Bioequivalence and Bioavailability Forum • Partial replicate for USA

balakotu
★

India,
2013-01-10 09:37
(4491 d 12:26 ago)

Posting: # 9810
Views: 5,530

Partial replicate for USA [RSABE / ABEL]

Dear All,

Recently I have done one partial replicate study for USFDA(N=15).

In our study the Swr < 0.294 for AUCt and AUCi then I use the unscaled average bioequivalence approach as given below

Calculation of unscaled 90% bioequivalence confidence intervals:

PROC MIXED 

data=pk; 

CLASSES SEQ SUBJ PER TRT; 

MODEL LAUCT = SEQ PER TRT/ DDFM=SATTERTH; 

RANDOM TRT/TYPE=FA0(2) SUB=SUBJ G; 

REPEATED/GRP=TRT SUB=SUJ;

B ESTIMATE 'T vs. R' TRT 1 -1/CL ALPHA=0.1; 

ODS OUTPUT LSMEANS=LSM

ods output Estimates=unsc1; 

run;

Based on the above program I got below WARNING for ESTIMATES and LSMEANS.

WARNING: Stopped because of infinite likelihood.

NOTE: The data set WORK.COVEST1 has 5 observations and 4 variables.

WARNING: Output 'ESTIMATES' was not created.  Make sure that the output object name, label, or path is spelled correctly. Also, verify that the appropriate procedure options are  used to produce the requested output object. For example, verify that the NOPRINT option is not used.

WARNING: Output 'LSMEANS' was not created. Make sure that the output object name, label, or path is spelled correctly. Also, verify that the appropriate procedure options are used to produce the requested output object.  For example, verify that the NOPRINT option is not used.

WARNING: Output 'G' was not created. Make sure that the output object name, label, or path is spelled correctly. Also, verify that the appropriate procedure options are used to produce the requested output object. For example, verify that the NOPRINT option is not used.

Please clarify the above program. If I am removing “RANDOM TRT/TYPE=FA0(2) SUB=SUBJ G”; in the above program I am getting the results.
Please clarify whether I have to remove above statement in the program.

Regards
Kotu.

d_labes
★★★

Berlin, Germany,
2013-01-10 11:24
(4491 d 10:40 ago)

@ balakotu
Posting: # 9812
Views: 4,414

Overspecified model

Post reply

Dear Kotu,

welcome to the club! Your observation is common in evaluating partial replicate designs with the FDA guidance code. The source of this is that the model is over-specified. You can't get a reliable estimate for the within-subject variance for the Test formulation in a design in which only the Reference is replicated. See discussions about this in this thread or this one for instance. You may find even more using Search.

Ways out? Don't know exactly :-(

. Leaving out the random statement only for the reason that then it gives a result is IMHO not a reasonable solution.
You may try to simplify the between-subject variance-covariance part of the model from FA0(2) to CS i.e. the RANDOM statement to
RANDOM TRT/TYPE=CS SUB=SUBJ G;
Sometimes this helps. But it bears the assumption that the between-subject variances of Test and Reference are the same and neglects the subject-by-formulation interaction, which is different from the original model.

Another model specification with SAS code may be found in this thread.

But as already said: Don't know exactly the correct way out.
Eventually you may consider to ask the FDA statisticians. Barbara Davit is a pleasant-natured woman as Helmut told me once.

—
Regards,

Detlew