - 10mg (0.41-0.68)

Raloxifene MORE 2 High 1539 21% 15 % 0.70

60 mg (0.6-0.9)

Risedronate VERT. US Medium 1628 16 % 11 % 0.51

5 mg (0.31-0.73)

Risedronate VERT. MN High 815 29 % 18 % 0.59

5 mg (0.43-0.81)
 TO USE PLACEBO IN OSTEOPOROSIS
WITHOUT FRACTURE

– Use of placebo in low risk patients is

legitimate
– RR is broadly similar between high / low risk
but absolute magnitude of treatment effect
different between both populations
– Is regulatory extrapolation of low risk to hig
risk possible?
Concept of Sustained vs. Unsustained
Efficacy
Drug A

Drug B
Efficacy

0 Time X Y
Concept of Sustained vs. Unsustained Efficacy

Cumulative 4 year
300 total events
RR = 0.50 for both
• 200 placebo
• 100 treatment
300 total events
1 100 events • 200 placebo
• 55 placebo • 100 treatment
• 45 treatment

0,75
Relative Risk

18% 100 events

200 events • 65 placebo
200 events • 135 placebo • 35 treatment
• 145 placebo • 65 treatment
0,5 • 55 treatment 46%
52%

68%
0,25

0
Years 0 - 3 Year 4 Years 0 - 3 Year 4
Unsustained Sustained
Drug A Drug B
 Risedronate in established PMO
3 years (VERT-MN) 1226 PMW with 2+ Vert Fx
Risedronate 5 mg/d

RR (95% CI) for incident FX 95% CI

1.2 RR

0.8

0.6

0.4

0.2

0
Vert Fx: 1st Year Vert Fx: 3 Year Vert Fx:Year 2-3

Reginster et al, OI. 2000; 11:83-91

 Risedronate in established PMO
3 years (VERT-US) 2458 PMW with 1+ Vert Fx
Risedronate 5 mg/d
95% CI
RR (95% CI) for incident FX RR
1.4
1.2
1
0.8
0.6
0.4
0.2
0
Vert Fx: 1st Year Vert Fx: 3 Year Vert Fx:Year 2-3

Harris et al, JAMA, 1999; 282:1344-1352

 Teriparatide
Fracture Prevention Trial
and Follow-up
Total Observation Period (39 mo)

Fracture Follow-Up
Prevention Trial (77% enrolled)

Baseline
Visit 1 Visit 2
(6 months) (18 months)

Endpoint
(median 21 months)
 Incidence of New Vertebral
Fractures
RR 0.52 (0.38-0.70)

RR 0.54 (0.40-0.73)
30 RR 0.55 (0.38-0.80)
25 RR 0.31 (0.18-0.54 RR 0.60 (0.42-0.85)
% of Women

20 RR 0.33 (0.20-0.55
15
* *
* †
10
5
* * 67 42 36 96 56 50
52 18 16
0
Subset - Fracture Follow-up Total Observation
Prevention Trial Period

Placebo TPTD20 TPTD40 *P<0.01 vs. Placebo

†
P<0.001 vs. Placebo
 Efficacy of Raloxifene by Study Period
Through 4 Years

Years 0-3 Cumulative Year 4 Alone

1.5 50%
55% 30% 38%
Relative Risk (95% CI)

Risk Reduction Risk Reduction

1.0

0.5

0.0
Without With Without With
Prevalent Vertebral Fractures Prevalent Vertebral Fractures

Lufkin E et al. Rheum Dis Clin No Amer 2001;27:163-185

Ettinger B et al. JAMA 1999;282:637-645
STRONTIUM RANELATE (SR) REDUCES THE

VERTEBRAL FRACTURE RISK IN WOMEN

WITH POSTMENOPAUSAL OSTEOPOROSIS

Spinal Osteoporosis Trial Intervention study

SOTI: Three-year results

_____________
INCIDENCE OF PATIENTS WITH NEW VERTEBRAL
FRACTURES: FIRST and THIRD YEARS
Placebo
% patients P < 0.001
P < 0.001 SR
16
14
12
10
- 49 % - 51 %
8
6
4
2
0 Years
First Third
ITT: N = 723 719 502 477
Kaplan-Meier; RR: Cox model
 CONCLUSION (1)

– Possible to shorten the duration of

confirmatory trials (but ethical concern
may persist with respect to placebo ?)
– Regulatory extrapolation (from low to
high risk patients)
 CONCLUSION (2)
– Regulatory extrapolation not possible
– Non inferiority trials in high risk patients
remain the only option
– Choice of delta : 20%, realistic sample
size
EXTRAPOLATION PERMITTED?
– Yes
• Placebo controlled trial in low risk patients
(endpoints: vertebral and hip fractures)
– No
• Placebo controlled trial in low risk patients
(endpoints: vertebral and hip fractures)
• Active controlled trial in high risk patients
(endpoint: vertebral fractures or BMD?)