# Presentation: 701479

## 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*

- *Not head-to-head comparison; †vs placebo.  Error bars represent 95% confidence intervals.
- 1Chesnut 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.

- Calcitonin1	Yes
- Raloxifene2	Yes
- Raloxifene2	  No
- Risedronate3	Yes
- Risedronate4	Yes
- Alendronate5	Yes
- Alendronate6	  No

**0**

**20**

**40**

**60**

**80**

**100**

- Prevalent
- Vertebral Fx

- % Reduction in Vert. Fx. Risk

## 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 ?

-  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

**ABOUT ACTIVE CONTROLLED TRIALS**

## 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

## 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?

## Efficacy

- Time

**Y**

**X**

- 0

**Drug A**

**Drug B**

**Concept of Sustained vs. Unsustained Efficacy**

## Concept of Sustained vs. Unsustained Efficacy

**0**

**0,25**

**0,5**

**0,75**

**1**

- 200 events
-  145 placebo
-  55 treatment

- 100 events
-  55 placebo
-  45 treatment

- 200 events
-  135 placebo
-  65 treatment

- 100 events
-   65 placebo
-   35 treatment

**Relative Risk**

- 300 total events
-  200 placebo
-  100 treatment

- 300 total events
-  200 placebo
-  100 treatment

- Cumulative 4 year
- RR = 0.50 for both

**Unsustained**
**Drug A**

**Sustained**
**Drug B**

**Years 0 - 3**

**Year 4**

**Years 0 - 3**

**Year 4**

- 68%

- 18%

- 52%

- 46%

## Risedronate in established PMO

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1**

**1.2**

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

**Risedronate in established PMO**
**3 years (VERT-MN) 1226 PMW with 2+ Vert Fx**
**Risedronate 5 mg/d**

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

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

## Risedronate in established PMO

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1**

**1.2**

**1.4**

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

**Risedronate in established PMO**
**3 years (VERT-US) 2458 PMW with 1+ Vert Fx**
**Risedronate 5 mg/d**

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

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

## Teriparatide Fracture Prevention Trial and Follow-up

**Visit 2**
**(18 months)**

**Total Observation Period (39 mo)**

**Fracture**
**Prevention Trial**

**Follow-Up**
**(77****% enrolled)***** ***

** **

**Endpoint**
**(median 21 months)**

**Teriparatide ****Fracture Prevention Trial ****and Follow-up**

**Visit 1**
**(6 months)**

**Baseline**

**Slide Modified: ****on:  09/27/2001 5:38:46 PM   Rev:  506**

**Validation: **

**Source: **

**Memo: **

**StatsMemo: **

**Review: **

**Reviewer Memo: **

## Incidence of New Vertebral Fractures

**Subset - Fracture**

**Prevention Trial**

** ****Follow-up**

** ****Total Observation**

**Period**

**Placebo**

**TPTD20**

**TPTD40**

*****

*****

*****

*****

*****

**% of Women**

**RR 0.31 (0.18-0.54**

**RR 0.33 (0.20-0.55**

**RR 0.52 (0.38-0.70)**

**RR 0.54 (0.40-0.73)**

**Slide Modified: ****on:  09/27/2001 5:38:51 PM   Rev:  506**

**Validation: **

**Source: **

**Memo: **

**RR 0.55 (0.38-0.80)**

**RR 0.60 (0.42-0.85)**

**50**

**56**

**96**

**36**

**42**

**67**

**16**

**52**

***P<0.01 vs.  Placebo **
**†****P**_**<**_**0.001 vs.  Placebo**

**†**

**StatsMemo: **

**Review: **

**Reviewer Memo: **

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**18**

## Efficacy of Raloxifene by Study Period Through 4 Years

**Years 0-3 Cumulative**

- Relative Risk (95% CI)

- 0.0

- 0.5

- 1.0

- 1.5

******55%**

******30%**

- Risk Reduction

**Year 4 Alone**

******50%**

******38%**

- Risk Reduction

- Lufkin E et al.  Rheum Dis Clin No Amer 2001;27:163-185
- Ettinger B et al.  JAMA 1999;282:637-645

## _____________

**VERTEBRAL FRACTURE RISK IN**** WOMEN **
**WITH POSTMENOPAUSAL OSTEOPOROSIS**
_**S**_**pinal **_**O**_**steoporosis **_**T**_**rial **_**I**_**ntervention study SOTI: Three-year results**

## INCIDENCE OF PATIENTS WITH NEW VERTEBRAL FRACTURES: FIRST and THIRD YEARS

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**First**

**Third**

**Placebo**

**SR**

**% patients**

**- 49 %**

**- 51 %**

**Years**

**P < 0.001**

**P < 0.001**

**INCIDENCE OF PATIENTS WITH NEW VERTEBRAL FRACTURES: **_**FIRST and THIRD YEARS**_

**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?)