Draft Guidance Document - Data Requirements for Safety and Effectiveness of Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma for Industry

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Contact: Bureau of Cardiology, Allergy and Neurological Sciences

Notice

September 19, 2011

Our file number: 11-116649-777

Subject: Release of the Draft Guidance Document Data Requirements for Safety and Effectiveness of Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma for Industry

Application

This guidance is intended to assist sponsors in the collection and analysis of data for Inhaled Corticosteroid (ICS) products for use in the treatment of asthma in order to meet the safety and effectiveness requirements under Part C, Division 8 of the Food and Drug Regulations. The data and standards outlined in this guidance are intended to be applied to a new inhaled corticosteroid product being compared to a product for which clinical safety and effectiveness data exist. For clarity, these types of products will be called "Subsequent Market Entry Products".

Context

Health Canada is pleased to announce the release of the Draft Guidance Document Data Requirements for Safety and Effectiveness of Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma for a 60-day external consultation.

The initial Draft Guidance Document dated August 1, 2007 was posted on Health Canada's website for Stakeholder consultation. The comments received during this consultation process, together with discussions and changes to the Guidance Document, have been collated in a separate Questions and Answers Document, which is available upon request. Requests for this Questions and Answers Document should be directed to the mailing and/or email address given below.

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

Bureau of Cardiology, Allergy and Neurological Sciences
Therapeutic Products Directorate, Health Canada
Building #2 (Address Locator 0202A1)
Tunney's Pasture
Ottawa, Ontario
K1A 0K9

Telephone: 613-941-1499
Facsimile: 613-941-1668
E-mail: bcans_enquiries@hc-sc.gc.ca

Draft Guidance Document
Data Requirements for Safety and Effectiveness of Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma

Published by authority of the Minister of Health

Draft Date 2011/09/19

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 Policy Statements
  • 1.3 Scope and Application
  • 1.4 Background
• 2. Guidance for Implementation
  • 2.1 Requirements
    • 2.1.1 General Filing Requirements for Subsequent Market Entry Inhaled Corticosteroid Products
    • 2.1.2 Therapeutic Equivalence Study Requirements for Subsequent Market Entry Inhaled Corticosteroid Products
    • 2.1.3 Clinical Study Requirements for Systemic Exposure to Subsequent Market Entry Inhaled Corticosteroid Products
• 3. Enquiries
• 4. Glossary of Abbreviations
• 5. References

1. Introduction

1.1 Policy Objectives

This guidance is intended to assist sponsors in the collection and analysis of data for Inhaled Corticosteroid (ICS) products for use in the treatment of asthma in order to meet the safety and effectiveness requirements under Part C, Division 8 of the Food and Drug Regulations. The data and standards outlined in this guidance are intended to be applied to a new inhaled corticosteroid product being compared to a product for which clinical safety and effectiveness data exist. For clarity, these types of products will be called "Subsequent Market Entry Products".

1.2 Policy Statements

A therapeutic equivalence study should be carried out to examine the efficacy of a subsequent market entry ICS product in comparison with a Canadian Reference ICS product using a clinically meaningful endpoint. One primary endpoint is required on which the action and effect of inhaled corticosteroid is primarily directed. A sensitive and specific airway inflammatory marker is recommended as the primary endpoint. Other endpoints such as Forced Expiratory Volume in one second (FEV1), symptoms, asthma control questionnaire (ACQ) are recommended as secondary endpoints. The primary endpoint should be analyzed accordingly such that the 90% confidence interval of the relative means for the test over reference is completely contained within the equivalence interval of 80-125%.

A pharmacokinetic (PK) study should be carried out to examine the safety of a subsequent market entry ICS product in comparison with a Canadian Reference ICS product. Systemic blood levels of the active substance should be measured and meet the usual bioequivalence standards for uncomplicated drugs.

