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OsteoporosisWRAP SlideCAST. Complexities and Challenges of Measuring Fracture End Points Interpreting the Results of Existing Trials. Steven T Harris MD FACP Clinical Professor of Medicine University of California, San Francisco.

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osteoporosiswrap slidecast
OsteoporosisWRAPSlideCAST

Complexities and Challenges ofMeasuring Fracture End Points

Interpreting the Results of Existing Trials

Steven T Harris MD FACP

Clinical Professor of Medicine

University of California, San Francisco

fracture endpoints
Regulatory approval of existing medications has been based on fracture reduction, rather than changes in surrogates such as bone mineral density (BMD) alone

The most common fracture endpoint has been the reduction in vertebral fracture

Vertebral fracture has most often been defined on the basis of morphometric changes, including both “new” and “worsening” fractures

“Clinical” vertebral fracture—defined as fracture associated with back pain—has usually been identified as a secondary endpoint

Fracture Endpoints
fracture endpoints con t
“Non-vertebral fracture” has most commonly been identified as a secondary endpoint as well

Varying definitions of “non-vertebral fracture”: all fractures vs fragility fractures vs a particular composite endpoint

Hip fracture has sometimes—but not always—been identified as a separate endpoint of particular interest

Fracture Endpoints, con’t
fracture endpoints con t1
Fracture reduction has most often been expressed —both clinically and commercially—as relative risk reduction, rather than absolute risk reduction

The rapidity with which fracture protection occurs has been of clinical—and commercial—interest

There are no head-to-head randomized trials with fracture as the primary endpoint

The pivotal fracture trials recruited patients with a certain “sameness”—but there were notable differences in demographics, baseline fracture status and baseline BMDs nevertheless

There were obvious differences in observed fracture rates—both vertebral and non-vertebral

Fracture Endpoints, con’t
slide5

RLX

ALN

RIS

IBN

Calcium

CT

ZOL

Vertebral Fracture Effects In Prospective Trials

Direct Comparisons Among Trials Cannot Be Made

49%

30

40%

% = Relative Fracture Risk Reduction

% of Patients

With New Vertebral Fractures

Over 3-5 Years

25

30%

20

41%

47%

15

70%

52%

10

50%

50%

5

0

PROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFA

With Prevalent Vertebral Fractures ± Vert Fx Without Vert Fx

Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637

Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077

Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83

Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356:1809

slide6

RLX

ALN

RIS

IBN

Calcium

CT

ZOL

Nonvertebral Fracture Effects

In Prospective Trials

Direct Comparisons Among Trials Cannot Be Made *

30

% = Relative Fracture Risk Reduction

25

% of Patients

With New Nonvertebral Fractures

Over 3-5 Years

33%

p = 0.06

12%

p = n.s.

20

20%

p = 0.06

12%

p = n.s.

15

25%

p < 0.001

10%

p = n.s.

39%

p < 0.05

p = n.s.

10

5

0

PROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZON

* Patient demographics and the definition of nonvertebral fracture varied among studies

Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637

Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077

Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83

Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356:1809

fracture endpoints1
If existing randomized clinical trials cannot reasonably address all issues of clinical relevance, then additional insights can be gleaned from:

Additional—post hoc—analyses of existing trial data

Meta analyses of existing trial data

Observational data

Fracture Endpoints
slide8

Nonvertebral Fracture ReductionPost-hoc analyses

Control

Risedronate

Control

Alendronate

14

12

*

36%

P=0.002

*

10

*

8

6

4

2

0

0

6

12

18

24

30

36

Time (months)

14

12

59%

P=0.002

10

8

% patients with nonvertebral fracture

6

*

*

*

*

*

4

*

*

*

*

2

*

*

0

6

12

18

24

30

36

Time (months)

n=1172; Patients with lumbar spine BMD T-score <-2.5. Nonvertebral fractures based on a composite endpoint of the following: clavicle, hip, humerus, leg, pelvis and wrist.

n= 3658; Patients with a baseline vertebral fracture or femoral neck T score of -2.5 or less. Nonvertebral osteoporotic fractures measured as a composite endpoint (sites are not defined).

