Dear all,
I updated the template for the EMA’s reference-scaling method “Average Bioequivalence with Expanding Limits – ABEL”.
New or changed:
- Supported designs:
- Partial replicate design with sequences RRT|RTR|TRR.1
- Full replicate design with sequences RTRT|TRTR.
- Full replicate design with sequences RTTR|TRRT (new).
- Full replicate design with sequences RTR|TRT (new).
- Full replicate design with sequences RTT|TRR (new).
- Not supported designs (and IMHO, should never be):
- Extra-reference design with sequences RTR|TRR.
Reason: Since T is not administered in period 3 the models will give a biased treatment estimate in the presence of period effects. - Balaam’s design with sequences RT|TR|RR|TT.
Reason: Very poor power characteristics (sample size ~8× of a 4-period replicate and ~5× of a 3-period replicate). If limited sampling volume is an issue, consider one of the 3-period designs instead. - Full replicate design with sequences RTTR|TRRT|RRTT|TTRR. For drawbacks of this design see the FDA’s Guidance for Industry: Statistical Approaches to Establishing Bioequivalence, Appendix B (2001).
- Extra-reference design with sequences RTR|TRR.
- The intra-subject CV(s) are reported to two digits (previously rounded to one digit as in the Q&A document) and used in full precision.
- The expanded limits above the scaling cap of CVwR 50% are no more hard coded to 69.84–143.19% but calculated in full precision according to
100*exp(±0.76*sqrt(ln(0.5^2+1))).
Reason: Rounded limits are not symmetrical around 100% and lead to discontinuities…
The inclusion of the 90% CI is still assessed based one the two-digits rounded percentages according to the guideline. The same holds for the GMR-restriction (within 80.00–125.00%). - Added a data wizard Design to the sub-workflow Prepare Dataset for Analysis:
- Checks whether the design is a partial replicate.1
- Checks whether the design is one of the 3-period full replicates (RTR|TRT or RTT|TRR).
#1 prevents the meaningless2 CVWT in ‘Method C’ to be shown in the Table Final Conclusion.
#2 will be used ‘downstream’ to assess whether at least 12 subjects are in sequence RTR in the RTR|TRT-design (required for a „reliable estimate of the CVwR” according to the Q&A document Rev. 12 of June 2015). Note: In a properly powered study such an outcome is not realistic anyway (more than 42% dropouts).
Although not mentioned in the Q&A document, the same assessment is performed for sequence TRR in the RTT|TRR-design.
- Sub-workflow Analysis|Standard Average BE|Other Methods object BE Method B log changed the Degrees of Freedom to ⦿ Residual in compliance with the Q&A – expected to be equivalent to SAS DDFM=CONTAIN (new in v1.4.3.1).
- Sub-workflow ABEL|Calculation Steps
- For validation purposes the Data Wizard Assessment gives the degrees of freedom of the difference and the log halfwidth (new in v1.4.3.1).
- If the Table Final Conclusion is executed, the calculation of all Methods (A, B, and C) is triggered.
- The Table Final Conclusion has additional columns:
90% CI (pass|fail), GMR (pass|fail), and overall (pass|fail). - If the design was RTR|TRT or RTT|TRR, an additional column Reliable estimate of CVwR (yes|no) will be given right to the column CVwR (%).
- If the design was a partial replicate1 the column CVwT (%) will not be displayed since due to the over-specified model the value estimated by ‘Method C’ is meaningless.2
- Sub-workflow ABEL|Outlier Analysis
- The filter for sequences and periods was hard-coded for RTRT|TRTR and RRT|RTR|TRR. Therefore, RTR|TRT and RTTR|TRRT did not work. Now the workflow accepts any of the supported designs.
- Nit-picky: Changed the outlier-flag from ±2 to ±1.959964.
- Removed the 3px-border of the Box Plot.
- PHX7-version of the template: Increased the Title Area Size of the Box Plot from 30 to 40.
- Documents folder.
- Added the current version of the EMA’s Q&A document.
- Updated the Instructions.
The template was developed in PHX 6.4.0.768 and tested in PHX 7.0.0.2535 as well. The template was cross-validated with 11 data sets (all designs, up to 360 subjects) against SAS 9.4 (Methods A, B, C), R 3.3.2 (A, B), STATISTICA (A), and partly (Q&A data sets I and II; Methods A, B) against STaTa 14, SPSS 22, and JMP 10. As usual, use at your own risk.
If you become aware of any defects, please report here.
Comments:
- The partial replicate is – in statistical terms – a lousy design. If you want to avoid trouble, please forget it or report here why you want to use it.
- ‘Method C’ is an over-specified model. It is essentially forcing the software to estimate the within-subject variability of T, which the data cannot provide (since T was not repeated!). Hence, Phoenix – correctly – throws a warning:
Newton's algorithm converged with modified Hessian. Output is suspect.
Model may be over-specified. A simpler model could be tried.
Similar in SAS:
Convergence criteria met but final hessian is not positive definite.
F.i. the Q&A data set II gives a CVWT 8.65% (Phoenix) or 3.87% (SAS). Both are meaningless.
I removed the 1.4.3 templates from this post. Please download v1.4.3.1 provided in this post or in the previous versions.use the workaround as described.
Edited by Helmut Schütz, 13 December 2016 - 04:21 PM.