Release of Draft Guidance Document: Submission Requirements for Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma

Date: 2007-08-01

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Contact Duc Vu

August 2, 2007

Notice

Our file number: 07-118017-24

Health Canada is please to release the above referenced draft guidance to industry for a 45 day comment period. Comments should be submitted to Health Canada no later than September 17, 2007.

Health Canada will review the comments received during this consultation and revise the Guidance as necessary. A final version of this document will then be posted.

Comments should be directed to:

Dr. Duc Vu
Director
Bureau of Cardiology, Allergy and
Neurological Sciences
Finance Bldg., A.L. 0202A1
101 Tunney's Pasture Driveway
Ottawa, ON K1A 0K9

Tel: 613-954-6498
Fax: 613-941-1668
E-mail: duc_vu@hc-sc.gc.ca

Draft guidance document

Submission Requirements for Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma

This guidance document is being distributed for comment purposes only.

Published by authority of the
Minister of Health

Draft Date: 2007/08/01

Health Products and Food Branch

Our mission is to help the people of Canada maintain and improve their health.

Health Canada

HPFB's Mandate is to take an integrated approach to managing the health-related risks and benefits of health related to health products and food by:

• minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
• promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.

Health Products and Food Branch

© Minister of Public Works and Government Services Canada 2007

Également disponible en français sous le titre : Exigences relatives à la présentation de corticostéroÏdes en inhalation de commercialisation subséquente utilisés dans le traitement de l'asthme

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

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 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 document, 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 guidance documents.

TABLE OF CONTENTS

1. INTRODUCTION

1.1 Policy Objectives
1.2 Scope and Application
1.3 Background

2. GUIDANCE FOR IMPLEMENTATION

2.1 Roles and Responsibilities
2.2 Requirements

2.2.1 General Requirements for Subsequent Entry Inhaled Corticosteroid Products
2.2.2 Therapeutic Equivalence Study Requirements for Subsequent Market Entry Inhaled Corticosteroid Products
2.2.3 Clinical Study Requirements for Systemic Exposure to Subsequent Market Entry Inhaled Corticosteroid Products.

2.3 Enquiries

3. GLOSSARY OF ABBREVIATIONS

4. REFERENCES

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1. Introduction

1.1 Policy Objectives

This guidance is intended to assist drug sponsors in filing submissions for subsequent market entry Inhaled Corticosteroid (ICS) Products.

1.2 Scope and Application

This guidance is intended to assist sponsors filing submissions for subsequent market entry Inhaled Corticosteroid (ICS) preparations for use in the treatment of asthma. It is not intended for other indications, e.g. COPD.

It should be noted that the term "subsequent" encompasses products which require filing Abbreviated New Drug Submissions (ANDS) as well as those which require filing Supplemental New Drug Submissions (SNDS).

1.3 Background

The Therapeutic Products Directorate (TPD) has been active since 1990 in trying to prepare guidance documents to assist drug sponsors in filing submissions for subsequent market entry (SME) Inhaled Corticosteroid (ICS) Products. The difficulties faced in finalizing such a document were related to the fact that bioequivalence of such locally acting ICS products cannot be reliably established based on blood levels and the unavailability of a validated model to test the therapeutic equivalence of the Second Entry (SE) product to that of the Canadian Reference (CR) product. The following gives the chronological background for these efforts:

• The first draft guideline entitled "Criteria for the establishment of safety and efficacy of a second or subsequent market entry metered dose inhaler for drugs intended for delivery to the lower respiratory tract" was finalized on February 7, 1990. This draft was sent for review and comments to interested parties including expert Canadian respirologists and the Canadian Thoracic Society.

• On February 13, 1992 the final draft entitled "In vivo criteria to establish equivalence of safety and efficacy of a generic drug delivered by metered dose inhaler: For drugs intended for delivery to the lower respiratory tract" was submitted to Health Canada. This second draft which outlined criteria to establish equivalence for both inhaled bronchodilators and inhaled steroids was issued on September 9, 1992.These guidelines have since been withdrawn as they became outdated.

• With the support of Health Canada (HC), the Canadian Thoracic Society held three symposia with international experts:

  1. Seattle, Washington, U.S.A.- May 1995
  2. Toronto, ON, Canada- December 1995
  3. Toronto, ON, Canada- May 2000

The first two symposia resulted in a publication entitled "Comparative assessment of safety and efficacy of inhaled corticosteroids: Report of a Committee of the Canadian Thoracic Society" ¹. The report of the third symposium resulted in a publication entitled "Clinical models to compare the safety and efficacy of inhaled corticosteroids in patients with asthma" ².

