Notice to stakeholders – Implementation of ICH M13A: Bioequivalence for immediate release solid oral dosage forms

June 27, 2025
Our file number: 25-102237-854

Background

The International Council for Harmonisation (ICH)'s guideline entitled, ICH M13A: Bioequivalence for Immediate Release Solid Oral Dosage Forms is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension. The ICH Assembly has endorsed the final draft and recommended its implementation by the membership of ICH.

The ICH M13A guideline should be read in conjunction with the relevant sections of other applicable Health Canada guidance documents. The ICH M13A guideline and other ICH Guidance documents are available on the ICH website. Please note that the ICH website is only available in English. If you would like to request a copy of the French version of the document, please e-mail the Health Products and Food Branch (HPFB) ICH inbox at ich@hc-sc.gc.ca.

By way of this notice, Health Canada is advising Canadians that the ICH M13A guideline will be implemented in Canada on December 27, 2025. As a result, BE studies included in submissions filed after this date will be expected to comply with the ICH M13A guideline and this notice.

With the implementation of the ICH M13A guideline, Health Canada's expectations for conducting comparative bioavailability / BE studies with orally administered IR solid dosage forms and the applicable BE standards will be those described in the ICH M13A guideline. Also, following consultation in early 2025 on the topic, and as further described below, the implementation of the ICH M13A guideline will also result in a change in the BE standards applicable to studies conducted with modified-release (MR) dosage forms.

Standards for modified-release (MR) dosage forms

Health Canada considers that the science supporting the changes to the BE criteria for IR solid oral dosage forms described in ICH M13A is equally applicable to MR dosage forms. Hence, in order to avoid inconsistent bioequivalence standards between dosage forms, Health Canada will apply these revised bioequivalence standards to both single-dose comparative bioavailability studies conducted with IR and MR dosage forms.

Impact on current Health Canada guidance documents

In order to implement the ICH M13A guideline, several sections of Health Canada's current BE guidance documents need to be revised. The changes described below highlight the required changes to these guidance documents. However, as the scope of Health Canada's current BE guidance documents exceeds that of the ICH M13A guideline, the remainder of Health Canada's current BE guidance documents will remain in effect.

The two relevant Health Canada BE guidance documents are:

• Conduct and Analysis of Comparative Bioavailability Studies; and
• Comparative Bioavailability Standards: Formulations Used for Systemic Effects.

The impact of the ICH M13A guideline on these Health Canada guidance documents is described below:

Conduct and analysis of comparative bioavailability studies

Section 1

The principles described in Sections 1.1, 1.2, and 1.3 of this guidance remain in place with the exception that for studies for IR dosage forms, the recommendations included in the ICH M13A guideline respecting study design and conduct, and statistical analysis of data should be followed in order to ensure compliance with the Regulations.

Section 2

For studies conducted with IR dosage forms, all subsections of Section 2 will be superseded by the ICH M13A guideline with the following exceptions:

• Section 2.3.2 – 2.3.3: These sections are not superseded by the ICH M13A guideline and remain in place.
• Section 2.5: This section is not superseded by the M13A guideline and remains in place.
• Appendix 1: The example sample analysis described remains in place.

All sections of this guidance remain applicable for studies conducted with MR products with the exception of Section 2.3.5. In order to harmonise approaches, Section 2.3.5 is superseded by the ICH M13A guideline.

Comparative bioavailability standards: Formulations used for systemic effects

Section 1

The principles described in Sections 1.1, 1.2, and 1.3 of this guidance remain in place with the exception that for pharmacokinetic (PK) studies for IR dosage forms, the relevant PK parameters should meet the standards described in the ICH M13A guideline. The standards that will be applied for the relevant PK parameters for studies conducted with MR dosage forms are described below.

Section 2

For studies conducted with IR products, all subsections of Section 2 will be superseded by the ICH M13A guideline with the following exceptions/modifications:

• Section 2.1.1: The BE standards as described in the ICH M13A guideline may require modification for certain medicinal ingredients or drug products, for example, those with the characteristics described in Sections 2.1.1.1, 2.1.1.6, 2.1.1.8, and 2.1.1.10 of this guidance.

• Section 2.1.1.1: Following consultation in early 2025 on the topic, the BE acceptance criteria described in Section 2.2.4 of the ICH M13A guideline will be applied to single-dose BE studies conducted with both IR and MR dosage forms. Further, the BE standards to be applied for steady-state studies conducted with MR dosage forms will be revised to read as follows:

  Steady‐state studies are not generally required. However, if a steady‐state study is conducted, the following standards should be met:

  1. The 90% confidence interval of the relative mean area under the concentration versus time curve at steady-state over the dosing interval (AUC_tau) of the test to reference product should be within 80.00% ‐125.00% inclusive.
  2. The 90% confidence interval of the relative mean C_max at steady-state of the test to reference product should be within 80.00% ‐ 125.00% inclusive.
  3. The relative mean minimum concentration (C_min) at steady state of the test to reference product should not be less than 80.0% inclusive.
• Section 2.1.1.6: This section is not superseded by the ICH M13A guideline.

• Section 2.1.1.8: Upon implementation of the ICH M13A guideline, Section 2.1.1.8 will apply to both PK parameters AUC and C_max. As such, the applicable standards for C_max will be Standards a) and b), therefore, Standard c) will become redundant. Therefore, the BE standards in Section 2.1.1.8 will be revised to read as follows:

  The following comparative bioavailability standards should be met for C_max and the applicable AUC:

  1. The 90% confidence interval of the relative mean of the test to reference product should be within the following limits, inclusive:

     1. 80.0%-125.0%, if S_WR ≤0.294 (i.e., CV ≤30.0%)
     2. [exp(-0.76 S_WR) × 100.0%]-[exp(0.76 S_WR) × 100.0%] if 0.294 < S_WR ≤0.534 (i.e., 30.0% <CV ≤57.40%) or,
     3. 66.7%-150.0%, if S_WR >0.534 (i.e., CV >57.4%)
  2. The relative mean of the test to reference product should be within 80.0% - 125.0% inclusive.
• Section 2.1.1.10: This topic is not addressed in the ICH M13A guideline and remains in place.

Contact information

For comments or inquiries related to this notice, please contact:

Health Canada - ICH Coordinator
E-mail: ich@hc-sc.gc.ca