Bioequivalence and Bioavailability Forum

Hi,

❝ Your article is a slap in the face of the ones devoting a lot of time and efforts into developing fast algorithms and setting up simulations. When in 2010 the FDA’s draft progesterone guidance and the EMA’s BE-GL were published statisticians were desperate because it became immediately evident (though still not to you, obviously) that common methods for sample size estimation cannot be applied.

❝ It was a big relief when the two Lászlós published their paper in 2011 and that since Feb. 2013 package PowerTOST allows simulations for any expected θ₀, CV_wR, and desired power..

❝ R and package PowerTOST come free of costs and are licensed under GPL-3. What do you mean by “not possible with us”?

I never questioned anyone’s paper or work what they have done, instead I have learned much out of it. I have done my exercise whatever is possible with me and produced the paper. If you find any limitation you don’t use it instead of criticizing, which is an easy job.

❝ ❝ In general sample size calculations are done using 80% power requirements; however, the post hoc power is not at all important, as long as you bioequivalence limits are within the acceptance range.

❝ Splendid! […]

❝ In many cases studies designed according to your tables will be (extremely) underpowered (i.e., producer’s risk larger than desired). Hence, the chances to fail are higher than expected as well. If you are working with a CRO and the sponsor seeks a second opinion by a learned statistician, you will loose a client.

❝ However, sometimes you’ll make a lucky strike (producer’s risk substantially smaller than targeted). Study overpowered, more subjects than required treated. Fortunately HVD(P)s are safe; low chances of AEs. But any intervention possesses risks. As a member of an IEC I would never accept the protocol. Anyhow: Study performed and easily passes BE. Cross you fingers that the sponsor is so happy with the outcome that he does not seek a second opinion. If he does, he would ask himself why he spent more money than necessary. Probably he will hire another CRO the next time.

❝ Almost needless to say that in the simulations β is always as close as possible to the desired level.

I can convince my client and I don’t need your suggestion in this case and it is my headache.

❝ ❝ In general, a generic player will always try to match innovator. To reserve the resources and to ensure the probability of success (to pass the study), a 10% difference can be considered low to moderate variable drugs as it demand less sample size and a 5% difference is always appropriate for highly variable drugs as it demands more sample size due high variability.

❝ Whereof one cannot speak, thereof one must be silent.  Ludwig Wittgenstein

I don’t have to respond for this.

❝ ❝ We have compared the obtained sample size by using our method with Tóthfálusi & Endrényi (2012) method and it was identified that the obtained sample size did not differed significantly using EMA approach. However it was differed using FDA method. This difference is expected as our approach is the formula based one as the calculations are different here due to change in the regulatory constants.

❝ Did you bother to look at the table and plots in my previous post? If you don’t see differences likely you are .

The paper produced is purely based on the sample size estimation formula and reference is already given to you many times. For this I don’t have to refer what you have suggested.

❝ I am confident that the formula used will definitely works, […] and the same formula know to everyone in the pharmaceutical industry.

❝ Old beliefs die hard even when demonstrably false.  E. O. Wilson

The paper produced is purely based on the sample size estimation formula and reference is already given to you many times.
Moreover as explained earlier I did not manipulated anything in it. The same old formula was used to meet the new regulatory requirement.

❝ ❝ I am not bothered about the ranking of journals …

❝ In earnest? If you were so confident that you discovered the “philosopher’s stone” – everybody is desperately seeking for so long – why didn’t you submit the manuscript to a reputable journal (free of costs, BTW)? Or were you in private afraid that it will fail to survive any serious peer-review?

I don’t have to afraid to any one since the same formula known to everyone and there is no manipulation in it.
You all people helped a lot because for all the questions raised by you all are answered all as well as all the people who are registered in the forum indirectly.
My sincere advice is that; please do not comment on anybody’s work/paper. If you did not find answer you just leave it a side and go ahead.

Best Regards
Someswara Rao

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Edit: Full quotes removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! The forum’s standard quote system restored. Please don’t use your own “private” one. [Helmut]