• Following the symposium in Toronto in May 2000, a draft guidance entitled "Guidance to Establish Equivalence or Relative Potency of Corticosteroid Inhalers" was reviewed by TPD's internal committee. This draft document could not be considered a set of guidelines because it only proposed the following unvalidated models: Uncontrolled asthma model, Steroid reduction model and Allergen inhalation model.

The above chronological background shows the urgent need for guidance to assist drug sponsors in filing submissions for subsequent market entry Inhaled Corticosteroid (ICS) Products.

The present guidance document has been prepared by the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) in collaboration with the Office of Sciences (OoS) of the Therapeutic Products Directorate (TPD) of the Health Products and Food Branch (HPFB) of Health Canada (HC). Organized consultation sessions and teleconferences have been held with the Science Advisory Committee on Respiratory and Allergy Therapies (SAC-RAT) to receive their advice on the guidance document. Drug sponsors have been given the opportunity to submit podium and/or written presentations before the SAC-RAT.

During its deliberations the SAC-RAT considered that since the cause of asthma is primarily related to inflammation ³, one of the primary measurement criteria in a proposed study should be an inflammatory biomarker, particularly one of eosinophilic airway inflammation (eosinophilic bronchitis).

Eosinophilic bronchitis responds to corticosteroid treatment and this is associated with clinical benefit ^4 5. The most specific, valid  ⁴ and discriminative ⁶ biomarker for eosinophils is quantitative (spontaneous or induced) sputum cell counts, particularly in patients with moderate to severe asthma. These are also repeatable and responsive and can identify noneosinophilic or neutrophilic inflammation which are common ⁷ and not/less responsive to steroid treatment. An alternative biomarker is exhaled nitric oxide (eNO) which can increase with sputum eosinophilia and is easier and quicker to perform ⁸. However, eNO is influenced by many factors ⁹ making it less specific, valid and discriminative than sputum cell counts, and the eNO biomarker cannot identify other types of airway inflammation. Therefore, quantitative sputum cell counts are the preferred biomarker.

2. Guidance for implementation

2.1 Roles and Responsibilities

Subsequent market entry ICS products that are considered to be new drugs are subject to the requirements of Division 8, Part C of the Food and Drug Regulations. Abbreviated New Drug Submissions (ANDS) and Supplemental New Drug Submissions (SNDS) in support of these drug products are required to contain evidence of safety and effectiveness under the proposed conditions of use, in conformity with the applicable sections of the Food and Drug Regulations namely: C.08.002.1 ¹⁰, C.08.003 ¹⁰ and C.08.005.1 ¹⁰.

For definition of terms and general information, reference should be made to the TPD guidance document entitled "Preparation of Comparative Bioavailability Information for Drug Submissions" ¹¹.

2.2 Requirements

2.2.1 General Requirements for Subsequent Entry Inhaled Corticosteroid Products

Submissions for Second Entry Market ICS products must include the following:

• Complete chemistry, manufacturing and quality control data;

• Appropriate comparative data versus the Canadian reference product as outlined in the TPD "Guidance For Industry: Pharmaceutical Quality of Inhalation and Nasal Products ¹¹;

• Since the drugs are used in adults and children, evidence of compatibility with existing spacer devices or chambers is required for both adults and children;

• Product Monograph: A copy of the current product monograph and labelling for the Canadian reference product must also be included in the submission. Any differences between the product monograph of the subsequent market entry product and that of the Canadian reference product must be annotated to supporting data. Copies of data or references to support such changes must be included in the submission. Please note that the labelling must be current at the time the Notice of Compliance is issued. Subsequently, it is important that submission sponsors monitor changes in the labeling related to their products so that, if necessary, they are prepared to revise the product monograph and labeling within the time frames specified under the TPD Policy on" Management of Drug Submissions" ¹¹, and

• Labels and other labelling material required for the product. A draft of every label to be used in conjunction with the product should be submitted.

2.2.2 Therapeutic Equivalence Study Requirements for Subsequent Market Entry Inhaled Corticosteroid Products

A study based on evaluating anti-inflammatory markers as primary endpoints is required:

An adequately designed, well controlled, double blinded, randomized study in which asthmatic patients are randomized into three parallel arms: Canadian Reference Product (R), Subsequent Market Entry Product (T), and Placebo (Formulation Placebo).

Although parallel studies require a larger sample size, they are generally considered more reliable. If a cross-over study is performed, the washout period should eliminate carry-over effect (i.e. original eosinophil counts should be recovered). It should be noted that approximately one third of patients will not recover their original eosinophil counts following the washout period. Therefore, the cross-over design is considered to be less reliable and justification may be required for choosing such design.

