Use of Foreign Comparators in Bioequivalence Studies for Health

Use of Foreign Comparators in Bioequivalence

Studies for Health Canada

Scott Appleton, PhD

Manager, Division of Biopharmaceutics Evaluation

Pharmaceutical Drugs Directorate

Health Canada

SBIA Meeting

February 28, 2024

Outline

• Canadian Food and Drug Regulations

• Development of HC’s Approach to Foreign Comparators

• Earlier

• Recent

• Risk associated with using foreign comparators

• Case Study

• International Collaborations

• Summary

Food and Drug Regulations (FDR)

Section C.08.001.1 of the FDR provides a definition for the Canadian

Reference Product (CRP):

• (a) a drug in respect of which a notice of compliance is issued pursuant

to section C.08.004 and which is marketed in Canada by the innovator

of the drug,

• (b) a drug, acceptable to the Minister, that can be used for the purpose

of demonstrating bioequivalence on the basis of pharmaceutical and,

where applicable, bioavailability characteristics, where a drug in

respect of which a notice of compliance has been issued pursuant to

section C.08.004 cannot be used for that purpose because it is no

longer marketed in Canada, or

• c) a drug, acceptable to the Minister, that can be used for the purpose

of demonstrating bioequivalence on the basis of pharmaceutical and,

where applicable, bioavailability characteristics, in comparison to a

drug referred to in paragraph a).

C.08.001.1 Paragraph (c)

Guidance documents regarding the use of foreign reference

product (FRPs) establish acceptance criteria to justify acceptable

FRPs, pursuant to paragraph (c) of the regulation:

• c) a drug, acceptable to the Minister, that can be used for the

purpose of demonstrating bioequivalence on the basis of

pharmaceutical and, where applicable, bioavailability

characteristics, in comparison to a drug referred to in paragraph

a).

Earlier Development of HC’s Approach to FRPs

• 1995: published first guidance document

– Canada first to accept FRPs for BE studies

– only a subset of products based on lower risk/complexity.

• 2000 – 2013: HC sought advice from Scientific Advisory

Committees (SACs) on expansion of scope.

– SAC did not support the expansion of the scope.

– The tests to establish identicality to CRP were not reliable.

Risk Factors

• Low solubility drugs

– Other chemicals (e.g., surfactants) required to solubilize the drug

– Testing not reliable to determine FRP is identical to CRP

• Modified-release drugs

– Number of unknown factors that contribute to drug release in the body

(e.g., modified-release mesalamine)

– Complex technology (e.g., OROS technology; complicated PK release

profiles)

• Drugs with NTI/CDD

– Very high risk (e.g., graft rejection)

Limitations in Establishing Identicality

• It is recognized that it cannot be established unequivocally that

the FRP is identical to CRP

HOWEVER …

• HC is of the opinion that, for the products in scope of the 1995

guidance, even if slight differences should exist between

products which meet the criteria, the differences would be of no

therapeutic consequence.

Recent Development of HC’s Approach to FRPs

• 2017: publication of updated draft guidance

– Solubility definition expanded for when drug is highly soluble (dose-

solubility volume < 250 mL over the pH range)

– Notice of guidance publication also made request for proposals to

industry on expansion of scope – No responses received to date.

• 2018: Guidance finalized following receipt of stakeholder

comments.

– No stakeholder comments provided any scientific rationale for expansion

of scope.

Expansion of Scope

• Dosage forms added to the guidance:

– immediate release inhaled dosage forms (e.g. orally inhaled solutions,

suspension and dry powders)

– immediate release nasal suspensions

• comparative tests should be conducted with regard to formulation,

physicochemical properties, and device attributes.

See the Health Canada Guidance Document: Use of a Foreign-sourced Reference Product as a Canadian Reference

Product (2018) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-

products/applications-submissions/guidance-documents/canadian-reference-product-guidance.html) for additional

information.

Risk of Using a Foreign Comparator

AUC

Cmax

lower

higher

Foreign vs.

Local

Comparator

Absorption

Case Study

• Prolonged-release suspension dissolves slowly after IM injection due

to low aqueous solubility

• Hydrolysed to active metabolite, which is absorbed into systemic

circulation.

• Dissolution rate at injection site is rate-limiting step for absorption.

• Complexity wrt MR not related to formulation but rather inherent

properties of API.

– Long Acting Injectable (IM) for treatment of schizophrenia

– Long elimination half-life

– MR and low solubility

– BE study conducted at large number of clinical sites and large number of

patients enrolled – CI’s were narrow

Case Study (continued)

Applicant provided:

• results of analytical studies comparing the CRP and biobatch of FRP demonstrating

their similarity including physiochemical, dissolution release, particle size distribution,

and morphology.

• a letter from the local regulatory authority stating that proposed generic product was

found, in a preliminary determination, to be Q1 and Q2 to the FRP.

Additional considerations:

• ethical and practical challenges of conducting an additional study in patients with

schizophrenia.

• Factors influencing the risk vs. benefit of requiring an additional bioequivalence study

include:

– large number of patients required

– Nature of the treated disorder

International Collaborations

• International Pharmaceutical Regulators Programme (IPRP)

– Publication: Survey of the Regulatory Requirements for the Acceptance of Foreign

Comparator Products by Participating Regulators and Organizations of IGDRP J

Pharm Pharm Sci (www.cspsCanada.org) 22, 28 - 36, 2019

– Publication: Survey of the Criteria Used for the Selection of Alternative Comparator

Products J Pharm Pharm Sci (www.cspsCanada.org) 25, 323 - 339, 2022

• ACCESS Generic Medicines Work Sharing Initiative

– Operational procedures with an appendix on FRP acceptance

Summary

• Use of foreign comparators allow generic pharmaceutical

companies to leverage BE studies conducted for other

jurisdictions.

– Reduce development costs

– Avoid unnecessary exposure of subjects in BE studies

• Applicable criteria used to identify eligible foreign comparators

where the risk of undetected differences are not likely to be

therapeutically significant.

• Flexibilities may be applied on a case-by-case basis.

Questions

• Bureau of Pharmaceutical Sciences

bpsenquiries@hc-sc.gc.ca