1.3 Scope and Application

This guidance is intended to be applied to all submissions involving the demonstration of therapeutic equivalence in order to provide pivotal evidence of the safety and efficacy of a new ICS preparation in various devices including metered dose inhalers (MDI's) and dry powder inhalers (DPI's) for use in the treatment of asthma. Examples of cases where this guidance applies are:

1. therapeutic equivalence studies in support of the equivalence of subsequent-entry products to the Canadian reference product [Abbreviated New Drug Submission (ANDS)];
2. bridging studies where the formulation to be marketed is different from the formulation used in the pivotal clinical trials [New Drug Submission (NDS), Supplemental New Drug Submission (SNDS)];
3. studies in support of significant post-marketing changes and line extensions [Supplemental Abbreviated New Drug Submission (SANDS), SNDS)].

This guidance applies to ICS preparations including only one active ingredient. It does not apply to combination products.

1.4 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) 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 SME product to that of the Canadian reference product (CRP).

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, the Canadian Thoracic Society held three symposia with international experts:
  1. Seattle, Washington, United States of America - May 1995
  2. Toronto, Ontario, Canada - December 1995
  3. Toronto, Ontario, 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" (Boulet, 1998). 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" (Parameswaran, 2003).
• TPD's internal committee reviewed, following the symposium in Toronto in May 2000, a draft guidance entitled "Guidance to Establish Equivalence or Relative Potency of Corticosteroid Inhalers". 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 ICS Products.

The Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) has prepared the present guidance document in collaboration with the Office of Science (OoS) of the TPD of the Health Products and Food Branch (HPFB) of Health Canada. Organized consultation sessions and teleconferences have been held with the Scientific 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 (Hargreave, 2006; Nair, 2007), 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 (Brightling, 2006; Pizzichini, 1996). The most specific, valid (Pizzichini, 1996) and discriminative (Lemière, 2006) biomarker for eosinophils is quantitative (spontaneous or induced) sputum cell counts, particularly in patients with moderate to severe asthma. These measurements are also repeatable and responsive and can identify noneosinophilic or neutrophilic inflammation, which are common (Jayaram, 2006). An alternative biomarker is the measurement of the fraction of nitric oxide (NO) in exhaled air (also known as fractional exhaled nitric oxide (FeNO)), which can increase with sputum eosinophilia and is easier and quicker to perform (Taylor, 2006). However, FeNO is influenced by many factors (American Thoracic Society; European Respiratory Society, 2005) making it less specific, valid and discriminative than sputum cell counts, and it is over-sensitive. Also the FeNO biomarker cannot identify other types of airway inflammation which might interfere with the interpretation of results. Therefore, quantitative sputum cell counts are the preferred biomarker. Alternative biomarker(s) may be used with supportive justification and validation.

2. Guidance for Implementation

2.1 Requirements

2.1.1 General Filing Requirements for Subsequent Market Entry Inhaled Corticosteroid Products

This Guidance should be read in conjunction with the following:

"Guidance for Industry: Pharmaceutical Quality of Inhalation and Nasal Products" (Health Canada, 2006). This guidance provides information on the data requirements related to pharmaceutical quality.

"Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in CTD Format" (Health Canada, 2004). This guidance provides information on how to file in the CTD format.

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

General Considerations

A sensitive and specific airway inflammatory marker (for example [e.g.] sputum eosinophils) is recommended as the primary endpoint. However, selection of other primary endpoint(s) (such as exhaled nitric oxide (FeNO) or FEV1) may be considered if adequate justification is provided and the study design is considered acceptable.

The following study design is recommended based on evaluating the anti-inflammatory marker - sputum eosinophil count as the primary endpoint. Requirements for alternative approaches are also briefly described.

Study Design

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) (P), is required.

It is recommended that the study be multicentre to avoid potential investigator bias.

Study blinding is a critical consideration, and it is recommended that a description of how the T, R, and P products are to be masked be carefully provided in the study protocol.

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 (e.g. 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. Furthermore, the longer duration of the study makes it more difficult to recruit patients and maintain stability of disease during the study. Therefore, the cross-over design is considered to be less reliable and justification will be required for choosing such a design.

