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Notice: Guidance for Industry: Bioequivalence Requirements: Comparative Bioavailability Studies Conducted in the Fed State

2005-06-08
Our file number: 05-114865-164

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Contact: Bureau of Policy, Science and International Programs Enquiries

Notice

July 21, 2005

Health Canada is pleased to announce the release of the finalized guidance document Bioequivalence Requirements: Comparative Bioavailability Studies Conducted in the Fed State. In June 2003, the Scientific Advisory Committee on Bioavailability & Bioequivalence made recommendations concerning requirements with respect to comparative bioavailability studies conducted in the fed state. A draft guidance document based on those recommendations was circulated to stakeholders for comment. This finalized version has been to updated include additional clarification as a result of comments that have been received (where appropriate) as well as to promote consistency with other Health Canada guidance documents. The comments received during the consultation process, together with discussions and recommendations, have been collated in a separate Questions and Answers (Q&A) Document, which is available upon request. Requests for this Q&A Document should be directed to the e-mail address given below.

Should you have any questions or comments regarding the content of the guidance, please contact

Policy Bureau Enquiries
E-mail: Policy_Bureau_Enquiries@hc-sc.gc.ca
Telephone: (613) 946-9491
Fax: (613) 941-1812

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

Purpose
Background
Scope
Definitions
Guidance
Responsibilities & Procedures
Effective Date

1. Purpose

This guidance presents the most current position of the Therapeutic Products Directorate (TPD) with respect to requirements for comparative bioavailability (BA) studies conducted in the fed state for purposes of demonstrating bioequivalence (BE) of two solid oral dosage forms.

2. Background

It is generally accepted that comparative BA studies conducted in the fasting state are the usual requirement for purposes of demonstrating BE of uncomplicated drugs in immediate-release dosage forms (Guideline A drug products). In the past however, the requirements for comparative BA studies conducted in the fed state for this category of drug products have been subject to misinterpretation (i.e., it is unclear when fed studies are required, if a fed study alone may be sufficient or if a fed study should be done in addition to a fasting study). For drugs in modified-release dosage forms (Guideline B drug products), where the usual requirement is for both fasted and fed studies, requests have been made at times to waive one condition. Similar uncertainty exists for other drug products where the usual BE requirements are that both fasted and fed studies are required such as with narrow therapeutic range drugs, highly toxic drugs (these two categories will be replaced by the category of critical dose drugs), and non-linear drugs.

In practice, the type and magnitude of the effects of food on a drug or drug product are largely unpredictable due to the number of complex and simultaneously occurring factors that may be at play. The effects may be due to the drug, the formulation, the type of meal, the volume of fluid ingested with the meal or the time interval between ingestion of the drug product relative to the meal. The issue is further complicated by uncertainty as to what magnitude or degree of change in the pharmacokinetic parameters of a drug induced by food intake constitutes a significant food-effect.

3. Scope

This guidance will apply to all cases where a comparative bioavailability study/ies constitutes the pivotal evidence of the safety and efficacy of a drug product. This includes uncomplicated drugs in immediate-release dosage forms (Guideline A drug products), complicated drugs in immediate-release dosage forms (i.e., specifically narrow therapeutic range drugs, highly toxic drugs [these two categories will be replaced by the category of critical dose drugs] and non-linear drugs currently described in Report C) and drugs in modified-release dosage forms (Guideline B drug products). This guidance may also have application to post-approval changes, manufacturing site changes, line extension products or bridging studies where BE data provides the pivotal evidence of safety and efficacy of a drug product.

It must be noted that specific BE requirements for narrow therapeutic range and highly toxic drugs (these two categories will be replaced by the category of critical dose drugs) and nonlinear drugs are currently under development. In addition, consideration must be given to all applicable TPD guidances for the type of drug or drug product for which comparative BA studies are being conducted.

4. Definitions

For the purposes of this guidance:

uncomplicated drugs in immediate-release dosage forms are those described in the TPD guidance: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations Used for Systemic Effects (Guideline A)
complicated drugs in immediate-release dosage forms (i.e., narrow therapeutic range drugs, highly toxic drugs and non-linear drugs) are those described in the Expert Advisory Committee on Bioavailability Report C: Report On Bioavailability of Oral Dosage Formulations, Not In Modified Release Form, Of Drugs Used for Systemic Effects, Having Complicated or Variable Pharmacokinetics (Report C)
drugs in modified-release dosage forms are those described in the TPD guidance: Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations (Guideline B)

Current TPD requirements for comparative BA studies conducted in the fed state for purposes of demonstrating BE are based upon Guideline A and B and Report C recommendations.

5. Guidance

5.1. Uncomplicated Drugs in Immediate-Release Dosage Forms

BE should be demonstrated in a single-dose study under fasting conditions.

For uncomplicated drugs in immediate-release dosage forms, if there is a documented serious safety risk to subjects from single-dose administration of the drug or drug product in the absence of food, then an appropriately designed study conducted in the presence of only a sufficient quantity of food to prevent the toxicity may be acceptable for purposes of BE assessment.

5.2. Complicated Drugs in Immediate-Release Dosage Forms (narrow therapeutic range drugs, highly toxic drugs and non-linear drugs)

In general BE should be demonstrated under both fasted and fed conditions. Please see section 5.3 below for exceptions.

5.3. Drugs in Modified-Release Dosage Forms

BE should be demonstrated under both fasted and fed conditions.

For complicated drugs in immediate-release dosage form [#5.2] and drugs in modified-release dosage forms [#5.3], if there is a documented serious safety risk to subjects from single-dose administration of the drug or drug product in either the absence or presence of food, then an appropriately designed study conducted in the indicated condition of use (fed or fasted state) may be acceptable for purposes of BE assessment.

It should be noted that drugs or drug products to which the above requirements apply would also be required to meet any additional study design requirements and standards for BE as outlined in Guideline A or B, or the most recent TPD guidance that has been issued in final form.

5.4. Standard Test Meal

The test meal employed in comparative BA studies conducted in the fed state for purposes of BE assessment should be a representative meal in which sufficient food is given to allow potential perturbation of systemic BA of the drug from the drug product. The sponsor should justify the choice of meal and relate the specific components and timing of food administration.

An example of a test meal that is expected to promote the greatest perturbation in gastrointestinal physiology so that systemic drug BA is maximally affected would be the following breakfast: 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter,120 gm of hash browns and 240 ml of whole milk. Sponsors must be able to justify the choice of meal in a fed BE study and relate the specific components and timing of food administration.