Harrington Calcif Tissue Int 2004;74:129

Black JCEM 2000;85:4118

slide9

Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis (PMO): results of a meta-analysis of

Phase III studies

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

study objectives
Study Objectives
  • To evaluate the nonvertebral and clinical fracture efficacy of different doses of ibandronate using a pooled analysis of data from 4 pivotal phase III clinical trials: BONE,1 IV Dose Fracture,2 MOBILE,3 and DIVA4
  • To estimate the fracture rate over time using the Kaplan-Meier method

1oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe. Chesnut CH, et al. Curr Med Res Opin. 2005;21:11-18.

2Recker R, et al. Bone. 2004;34:890-899.

3Monthly Oral iBandronate In LadiEs. Reginster JY, et al. Ann Rheum Dis. 2006;65:654-661.

4Dosing IntraVenous Administration. Delmas PD, et al. Arthritis Rheum. 2006;54:1838-1846.

pooled fracture analysis methods
Cox regression analyses were adjusted for variables to allow for meaningful comparisons among trials

Age

Previous clinical fracture

Baseline BMD

Lumbar spine BMD for models with all clinical fractures

Hip BMD for models with nonvertebral fractures (NVFs) or key NVFs

Kaplan-Meier methods were used to:

Plot survival curves for time to fracture

Compare rates using a log-rank test

Pooled Fracture AnalysisMethods

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

pooled fracture analysis methods cont
Fracture rates were determined by tabulating the proportion of all ITT patients with at least 1 fracture

Doses were pooled based on annual cumulative exposure (ACE)

ACE was calculated by multiplying the drug strength by the number of annual doses and by an absorption factor (0.6% for oral dosing and 100% for IV dosing)

For example, the ACE for oral BONIVA 150 mg once-monthly would be 10.8 mg = 150 x 12 x 0.006

Pooled Fracture Analysis Methods (cont.)

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

iv and oral ibandronate annual cumulative exposure across studies
IV and oral ibandronate annual cumulative exposure across studies

12 mg

12

10.8 mg

8 mg

8

5.5 mg

Annual cumulative exposure (mg)

4 mg

4

0

Quarterly IV

Oral daily

Quarterly IV

Oral monthly

Quarterly IV

MF43801

BONE2

IRIS3

MOBILE4

DIVA5

1. Recker R, et al. Bone. 2004;34:890-899. 2. Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-1249. 3. Adami S, et al. Bone. 2004;34:881-889. 4. Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. 5. Data on file (Reference #161-153), Hoffman-La Roche Inc, Nutley, NJ 07110

fracture risk reductions for high dose of ibandronate 10 8 mg yr by fracture type
Fracture risk reductions for high dose of ibandronate (≥10.8 mg/yr), by fracture type

Nonvertebral fractures

Key nonvertebral sites

All clinical fractures

0

-10

%

-20

-30

Relative risk reduction,

-40

-50

28.8%*

29.9%*

34.4%*

-60

*P<0.05

+/- 95% Confidence Intervals

†Relative risk reduction adjusted for age, baseline BMD, and fracture history.

pooled ibandronate fracture analysis

ACE ≥10.8 mg

Placebo

Pooled Ibandronate Fracture Analysis

10

8

6

4

2

0

Relative Risk Reduction28.8%

P<0.05†

Estimated Clinical

Fracture Rate, %

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750

Days

†Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo.Kaplan-Meier plot (2-year data).

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

pooled ibandronate fracture analysis con t

ACE ≥10.8 mg

Placebo

Pooled Ibandronate Fracture Analysis, con’t

10

8

6

4

2

0

Relative Risk Reduction 29.9%

P<0.05†

Estimated Nonvertebral

Fracture Rate, %

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750

Days

†Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo.Kaplan-Meier plot (2-year data).