Study Population

Patients should be steroid-naÏve with stable mild asthmatic symptoms and eosinophils 3% or more. Studying a more severely symptomatic population would be considered unethical as patients may be placed in the placebo group, not receiving active therapy. The diagnosis of asthma should be based on ATS standards (with a minimum of 6 months history of asthma) including pre- and post-bronchodilator FEV1₁, steroid naÏve (minimum 6 weeks off ICS), and sputum eosinophils 3% or more.

Study Duration

For a parallel design, a three-week trial is required, when using sputum eosinophils as inflammatory marker, in order to see inflammatory and clinically significant improvement and/or to allow time for the endpoints to plateau.

For a cross-over design, or use of other inflammatory marker, justification must be submitted for the proposed study duration.

Choice of Dose

One dose, the lowest dose available, should be used to determine efficacy.

Efficacy Endpoints

The use of two co-primary efficacy endpoints is required: an inflammatory marker and pre-bronchodilator FEV₁. Both endpoints must meet the clinical efficacy criteria and the clinical equivalence criteria, and therefore no statistical adjustment of P values is necessary.

Clinical Efficacy Criteria

Using both an anti-inflammatory marker and FEV₁ as co-primary efficacy endpoints, the clinical significance criteria should be as follows:

• A difference in the mean sputum eosinophil count (expressed as a percentage of the total count) of at least 50% between the active treatment (pre-treatment minus post-treatment, for both test and reference) and the placebo treatment (pre-treatment minus post-treatment) will be considered clinically significant.

• A difference in the mean FEV₁ (expressed as percentage of predicted) of at least 10% between the active treatments (post-treatment minus pre-treatment, for both test and reference) and the placebo treatment (post-treatment minus pre-treatment) will be considered clinically significant.

Therapeutic Equivalence Criteria

The 90% confidence interval of the relative mean FEV₁ and eosinophil count (based on the log transformed data) of the test to the reference product should be within 80-125%.

2.2.3 Clinical Study Requirements for Systemic Exposure to Subsequent Market Entry Inhaled Corticosteroid Products

Systemic exposure must be shown to be comparable between the test (T) and the reference (R) products. Data may be obtained from a pharmacokinetic (PK) study evaluating the systemic exposure following administration of the subsequent market entry Inhaled Corticosteroid product relative to the Canadian reference product as a surrogate for possible long-term systemic effects.

The PK study should be a single dose study at the upper limit of the dosing range in which the following PK parameters should be determined: AUC_t, AUC_i, C_max, T_max, t_1/2 and K_el. The study should be conducted with reference to the TPD guidance document entitled "Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies. Part A: Oral Dosage Formulations used for Systemic Effects" ¹¹.

The following standards will be applied to the PK study, based on log transformed data:

• The 90% confidence interval of the relative mean AUCt of the test to reference product should be between 80 and 125%

• The relative mean measured Cmax of the test to reference product should be no greater than 125%.

Should blood or plasma levels be too low to allow for reliable analytical measurement, systemic exposure should be determined in a pharmacodynamic (PD) study by assessment of the effect on the hypothalamic pituitary-adrenal axis (HPA).

The PD study should be single or multiple dose study in which the test and reference products are compared. The sponsor is required to give supporting rationale for choice of dose(s). The serum cortisol is measured, after dosing, every two hours for 24 hours and the effect is expressed as the serum cortisol area under the 24 hour curve (SCO-24 AUC). The study should be conducted with reference to the "Report of a Committee of the Canadian Thoracic Society on Comparative Assessment of Safety and Efficacy of Inhaled Corticosteroids" ¹ and the TPD guidance document entitled : "Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies, Part A: Oral Dosage Formulations used for Systemic Effects" ¹¹.

The following standard should be applied to the PD study based on log transformed data:

• The 90% confidence interval of the relative mean SCO-24 AUC of the test to reference product should lie between 80% and 125%.

2.3 Enquiries

For questions, clarification, and further assistance concerning the preparation and filing of submissions for subsequent market entry Inhaled Corticosteroid (ICS) products, contact the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) at the following e-mail address: BCANS_enquiries@hc-sc.gc.ca

For questions, clarification, and further assistance pertaining to the design and conduct of clinical pharmacokinetic studies assessing the systemic exposure of the subsequent market entry products, contact the Bureau of Pharmaceutical Sciences (BPS), Division of Biopharmaceutics Evaluation at the following e-mail address: BPS_enquiries@hc-sc.gc.ca.

3. Glossary of abbreviations

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4. References