2 Groups model FDA [Two-Stage / GS Designs]

posted by Helmut Homepage – Vienna, Austria, 2013-04-17 16:37  – Posting: # 10428
Views: 34,643

Hi Detlew!

» I have another 'better' one (from a Letter of FDA, Barbara M. Davit)! :cool:
» […]
»   Group
»   Sequence
»   Treatment
»   Subject(nested within Group*Sequence)
»   Period(nested within Group)
»   Group-by-Sequence Interaction (sic!)
»   Group-by-Treatment Interaction
» Subject(nested within Group*Sequence) is a random effect and all other factors are fixed effects. ..."
»
» Enormous effect(s) :-D.

Wow, this will send ElMaestro’s Silly-o-Meter into nirvana!
I have seen some FDA code a good while ago:
PROC GLM DATA = DATASET;
  CLASS SUB TRT PER SEQ GRP;
  MODEL Y = GRP SEQ SEQ*GRP SUBJ(SEQ*GRP) PER(GRP) TRT TRT*GRP /SS3;
  RANDOM SUBJ(SEQ*GRP);
  TEST H = SEQ GRP E = SUBJ(SEQ*GRP)/HTYPE=3 ETYPE=3;
  ESTIMATE 'T VS R' TRT 1 -1;
  LSMEANS TRT/STDERR PDIFF CL ALPHA=.1;
RUN;

Followed by:

If the Group-by-treatment interaction test is not statistically significant (p ≥0.1), only the Group-by-treatment term can be dropped from the model.
If the Group-by-treatment interaction is statistically significant (p <0.1), DBE requests that equivalence be demonstrated in one of the groups, provided that the group meets minimum requirements for a complete bioequivalence study.
Please note that the statistical analysis for bioequivalence studies dosed in more than one group should commence only after all subjects have been dosed and all pharmacokinetic parameters have been calculated. Statistical analysis to determine bioequivalence within each dosing group should never be initiated prior to dosing the next group; otherwise the study becomes one of sequential design.


EMA & random effects… :crying: Phoenix gives me headaches if all effects are fixed (remember this thread?)…

» BTW: Helmut, how had you planned the evaluation of the second stage, if it would be necessary?

Probably too naïvely:
fixed:  sequence, treatment, stage, period, group,
        group × treatment, stage × treatment
random: subject(sequence × stage)


» BTW2: In context of a 2-Stage design, also a 2-group design with groups here called stage, the mighty oracle prohibit us the Group-by-Treatment Interaction! From the EMA Q&A Rev.7 :
» "Conclusion ... A term for a formulation*stage interaction should not be fitted."

Ah-ja!

» BTW3: NOL = no objection letter ?

Good idea. The reports contained a copy of the IEC-approval and a section “Notification to Health Authorities”:

All approvals needed for conducting the trial were obtained; the trial was performed in accordance with the German Medicines Act (AMG). The study was approved by the BfArM on DD Mon YYYY. The study notification to the BfArM [§ 42 (2) AMG,1 § 9 (1) GCP-V] was performed by ███ on DD Mon YYY. Local authorities were notified according to § 67 AMG (‘█████’ for the clinical site ███ and ‘█████’ for the sponsor). On DD Mon YYYY end of the trial was reported by ███ to the BfArM.

Will submit a copy of BfArM’s approvals (protocol, study notification).

Cheers,
Helmut Schütz
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