Upload
bridget-sumter
View
214
Download
0
Tags:
Embed Size (px)
Citation preview
Comparison of two treatments
Population of animals
R = 17.8
Treatment effect
T = 16.8
Aim of all trials : to compare treatments on the population of individuals
Impossible in practice
Effect of inference
XR = 16.2
Observed on the samples
XT = 17.8
Truth in the population
R = 17.8
T = 16.8
New Treatment T > Ref Ref > New Treatment T
Lead to a wrong conclusion
A good trial
Minimize the risk of bias in samplingMinimize the risk of a wrong conclusion in inference
- All Randomised Study Animals- Per Protocol Set of Study Animals- Response Variable- Experimental (study) design- Consumer Risk- Producer Risk- Relevant difference
Non inferiority
R - Values of TR
R - T
Unacceptable for primary efficacy variable in clinical trialDoes not prove that the treatment T works
Equivalence
Equivalence range
Values of T
R - RR +
Does not prove that the treatment T worksFor secondary efficacy variables in clinical trials
Even with a good question, a poor design leads to poor conclusions
Superiority clinical trials
Cure rate = 83%N = 2400
REFERENCE
Cure rate = 79%N = 2100
New TRT
Reference < New TRT (P<0.001)
Even with a good question, a poor design leads to poor conclusions
Clinical trial 1REFERENCENew TRT
New TRT< RefP<0.001
Clinical trial 2
Cure rate = 90%N = 2000
REFERENCE
Cure rate = 96%N = 1000
New TRT
New TRT < RefP<0.001
Conclusion : Reference > New TRT
Superiority trials
Cure rate = 50%N = 400
Cure rate = 63%N = 1100
Even with a good question, a poor design leads to poor conclusions
Superiority clinical trials
X = 39N = 100SD = 1
REFERENCE
X = 37N = 100SD = 1
New TRT
Reference < New TRT (P<0.001)
Even with a good question, a poor design leads to poor conclusions
Clinical trial 1
X = 40N = 90SD = 1
REFERENCE
X = 42N = 50SD = 1
New TRT
New TRT< RefP<0.001
Clinical trial 2
X = 30N = 10SD = 1
REFERENCE
X = 32N = 50SD = 1
New TRT
New TRT < RefP<0.001
Conclusion : Reference > New TRT
Superiority trials
Usual statistical tests are not intended to answer to useful questions
Efficacy variable on two groups of dogsRef Test
Mean 15.4SD 2.4
20.02.6
Student t-test
P = 0.23N 3 3
In the population R = 14.5 ; T = 19.7
this difference is clinically important
Conclusion : “EQUIVALENCE”
Comparison of two treatments
Efficacy variable on two groups of dogsRef Test Student t-test
Mean 16.0SD 2.4
18.12.6
N 15 15 P = 0.03
In the population R = 16.8 ; T = 17.8
This difference is not clinically important
Conclusion : NO EQUIVALENCE
Study 1
Comparison of two formulations
Efficacy variable on two groups of dogsRef Test Student t-test
Mean 16.0SD 4.9
18.15.1
N 15 15 P = 0.26
This difference is not clinically important
Conclusion : EQUIVALENCE
Study 2
In the population R = 16.8 ; T = 17.8
Consequences
Large samples sizeSmall variability
Small sample sizeLarge variability
"Equivalence"
Penalty for companies to show equivalence
An ill-posed problem that encourages poor trials
A bad answer to a wrong question
A wrong question ?
H 0 : T = R
Classical hypotheses for student t-test
H 1 : T R
Treatments are equivalent
T = population mean for test treatment
R = population mean for reference treatment
Too restrictive and not relevant
T and R are close
Treatments are not equivalent
A bad answer ?
H 0 : T = R
Classical test of null hypothesis (student t-test)
H 1 : T R
The controlled risk = risk to wrongly reject H0
= risk to declare not equivalent formulations that are equivalent= risk for drug companies
Not important from a regulatory point of viewThe consumer risk is uncontrolled
Treatments are equivalent
Treatments are not equivalent
Bioequivalence : objectives
Check that T and R are close
Control the consumer risk
risk to declare equivalent treatments that are not
with regard to clinical relevance
Check thatT and R are close
T - R bioequivalence
Close in an absolute way
Close in a relative way
bioequivalence 21 R
T
equivalence range (to be discussed)
T - R < or
T - R
bioinequivalence
bioinequivalenceR
T
R
T
21 or
Control the consumer risk
A test controls the risk to wrongly choose the H1 hypothesis
Consumer risk : the risk to wrongly conclude to bioequivalence
BioequivalenceH1
Equivalence range
T - R
R
T
Possible values of
BioinequivalenceH0
BioinequivalenceH0