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

limitations
Not all studies were placebo-controlled

A limited number of baseline patient characteristics (age, previous fracture, baseline BMD) were available for use in multivariable models

This was an exploratory, post hoc analysis with no adjustment for multiple comparisons

Limitations

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

conclusions
In this pooled analysis, doses of ibandronate resulting in an ACE of ≥10.8 mg—which include the marketed doses of 150 mg monthly oral and 3 mg IV quarterly—significantly reduced the risk of clinical fractures and non-vertebral fractures compared to placebo

The high ACE group (≥10.8 mg) had a longer time to fracture compared to placebo for all clinical fractures, non-vertebral fractures and key non-vertebral fractures

Conclusions

Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

observational studies strengths and limitations of claims data
Strengths

Treatment patterns are those in “real world” clinical practice

A large number of patients can be followed over time

Limitations

No chart review available to validate the ICD-9 codes

Selection bias is possible—if not probable

Cannot assess the use of samples or OTC products

Extraneous variables are not controlled

Observational StudiesStrengths and Limitations of Claims Data
protocare sciences database nonvertebral fracture incidence

RIS vs. ALNRR=0.46(p=0.067)

RIS vs. ALNRR=0.41(p<0.05)

59%

54%

Protocare Sciences DatabaseNonvertebral Fracture Incidence

ALN vs. CAL RR=0.74(p=NS)

ALN vs. CAL RR=0.75 (p=NS)

RIS vs. CALRR=0.31(p<0.05)

RIS vs. CALRR=0.25 (p<0.01)

4.0

3.0

25%

Fracture incidence (%)

75%

2.0

26%

69%

1.0

0.0

6-months

12-months

Nasal calcitonin

Alendronate

Risedronate

*Adjusted for age, sex, HRT use, number of concomitant medications and fragility fractures in pre-treatment period

Watts N, et al. J Manag Care Pharm 2004;10:142-151

slide21

Effectiveness of Bisphosphonates on Nonvertebral and Hip Fractures in the First Year of Therapy: The Risedronate and Alendronate (REAL) Cohort Study

Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R

Silverman L et al. Osteoporos Int. 2007;18:25-34

slide22

Study Objective

  • To evaluate the onset of fracture reduction by bisphosphonate therapies in clinical medical practice by measuring the incidence of hip and nonvertebral fractures among women 65+ in the year following initiation of either once-a-week doing of risedronate or alendronate
slide24

Study Population

  • Inclusion Criteria
  • All women
  • > 65 years of age
  • Once-weekly bisphosphonate (BP) use between July 2002 and September 2004
  • Exclusion criteria
  • < 6 months of health plan enrollment before first BP use
  • < 3 months of health plan enrollment after first BP use
  • Any BP use during 6-month history period
  • Diagnosis of malignancy or Paget’s disease
  • Discontinuation of BP therapy with first 3 months of exposure period
slide30

Conclusion

  • In an observational study of medical practice, patients using risedronate had a lower incidence of nonvertebral and of hip fractures in the first year of therapy than those using alendronate
slide31

TheVIBEStudy:eValuation of IBandronateEfficacy

  • A retrospective cohort study comparing fracture rates for women receiving monthly ibandronate versus weekly bisphosphonates
objective
To investigate the efficacy of monthly ibandronate versus weekly BPs by comparing rates of incident clinical fractures over 12 months in a retrospective cohort study Objective

BP = bisphosphonate

methodology
Longitudinal patient data from health plans: eligibility, medical and pharmaceutical claims (anonymous, HIPAA-compliant)

i3 Research database (single, large health plan with 14 million annual enrolment)

i3 Innovus IMPACT database (multiple, unaffiliated health plans with over 70 million enrolled 1997–2007)

Endpoints: new fractures

hip

non-vertebral (inclusive of hip)

vertebral (clinical)

any (inclusive of all the above)

Analysis

time to first incident fracture (Kaplan-Meier methods)

relative risk (hazard ratio) from Cox regression, controlled for baseline covariates

