E-DRUG: Bio equivalence studies of endogenous substances
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Dear e-druggers
Some of you may have followed the Levothyroxine crisis in France.
To avoid overloading this discussion group, I will not relate the crisis
itself and will keep my question very simple: How does your country manage
approval of endogenous substance substitutes, based on bioequivalence
studies ? Or in other terms what norms of bioequivalence does your country
apply? Especially for Levothyroxine.
A small background information:
As you know, generic medicines can be approved based on bioequivalence
studies. However, these bioequivalence studies are difficult to realise for
substitutes of endogenous hormones such as thyroxine.
Bioequivalence on healthy volunteers is problematic because these subjects
have a natural production of T4 that will bias the results.
FDA requirements are therefore to do bioequivalence studies with
supra-therapeutic doses (600 mcg bolus dose) and measurement of plasmatic
T4 levels corrected for baseline (the correction being negligible because
of the large bolus dose)
The American Endocrine Society disputes these norms because of the narrow
therapeutic range of Levothyroxine and urges FDA to either change their
requirements (and require switch studies of therapeutic doses on patients
without a thyroid) or to NOT declare thyroxine substitutes as equivalent.
Several publications also contend this approach to bioequivalence of
Levothyroxine.
However,the alternative option is to test new formulations on patients
without a thyroid, and checking for TSH levels rather than T4: this
alternative raises an ethical issue of subject recruitment and length of
the study (several weeks, to allow TSH levels to stabilize).
Hence my question: do you know what requirements your country applies? And
can you share these with me?
Many thanks in advance
Maryam Bigdeli
Health Systems Speciaist
Maryam Bigdeli <maryam.bigdeli@zenerves.net>