In-vitro Population Bioequivalence [Regulatives / Guidelines]

posted by kumarnaidu – Mumbai, India, 2019-02-05 15:32 (721 d 20:18 ago) – Posting: # 19869
Views: 1,090

Hi,

We have questions on In-vitro Population BE study.

The approach used was the proc GLM for calculation MSW_R, MSW_T, MSB_R and MSB_R for parameters of D50 and Span to population bioequivalence.

We use standard algorithm for one life stage (m=1) as defined in draft budesonide guideline recommend sept 2012.

Now problem is our results does not matches with the sponsor results, when we calculated SD_R and SD_T for one life stage (m=1) from Proc GLM model.

There are large differences for the values of SD_R, SD_T and 95% upper confidence bound for linearized criteria of reference-scaled and constant scaled my approach, but the Geometric mean are very similar for both D50 and Span.

They have used the proc mean procedure and directly extracted SD_T and SD_R value and used all remaining calculation.

As mentioned in draft budesonide guideline, for data collected on one life stage (m=1), ignore E2, E4c and E4s and their corresponding H and U terms in the calculation.

Calculation formula for sigmaR and sigmaT (for more than one life stage (m>1)) are as below:

data FinalRef;           
merge both (where=(TRT='R' and _SOURCE_='ERROR') rename=(Mean=Mean_R MS=MSW_R))
      both (where=(TRT='R' and _SOURCE_='Container') rename=(MS=MSB_R));
    by _name_;
run;
data FinalTest;             
merge both (where=(TRT='T' and _SOURCE_='ERROR') rename=(Mean=Mean_T MS=MSW_T))
      both (where=(TRT='T' and _SOURCE_='Container') rename=(MS=MSB_T));
    by _name_;
run;
m_T=1;/* no. of stages-to modify*/
m_R=1;/* no. of stages-to modify*/
n_T=10;/* no. of bottles per batch-to modify*/
n_R=10;/* no. of bottles per batch-to modify*/
l_T=4;/* no. of batches-to modify*/
l_R=4;/* no. of batches-to modify*/
GM_Ratio=exp(mean_T)/exp(mean_R);
SD_R=sqrt ((MSB_R/m_R)+(((m_R-1)*MSW_R)/m_R));
SD_T=sqrt ((MSB_T/m_T)+(((m_T-1)*MSW_T)/m_T));
HD=(abs(meandiff)+tval*sqrt((MSB_T/(n_T*l_T*m_T))+(MSB_R/(n_R*l_R*m_R))))**2;
UD=(HD-ED)**2;
E1=MSB_T/m_T;
H1=(l_T*n_T-1)*E1/(cinv(&alpha,(l_T*n_T-1)));
U1=(H1-E1)**2;
E3s=-(1+&thetap)*MSB_R/m_R;
H3s=((l_R*n_R-1)*E3s)/(cinv((1-&alpha),(l_R*n_R-1)));
U3S=(H3s-E3s)**2;
E3c=-MSB_R/m_R;
H3c=(l_R*n_R-1)*E3c/(cinv((1-&alpha),(l_R*n_R-1)));
U3c=(H3c-E3c)**2;
Eqr=ED+E1+E3s;
Hn1=Eqr+sqrt(UD+U1+U3s);
Eqc=(ED+E1+E3c-&thetaP*&Sigma2T0);
Hn2=Eqc+sqrt(UD+U1+U3c);


We did not found the algorithm with sigmaR and sigmaT calculation for one life stage (m=1). We have slightly modified SD_R and SD_T formula for one life stage (m=1) and remove (((m_R-1)*MSW_R)/m_R)) and (((m_T-1)*MSW_T)/m_T)) from above equation.


Modified equation are as below:
SD_R=sqrt (MSB_R/m_R)
SD_T=sqrt (MSB_T/m_T)


Here we are confuse with approach which is based on the draft guideline.

Can anybody comment of formula on SD_R and SD_T calculation for one life stage (m=1)?

https://www.fda.gov/downloads/Drugs/.../Guidances/UCM319977.pdf

Kumar Naidu

Complete thread:

Activity
 Admin contact
21,316 posts in 4,446 threads, 1,489 registered users;
online 8 (1 registered, 7 guests [including 3 identified bots]).
Forum time: Wednesday 11:51 CET (Europe/Vienna)

Nothing fails like success because you do not learn anything from it.
The only thing we ever learn from is failure.
Success only confirms our superstitions.    Kenneth E. Boulding

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5