Bioequivalence and Bioavailability Forum

Hi Naghma,

❝ 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 C_max is the most reasonable approach. The WHO’s SOF-guidance starts with conventional (unscaled) ABE:

• The 90% confidence interval of the relative mean C_max of the test to reference product should be within 80–125%.

If (!) your regulators insist in ABE¹, you would need hundreds of subjects.
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 

Study costs are closely related to the number of administrations/biosamples. Considering the 80% power variant we have 28×4=112 administrations in the 4-period full replicate, 44×3=132 in the 3-period full replicate, and 42×3=126 in the partial replicate. Hence, the 4-period full replicate is the winner. If you are not limited by the sampling volume (check with the bioanalyst) that’s the way to go. You might expect a higher dropout-rate in the 4-period replicate than in the two others but the impact on power is limited.
Please read the applicable section of the EMA’s BE-GL. You have to justify in the protocol that widening the acceptance range of C_max will not impose a risk on the patients (safety, efficacy) and that a high CV_wR 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.

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• 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.

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1. I don’t have the slightest idea.
   
2. 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 six members in the forum. Until someone of them post their experiences with your agency about acceptance of ABEL you will be fishing in troubled waters.