Surrogate endpoints for fractures ?? - European …© CBG-MEB 16 Time for an update ? Why surrogate...
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Transcript of Surrogate endpoints for fractures ?? - European …© CBG-MEB 16 Time for an update ? Why surrogate...
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Surrogate endpoints for fractures ??regulatory perspective
Dr. Frits LekkerkerkerCHMP alternate member
Chairman Medicines Evaluation Boardin The Netherlands
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Time for an update ?
Surrogate Endpoints in Clinical Trials for osteoporosis:
are they reliable ?is there any validation
are we being misled?
better is to use the terminology (bio)markersonly if validated - surrogates
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guideline on the evaluation of medicinal products in the treatment of primary osteoporosis
released November 2006
For new products there is a need for demonstration of effect both on spinal and on non spinal fractures Biomarkers are not considered as an appropriate
surrogates as endpoints in confirmatory studies
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Biomarkers in clinical trials for osteoporosis can be used as tools when:
understand the biology of the processunderstand the effect of a new medicineprovide information on sub- or other populations that might
respond?
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Endpoints in studiesfractures (vertebral /other)pharmacodynamic endpoints - biomarkers
BMDbone turn-over parameters
– osteocalcin, alk fosf– N- or C-telopeptide of type I collagen
o two independent factors relating to efficacy treatment
o two factors with different measurement accuracy
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Why there will be a need for surrogate endpointsfracture studies difficult to perform concerns about performing placebo controlled studiesnew formulations with same active substancesdosage rangenew indications
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Why there will be a need for surrogate endpointsfracture studies difficult to perform
long follow upcostly fracture is a relative rare event.
concerns about performing placebo controlled studiesnew formulations with same active substancesdosage rangenew indications
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Endpoints in studiesfractures (vertebral /other)surrogate endpoints or pharmacodynamic endpoints
BMDBMD not // fracture reduction
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Fractures with Risedronate
0
5
10
15
20
25
30
35
40
Year 0-1 Year 0-3
PBO -NARIS -NAPBO-MNRIS - MN49%
50% 33%
41%
Reductions in New and Worsening Vertebral
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Month
0
2
4
6
8
10
12
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0 3 6 12 18 24 30 36 48 60 72 84
Mea
n P
erce
nt C
hang
e (±
SE
)
Progressive Increases in Spine BMD over 7 yrs
Progressive Increases in Spine BMD over 7 yrs
5 mg Alendronate10 mg Alendronate20mg/5 mg/Placebo 1 - 5 year20mg/5 mg/Placebo 6 - 7 year 11.2%
8.0%9.0%
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Reduction in fracture risk for bisfosfonatesin relation to BMD
after first year already on there maximumfurther increase in BMD doesn't relate to an increase in
fracture reduction
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Month
0 6 12 243036 48 60 72 84
Cha
nge
in U
rine
NTX
(%)
-100-90-80-70-60-50-40-30-20-10
05 mg Alendronate10 mg Alendronate20mg/5 mg/Placebo 1 - 5 year20mg/5 mg/Placebo 6 - 7 year
Month
0 12 24 36 48 60 72 84-100
-90-80-70-60-50-40-30-20-10
0
Cha
nge
in S
erum
BSA
P (%
)
5 mg Alendronate10 mg Alendronate20mg/5 mg/Placebo 1 - 5 year20mg/5 mg/Placebo 6 - 7 year
Bone Resorption Bone Formation
Normalization of Bone Turnover MaintainedNormalization of Bone Turnover Maintained
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Reduction in fracture risk in relation to BMDBisphosphonatesHRTSERM/raloxifeneCalcitoninFluorStrontiumPTH
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Why there will be a need for surrogate endpointsfracture studies difficult to perform concerns about performing placebo controlled studiesnew formulations with same active substancesdosage rangenew indications
effect on non vertebral fractureseffect on man
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Why surrogate endpointsfracture studies difficult to perform concerns about performing placebo controlled studies
easier / quicker to measurereduce trials size, duration size costsbut should be measured accurately and reproduciblychange in proportion to what it representsit is a misunderstanding that, if their outcome is correlated with true outcome for one product, it could be used as a validated surrogate endpoint when studying other products
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Why surrogate endpointsfracture studies difficult to perform concerns about performing placebo controlled studiesnew formulations with same active substancesdosage range
daily to weekly, monthly, 3 monthlydifferent effect on different biomarkersbridging studies
new indicationseffect on non vertebral fractureseffect on man
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Why surrogate endpointsfracture studies difficult to perform concerns about performing placebo controlled studiesnew formulations with same active substancesdosage rangenew indications
effect on non vertebral fractureseffect on man
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Why surrogate endpointsfracture studies difficult to perform
new indicationseffect on non vertebral fractureseffect on man
o duration one yearo dosage justifiedo inclusion criteria the sameo magnitude is the same o if mode of action is not gender specific
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final update
Fracture studies are required However, biomarkers can be used
dose finding studiesif fracture reduction have been demonstrated
new dose regimeo both biomarkers
new route of administrationnew indication in men if according guideline
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