Primary Efficacy Endpoint

The use of one primary efficacy endpoint is required on which the action and effect of the drug is primarily directed. A sensitive and specific airway inflammatory marker (e.g. sputum eosinophils) is recommended as the primary efficacy endpoint. A standardized method of sputum induction and selection should be used for assessment of airway inflammation. The primary endpoint should meet both the clinical efficacy criteria and the clinical equivalence criteria, and therefore no statistical adjustment of P values is necessary.

Other inflammatory markers (e.g. FeNO) or alternative outcome measurements (e.g. FEV1) may be acceptable as the primary endpoint provided they are supported by a study design of sufficient power and validity.

Secondary Efficacy Endpoints

FEV1 is recommended as a secondary clinical endpoint because it is influenced secondarily to the drug effect on inflammation and by other factors. Other secondary endpoints (such as asthma symptoms or Asthma Control Questionnaire) may be considered as additional to FEV1.

Alternatively, if FEV1 is used as the primary endpoint, it is recommended that airway inflammatory markers (e.g. sputum eosinophils or FeNO) be secondary endpoints.

Study Population

The inclusion of steroid-naïve patients (never used ICS or minimum 6 weeks free of ICS) with mild to moderate uncontrolled but stable asthma symptoms (e.g. no emergency visits for 6 months, never intubated, not awake at night due to asthma more than once a week) is recommended. Inclusion of patients on low-dose inhaled steroid can be considered with justification. Patients should have at least 3% eosinophils measured in their sputum and FEV1 > 60% of predicted.

Studying a 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 recognized standardized case definitions.

Sample Size

Sample size of the study should be calculated based on the primary efficacy endpoint (that is [i.e.] sputum eosinophil counts) to ensure there is a reasonably powered sample size in order to demonstrate therapeutic equivalence.

The use of FEV1 as the primary endpoint usually requires a large sample size to demonstrate therapeutic equivalence. Sample size calculation based on FEV1 should make sure that the study is adequately powered.

Study Duration

When sputum eosinophil counts are used as the primary endpoint in a parallel design, a study of at least three-weeks in duration is required. This should allow sufficient time to see a clinically significant inflammatory improvement in the patients, and a plateau of efficacy to be achieved.

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

If FEV1 is considered as the primary endpoint, the duration of a study is usually longer and adequate justification must be provided.

Choice of Dose

One dose, the lowest dose marketed by the sponsor of the Canadian Reference Product, should be used to determine efficacy assuming that the requirements of pharmaceutical equivalence criteria (Health Canada, 2006) have been met between the test and the Canadian reference products, and the excipients are proportional among different strengths of the test product. Any deviations from these assumptions will require adequate justification.

Clinical Efficacy Criteria

If an anti-inflammatory marker (i.e. sputum eosinophil counts) is used as the primary efficacy endpoint, a difference in the mean sputum eosinophil count (expressed as a percentage of the total count) of at least 50% between the active treatments and the placebo treatment will be considered clinically significant. For each treatment, the change should be calculated according to the following formulas:

Drug Effect = % Δ Eosinophil Count of Active Treatment- % Δ Eosinophil Count of Placebo

Alternatively, if FeNO is used as the primary endpoint, adequate clinical justification should be provided for a clinically meaningful difference between active treatments and placebo.

If FEV1 is used as the primary endpoint, a difference in the mean FEV1 of at least 12% between the active treatments and the placebo treatment will be considered clinically significant. For each treatment, the change in FEV1 should be calculated according to the following formula:

Therapeutic Equivalence Criteria

To demonstrate the bioequivalence of the test (T) product compared with the reference (R) product, the 90% Confidence Interval (CI) of the T/R ratio of mean change from baseline of the primary efficacy endpoint (e.g. sputum eosinophil count, or FeNO, or FEV1) should be within 80-125% based on log transformed data or untransformed data.