Methodology
study population
Women aged ≥45 years newly started on an oral BP

received ≥1 prescription between 1 April and 31 December 2005 (index date) for ibandronate (Boniva/Bonviva) 150mg once monthly, alendronate (Fosamax) 35mg or 70mg weekly or risedronate (Actonel) 35mg weekly

no BP in baseline period (6 months prior to index date)

Continuous enrolment in health plan for ≥9 months

6 months before starting BP therapy

≥3 months after the first BP prescription

Excluded women with Paget’s disease of bone or malignant neoplasm

Study population
baseline characteristics
Patient

age at index date

co-pay of index treatment

GI diagnosis

Osteoporosis

fracture history

bone densitometry procedure

osteoporosis diagnosis

osteopenia diagnosis

Healthcare utilisation

number of outpatient visits

hospitalisation

Medication use

number of therapeutic classes

Estrogen

Non-estrogen anti-osteoporotics (calcitonin, SERMs)

GI medication (PPI, H2B, CTP)

corticosteroid

Baseline characteristics

GI = gastrointestinal; SERM = selective estrogen receptor modulatorPPI = proton pump inhibitor; H2B = H2B=H2 blocker; CTP = cytoprotective

period of observation
Each subject required to have a 6 month baseline period

to examine medication use and medical history

After starting BP therapy (index date) each subject was observed for fracture for up to 12 months, or until

loss to follow-up (end of health plan enrolment)

discontinue therapy (for primary analysis only)

change in BP therapy

switched to a different BP

switched dosing regimen (e.g. weekly to daily)

Further observations were then stopped (censored)

Period of observation
study design retrospective cohort study
Study design: retrospective cohort study

Patient intake period: start BP therapy (index date)1 April 2005 31 December 2005

Baseline period: 6 months1 October 2004 30 June 2005

Follow-up period: up to 12 months1 April 2005 31 December 2006

overview of analyses
Primary analysis: adherent patients

“Head-to-Head” comparison of drug efficacy

patients received minimum of 90 days therapy

observed for fracture after 90 days, only while remaining on therapy

Secondary analysis: all patients starting BP therapy

patients required to have received ‘≥1 BP prescription’

observed for fracture after index prescription

Sensitivity analyses

exclude patients with clinically important baseline differences: use of oestrogen or other anti-osteoporotics, corticosteroids, GI medications, etc.

definitions of adherence: refill gap for ibandronate* (30 days vs 45 days), requiring 90-day minimum adherence

Overview of Analyses

*Gaps for monthly ibandronate (always 30 days for weekly BPs)

statistical analysis
Time-to-event analysis of fracture incidence with Kaplan-Meier methods

Cox regression used to estimate RR (hazard ratio) of fracture comparing monthly versus weekly cohorts, adjusted for covariates

results shown are from stepwise regression models with all baseline characteristics entered as candidate variables, retaining statistically significant variables

age, osteoporosis diagnosis, use of DXA, fracture history

number of medication classes used, oestrogen use

number of outpatient visits

Conclusions were unchanged in models that included other clinically important variables

use of other anti-osteoporotics (calcitonin, SERMs)

use of glucocorticosteroids

Statistical Analysis

RR = relative risk; DXA = dual energy X-ray absorptiometry

patient disposition primary and secondary analyses
Patient disposition:primaryand secondary analyses

Candidate patients

≥1 prescription for BP*

(n=445,430)

1

  • Aged <45 years or male (n=13,217)
  • >1 study drug (n=19)

Females aged ≥45 years

(n=338,872)

2

  • BP pre-index (n=237,480)
  • Cancer pre-index (n=9,681)
  • Paget’s disease (n=81)

Eligible patients

First treatment, no cancer or Paget’s disease

(n=91,630)

3

  • Invalid data: negative costs (n=32)

Secondary analysis population:

all patients starting BPs

(n=91,598)

4

  • Discontinue BP <90 days (n=27,416)

Primary analysis population:

adherent patients

(n=64,182)

*Alendronate, ibandronate or risedronate

primary analysis monthly ibandronate vs weekly bisphosphonates at 12 months

RR=0.82

p=0.052

RR=0.88

p=0.26

Weekly oral BPs(n=56,837)

