Science ≠ truth ∧ regulations ≠ science [Regulatives / Guidelines]
Hi Naghma,
Your regulatory body (Pakistan’s?) cannot “literally follow” the WHO guidelines. The WHO’s GLs in many cases offer the respective agency a series of approaches followed by other regulations to select from. You can only guess what they might prefer (or even worse: solely accept). Therefore, ask them. I’m certain they will not bite.
When it comes to the question of fasting/fed of Sofosbuvir I would say that the design primarily depends on what the label/SmPC of the orginator’s formulation approved according to your jurisdiction*1 states. Secondly, if it’s similar to the US RLD’s in regard to intake with food, still the FDA’s product-specific guidance should be taken into account. Hence:
I wrote already that in my opinion reference-scaling for Cmax is the most reasonable approach. The WHO’s SOF-guidance starts with conventional (unscaled) ABE:
However, in the next paragraph of the GL the EMA’s ABEL is mentioned as an alternative (please note the tentative wording: “might be acceptable”). If (!) your regulators accept this approach1, sample sizes for desired levels of power would be:
Please read the applicable section of the EMA’s BE-GL. You have to justify in the protocol that widening the acceptance range of Cmax will not impose a risk on the patients (safety, efficacy) and that a high CVwR observed in the study is a reliable estimate (not caused by “outliers”). That’s different to the FDA’s RSABE, where such conditions are not required.
A final note:
In the forum we are discussing both scientific and regulatory approaches – which are not necessarily identical. Even if a seemingly unambiguous2 GL exists, it is still open to interpretation. To give an example:
❝ By "WHO regulations" mean that our regulatory body follow WHO guidelines, sorry for the inappropriate statement which was mistranslated.
Your regulatory body (Pakistan’s?) cannot “literally follow” the WHO guidelines. The WHO’s GLs in many cases offer the respective agency a series of approaches followed by other regulations to select from. You can only guess what they might prefer (or even worse: solely accept). Therefore, ask them. I’m certain they will not bite.
When it comes to the question of fasting/fed of Sofosbuvir I would say that the design primarily depends on what the label/SmPC of the orginator’s formulation approved according to your jurisdiction*1 states. Secondly, if it’s similar to the US RLD’s in regard to intake with food, still the FDA’s product-specific guidance should be taken into account. Hence:
- If like the European SmPC: One study fed.
- If like the US RLD’s label: Two studies (fasting/fed).
❝ Secondly, objective is to get honorable forum member's scientific comments over the issue (not to adopt crystal ball theory) in order to get a reasonable sample size so that regulatory body could be justified on scientific ground.
I wrote already that in my opinion reference-scaling for Cmax is the most reasonable approach. The WHO’s SOF-guidance starts with conventional (unscaled) ABE:
- The 90% confidence interval of the relative mean Cmax of the test to reference product should be within 80–125%.
However, in the next paragraph of the GL the EMA’s ABEL is mentioned as an alternative (please note the tentative wording: “might be acceptable”). If (!) your regulators accept this approach1, sample sizes for desired levels of power would be:
design 80% 85% 90%
────────────────────────
RTRT|TRTR 28 34 38
RTR|TRT 44 50 60
RRT|RTR|TRR 42 48 57
Please read the applicable section of the EMA’s BE-GL. You have to justify in the protocol that widening the acceptance range of Cmax will not impose a risk on the patients (safety, efficacy) and that a high CVwR observed in the study is a reliable estimate (not caused by “outliers”). That’s different to the FDA’s RSABE, where such conditions are not required.
A final note:
In the forum we are discussing both scientific and regulatory approaches – which are not necessarily identical. Even if a seemingly unambiguous2 GL exists, it is still open to interpretation. To give an example:
- The EMA’s GL is applicable in 31 countries (28 EU members states + Norway, Iceland, Lichtenstein).
Two-Stage Designs are acceptable according to the GL.
- Study protocol submitted and approved in “Reference Member State” A (GL & science).
- Study performed and its design (!), the method of evaluation, and outcome not accepted by “Concerned Member State” B (interpretation).
Too bad. Deficiency letters of the second degree. Couple of months lost.
- If the originator product is not (more) marketed in your country, see the WHO’s “Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products”. Talk to your agency which product will be acceptable.
- ───────────
- I don’t have the slightest idea.
- If your regulators follow “all-encompassing” GLs – like the WHO’s – it would be extremely risky to either select something you prefer (even if scientifically just) or presume what they might accept. Talk to them!
We have sixmembers in the forum. Until someone of them post their experiences with your agency about acceptance of ABEL you will be fishing in troubled waters.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png)
Helmut Schütz
![[image]](https://static.bebac.at/img/CC by.png)
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- Bioequivalence study of Sofosbuvir Dr Naghma Hashmi 2016-03-18 12:34 [Regulatives / Guidelines]
- Which “target regulation”? Helmut 2016-03-18 14:23
- Bioequivalence study of Sofosbuvir Dr Naghma Hashmi 2016-03-19 10:59
- No “WHO regulation”! Helmut 2016-03-19 18:03
- No “WHO regulation”! Dr Naghma Hashmi 2016-03-22 04:51
- Science ≠ truth ∧ regulations ≠ scienceHelmut 2016-03-22 14:06
- No “WHO regulation”! Dr Naghma Hashmi 2016-03-22 04:51
- No “WHO regulation”! Helmut 2016-03-19 18:03
- Which “target regulation”? nobody 2016-04-27 09:15
- Bioequivalence study of Sofosbuvir Dr Naghma Hashmi 2016-03-19 10:59
- Which “target regulation”? Helmut 2016-03-18 14:23