The Statistical Consensus of Non-Inferiority Clinical Trail for NDA in CHINA

XIA J.L., PhD.Prof of Biostatistics of FMMU

On behalf of CCTS Working Group

--夏结来执笔

Outline

• Introduction of CCTS• Introduction of the Consensus

BACKGROUNDGENERAL CONSIDERATION OF NON-INFERIORITY STUDIES CHOOSING THE NON-INFERIORITY MARGIN ANALYZING THE RESULTS OF AN NI TRIAL

4th DIA China Annual Meeting: Collaboration and Innovation in China

May 20-23, 2012 | Shanghai, China

Introduction of CCTS

• China Clinical Trial Statistics working group （ CCTS ） is a branch of Biostatistical Theory and Method Committee of China.

• Most of the members of CCTS are External/Internal Statistical Reviewer in CDE of SFDA.

• CCTS is a open academic group.

Introduction of CCTS

• CCTS Academically serves statistical design and analysis for clinical trial for NDA in China

• Bridge ICH related Guidelines into China

• Reach Some Statistical Consensus for drug evaluation

• Put impact on Clinical trial in China

Background

• NI Trial was introduced to China almost 10yrs ago.

• Expression of the result of statistical test was totally changed.

• Absence of evidence is not the evidence of Absence.

• The Concept of NI was metaphysically adopted and abused in most of trial design.

Background

• The Consensus of NI trial was reached last OCT. in Tangshan,Nanking

• Published on The Journal of Chinese Health Statistics.

• Main references are FDA’s “Guidance for Industry Non-Inferiority Clinical Trials” ,ICH E9 ,E10 and some related topics of EMEA’s “GUIDELINE ON THE CHOICE OF THE NON-INFERIORITY MARGIN”.

NI in FDA

• 43 of 175 NDAs for new molecular entities that were submitted to FDA from 2002 to 2009 on the basis of evidence from Non-inferiority trials

– 18 of 43 were approved by FDA

– 9 of 43 were poorly designed

– 16 of 43 trials were failure

Highlight

• Clarify the Concept of NI trial

• NI trials may demonstrate that the new drug has some effect that is not too much smaller than the active control.

• NI, in Chinese, literally is not bad than the active control.

• Algebraically ， NI means “≤” ， but “≥” .

Highlight

• Declare the applicability and the limitation of NI trial

• Principle of Choosing Active control, determining Margin, calculating Sample size and statistical inference etc.

• NI trial objectives: one is evaluating the effect of new drug (Superior than putative placebo) and another is that the effect is not too much smaller than the active control.

Applicability of NI trial

• not ethical to use placebo or naive control

• Only one Primary endpoint

• historical evidence of sensitivity to drug effects (HESDE)

• The consistence effectiveness should be assumed (Consistency Assumption （ AC）

• study with good quality (GQS )

Limitation of NI Trial

• Assay sensitivity not determined• Most of symptom relief medicine not

suitable for NI trial (such as some TCM)• Smaller effectiveness lead to unpractical

large sample size• Lack of well designed historical trial of

active control• Effectiveness of Active Con. Changed,

such as some antibiotics

NI Margin ≡ △

• M1= the entire effect of the active control assumed to be present in the NI study , which was estimated by C-P considering variability

• M2= the largest clinically acceptable difference, M2=(1-f) M1, 0.5≤f ≤0.8

• Pre-specified < M△ 1 for superior than Putative Placebo

• Pre-specified < M△ 2 for Non-inferiority than active control

Positive △

• In order to stat the margin be positive, endpoints were classified into HB endpoints and LB endpoints

• HB=the higher the better （ such as cure rate )

• LB=the lower the better （ such as motality rate or morbidity rate )

Positive △

Active Control?!

• For HB, C-P or ln(C/P) is positive

△< M1:

△< M2:

• For LB, P-C or ln(P/C) is positive

△< M1:

△< M2:

0C T T P C P

0T C P T P C

)()1 1 PCfPTMfPCPTTC （

)()1 1 CPfTPMfCPTPCT （

Hypotheses

Tab.1 Hypotheses of NI Trial

Scenarios Difference (proportion, mean)

Ratio （ RR,HR,OR）

HB (Higher, better)

LB (lower, better)

TEST LEVEL

1H : ln( / )T C 1H : -T C

0H : ln( / ) , 0T C

0.025

0H : - , 0C T

1H : -C T

0H : ln( / ) , 0C T

1H : ln( / )C T

0H : - , 0T C

• Proportion Difference

• Ratio

Sample size

21 1

2

( ) (1 )[ (1 )] (1)

( )c

Z Z T Tn C C

K

- 0C T 0

21 1

2

( ) 1 1( ) (2)

( ) (1 ) (1 )c

Z Zn

KT T C C

- 0C T 0

• mean Difference

• When calculating Sample size, commonly, C=T was assumed.

• In some fewer cases, T may be assumed a little better than C (according to HESDE), but nominal β may be inflated.

Sample size

- 0C T 0

21 1 2

2

( ) 1[1 ] (3)

( )c

Z Zn

K

’Cause variability puts heavy weight to sample size estimation. One should be conservatively estimate variability at initial and can do sample size reestimation under blind at some pre-specified time. This do no harm to type I error inflation.

Sample size

Unblind sample size reestimation, if needed, should be done under the supervision of DMC and must be carefully pre-planed in the protocol, especially, the αspending function should be depicted in detail.

Sample size

Sample size

Generally, Sample size of Ni trial is larger than that of superiority trial. Philosophically, it is reasonable and is the trade off between ethics and science.

Sample size of mean difference test2

1 /2 1

2

( ) (1 )[ (1 )] c

Z Z T Tn C C

K

21 1

2

( ) (1 )[ (1 )] NI trial

( )c

Z Z T Tn C C

K

Missing value imputation

• Missing value is inevitable in clinical trial.

• The imputation method should be carefully applied. LOCF do not take for granted. If do so, Ni trial will be beneficiate for poor quality trial.

• MMRM model may be a candidate imputation method.

• IIT principle is not conservative for NI trial

Inferences

• Interval estimation of C-T for HB or T-C for LB was recommended, generally 95%CI

• If the upper limit < ,trial objective can △be concluded

• 95%-95% principle, though conservative, was proposed in the consensus

M1NI

HESDE

NI

HESDE

M1M2

1

95%CI of C/P

95%CI of C/T

1.12 1.25

M1M2

1

95%CI of P/C

95%CI of T/C

1.12 1.25

NI

HESDE

NI

HESDE

M1

M2 M1

0

95%CI of C-P

95%CI of C-T

0.11 0.22

M2

0

95%CI of P-C

95%CI of T-C

0.11 0.22

Fig.1 Statistical inference principle of 95%-95% method

LB

HB

Switching between NI and Superiority

• If the upper limit for respective 95%CI be less than 0 in NI trial, Superiority can be claimed without adjustment of type one error

• If P>0.05 in superiority trial, even if the upper limit for respective 95%CI be less than △(post hoc), NI should not be claimed.

epilogue

• Two arms NI trial should be considered as the last choice. Do pay attention to biocreep.

P=Tn<…T2<T1<C

Three arms design would be the best choice, especially a good way for R&D of TCM

Thanks.

xiajielai@fmmu.edu.cn