Monthly oral ibandronate(n=7,345)

1.6

1.2

0.8

0.4

0

1.51

1.40

1.30

1.29

Fracture incidence (%)

RR=1.06

p=0.84

RR=0.36

p<0.01

0.24

0.20

0.19

0.11

Fx=95

Fx=106

Fx=15

Fx=858

Fx=103

Fx=738

Fx=135

Fx=8

Non-vertebral Hip Vertebral Any

Fractures

Primary analysis: monthlyibandronatevsweekly bisphosphonates at 12 months

RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

primary analysis monthly ibandronate versus weekly alendronate at 12 months

Weekly oral alendronate(n=35,865)

Monthly oral ibandronate(n=7,345)

Primary analysis: monthlyibandronateversus weekly alendronate at 12 months

RR=0.80

p<0.05

RR=0.88

p=0.26

1.6

1.2

0.8

0.4

0

1.51

1.40

1.29

1.29

Fracture incidence (%)

RR=1.00

p=1.00

RR=0.34

p<0.01

0.24

0.20

0.19

0.11

Fx=542

Fx=103

Fx=464

Fx=95

Fx=68

Fx=15

Fx=86

Fx=8

Non-vertebral Hip Vertebral Any

Fractures

RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

primary analysis monthly ibandronate versus weekly risedronate at 12 months

Monthly oral ibandronate(n=7,345)

Weekly oral risedronate(n=20,972)

Primary analysis: monthlyibandronateversus weekly risedronate at 12 months

RR=0.85

p=0.14

RR=0.91

p=0.42

1.6

1.2

0.8

0.4

0

1.51

1.40

1.31

1.29

Fracture incidence (%)

RR=1.19

p=0.57

RR=0.39

p<0.01

0.23

0.20

0.18

0.11

Fx=274

Fx=95

Fx=38

Fx=15

Fx=49

Fx=316

Fx=103

Fx=8

Non-vertebral Hip Vertebral Any

Fractures

RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

sensitivity analyses exclude patients with clinically important baseline differences
In order to understand whether the results were due to baseline differences in the populations, sensitivity analyses were performed which excluded patients with the following during baseline

Estrogen or other anti-osteoporotic medication use (SERMS, calcitonin)

corticosteroid use

fracture

GI medication use

corticosteroid use and/or osteopenia

The conclusions regarding fracture endpoints remained unchanged in the analyses

Sensitivity analyses: exclude patients with clinically important baseline differences
limitations1
Observational studies are subject to potential confounding (not randomised)

there may be residual confounding that was not adequately controlled for

but this was also evaluated with multiple sensitivity analyses

Diagnosis data was collected for billing purposes, not for research

a diagnosis code on a medical claim is not necessarily confirmation of a fracture

vertebral fracture may be coded on basis of patient symptoms, rather than X-ray

it is unlikely that fracture misclassification is differential and clinical fractures are the most important

There is no perfect measure of patient compliance

a filled prescription does not mean the medication was taken, and medication samples are not recorded in prescription claims data

the above would underestimate antifracture benefit (and unlikely to be differential)

Duration of follow-up period was limited to 12 months by the available data

P values were not adjusted for multiple comparisons

Limitations
strengths
Large observational study in a real-world population

findings more appropriate for generalisation and representative than clinical trials

learnings from other observational studies considered in study design

All potential confounders were entered into the Cox-regression model and results were unchanged

Results consistent across a broad range of sensitivity analyses

Strengths
discussion
Risk of hip and non-vertebral fractures was the same with monthly ibandronate and weekly bisphosphonates

Suggests efficacy of ibandronate on non vertebral fractures, consistent with data obtained in a recent meta-analysis1

The rates of vertebral fractures were significantly lower with monthly ibandronate versus weekly bisphosphonates in the primary analysis, but the number of patients with vertebral fracture with monthly ibandronate was limited (n=8)

Discussion

1Adachi R, et al. J Bone Miner Res 2007;S221:S210–11 (Abstract M428)