Bioequivalence and Bioavailability Forum

Dear Helmut,

❝ It seems that our members are not overly interested in these issues.

Too busy watching Virat's 29th test century, maybe ?

Dear Mittyri,

❝ Could you please elaborate how is it possible?

❝ What is the method CRO used for duplication? just copy all concentration points to another subject? what about chromatograms? Did they fake date/time of that?

No. Simply re-analyse samples of subjects already analysed, under a different subject number. Your T/R is too high ? You want to bring it lower ? Select one previous subject with known expected concentrations, or periods from different subjects (let's say 10 and 14), write everywhere these were the samples of subject 45, and you're done. The first description I have seen of this was made in an inspection report, which somebody obtained under a freedom of information regulation and posted on internet. See document A3 - ANSM Preliminary Report. See also FDA's letter to Semler Research, a few years later.

❝ Why experts didn't find it before? Are the methods of data manipulation recognition just implemented?

Well, that French report from 10 years ago already described the general principle. A well-known usual suspect made a detailed publication describing tools and methods.

The problem is not just detecting data manipulation. The problem is collecting enough evidence. If you find signs of data manipulation in one study, you can reject that study. Triggering an article 31 referral to reject all studies from a given CRO probably requires a solid level of evidence. Not just to convince the CHMP: to convince lawyers.

Dear all,

I presented this topic at the GCC summit, which took place in Dubai in March of this year. Here is a summary:

The manipulation of a failing study involves performing an undocumented interim statistical analysis after unblinding the results, typically after half of the subjects have been analyzed. For example, if we have N=36 subjects, an interim analysis can be conducted after the analytical results of the first 18 subjects are known. If the point estimate (PE) or confidence interval (CI) after the first half of subjects is particularly low or high (e.g., GMR ~ 75%) and suggests that the bioequivalence (BE) study is failing, we identify those subjects that are causing the PE or CI to be skewed (high) and switch them.

As Ohlbe explained, the initially analyzed samples that do not fit will either be re-analyzed or diluted by a factor of 2. By doing this, the BE study will pass even if the product formulation is not bioequivalent, as there is a counterpart Y elsewhere in the data set with a T/R that eliminates or mitigates the issue with subject X.

Finding evidence of such manipulation is not easy because the paperwork, audit trials in the chromatographic system, audit trials in the statistical system, and plasma accountability are all clean. We can say that this switching process is an operation that leaves no classical trace, so it cannot be seen through audits or inspections. In other words, we don't have any evidence, only suspicions. Some of these suspicions include: 1) The manipulation revealing itself as trends (Cmax fingerprint), and 2) The manipulation revealing itself as profile similarities.

Dr. Anders Fuglsang has developed several software programs to detect such manipulation, including the Buster routines software, which detects the switch issue (trend manipulation), and the SaToWIB routines software, which detects profile similarities and issues with dilutions. For more details, you can refer to a published article by Dr. Fuglsang.

https://www.sciencedirect.com/science/article/abs/pii/S0928098720303833