Bioequivalence and Bioavailability Forum

Hi Suchit,

why do you bother setting up a statistical analysis according to an (18 years old) obsolete guid­ance – which has been removed from Health Canada’s website in 2012 – and is only available in the Internet Archive any more? See the guidance published on May 22, 2012.

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The documents which will be superseded by these guidances when they come into effect, are as follows:

1. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations Used for Systemic Effects (1992).
   
2. Report C (of the Expert Advisory Committee on Bioavailability and Bioequivalence): Report on Bioavailability of Oral Dosage Formulations, Not in Modified Release Form, of Drugs Used for Systemic Effects, Having Complicated or Variable Pharmacokinetics (1992).
   
3. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part B: Oral Modified Release Formulations (1996).
   
4. Draft Policy: Bioequivalence Requirements: Drugs Exhibiting Non-Linear Pharma­co­ki­ne­tics (2003).
   
5. Notice to industry: Removal of Requirement for 15% Random Replicate Samples (2003).
   
6. Draft Guidance for Industry: Use of Metabolite Data in Comparative Bioavailability Studies (2004).
   
7. Notice to industry: Bioequivalence requirements for combination drug products (2004).
   
8. Guidance for Industry: Bioequivalence Requirements: Comparative Bioavailability Studies Conducted in the Fed State (2005).
   
9. Notice to Industry: Bioequivalence Requirements for Drugs for Which an Early Time of Onset or Rapid Rate of Absorption Is Important (rapid onset drugs) (2005).
   
10. Notice to Industry: Bioequivalence Requirements for Long Half-life Drugs (2005).
    
11. Guidance for Industry: Bioequivalence Requirements: Critical Dose Drugs (2006).

These guidance documents will come into effect for submissions filed on or after July 1, 2012, with the following exceptions. Where the requirements in these guidance docu­ments are reduced relative to existing guidance, the reduced requirements will be effective imme­di­ate­ly. Where the requirements in these guidance documents are increased relative to exist­ing guidance, the increased requirements will only be applied to studies initiated on or after July 1, 2012.

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BTW, any multivariate method assessing whether steady state was achieved is not desirable, IMHO. If either time or time × formulation is significant, you would have to throw away the entire study. That’s stupid, but HC improved and harmonized with the FDA and EMA:
According to the current guidance, Section 2.7.2 j) …

Pre-dose concentrations determined immediately before a dose at steady state (C_pd).

… have to be reported only.