The choice between using log-transformed or untransformed analysis is to be made based on model check of the data. The facilities for assessing normality within the SAS statistical package plus a thorough visual inspection of various plots of the data are usually sufficient. The scale that renders the data closer to normality is the scale to be used. After transformation, check normality again. If the log-transformed data is closer to normality, then the log-transformed data can be used to demonstrate therapeutic equivalence. Otherwise, use the original scale.

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

Systemic exposure should 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 (the maximum labeled adult dose) in which the following PK parameters should be determined: Area under the curve to the last quantifiable concentration (AUC_T), Area under the curve to infinity (AUC_I), AUC_T/AUC_I, Maximum observed concentration (C_max), Observed time at which C_max occurred (t_max), Half-life (t_½) and Terminal elimination rate constant (K_el). The study should be conducted with reference to the Health Canada Guidance for Industry entitled "Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects" (Health Canada, 1992) which indicates that adult healthy volunteers are preferred.

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

• The 90% confidence interval of the relative mean AUC_T of the test to reference product should be between 80 and 125%;
• The relative mean measured C_max of the test to reference product should be between 80 and 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).

A PK study for systemic exposure would be preferred to a PD study for systemic absorption. If a sponsor has convincing data based on unsuccessful attempts to conduct the PK study, a PD study for systemic absorption could be used.

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 "Comparative Assessment of Safety and Efficacy of Inhaled Corticosteroids: Report of a Committee of the Canadian Thoracic Society" (Boulet, 1998) and the Health Canada Guidance for Industry entitled: "Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects" (Health Canada, 1992).

The following standard should be applied to the PD study based on either the log or the original scale (See method for model check described in section 2.1.2.):

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

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 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.

4. Glossary of Abbreviations

ACQ

Asthma control questionnaire

ANDS

Abbreviated New Drug Submission

ATS

American Thoracic Society

AUC_I

Area under the curve to infinity

AUC_T

Area under the curve to the last quantifiable concentration

BCANS

Bureau of Cardiology, Allergy and Neurological Sciences

BPS

Bureau of Pharmaceutical Sciences

C_max

Maximum observed concentration

CI

Confidence interval

COPD

Chronic Obstructive Pulmonary Disease

CRP

Canadian reference product

FeNO

Fractional Exhaled Nitric Oxide

FEV1

Forced expiratory volume in one second

HPA

Hypothalamic-pituitary-adrenal axis

HPFB

Health Products and Food Branch

ICS

Inhaled Corticosteroids

K_el

Terminal elimination rate constant

MCID

Minimal clinically important difference

NDS

New Drug Submission

OoS

Office of Science

PD

Pharmacodynamic

PEF

Peak expiratory flow

PK

Pharmacokinetic

RAT

Respiratory and Allergy Therapies

SAC

Scientific Advisory Committee

SAC-RAT

Scientific Advisory Committee on Respiratory and Allergy Therapies

SANDS

Supplemental Abbreviated New Drug Submission

SCO

Serum cortisol

SME

Subsequent Market Entry Product

SNDS

Supplemental New Drug Submission

t_½

Half-life

t_max

Observed time at which C_max occurred

T/R

Test-to-reference ratio

TPD

Therapeutic Products Directorate

5. References

American Thoracic Society; European Respiratory Society. 2005. ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. Am. J. Respir. Crit. Care. Med. 171: 912-30.

Boulet, LP., DW. Cockcroft, J. Toogood, Y. Lacasse, J. Baskerville, and FE. Hargreave. 1998. Comparative assessment of safety and efficacy of inhaled corticosteroids: Report of a Committee of the Canadian Thoracic Society. Eur. Respir. J. 11: 1194-1210.

Brightling, CE. 2006. Clinical applications of induced sputum. Chest. 129: 1344-348.

Hargreave, FE., and K. Parameswaran. 2006. Asthma, Chronic Obstructive Pulmonary Disease (COPD) and bronchitis are just components of airway disease. Eur. Respir. J. 28: 264-74.

Health Canada Guidance for Industry Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part A: Oral Dosage Formulations used for Systemic Effects. Public Works and Government Services Canada, 1992.

Health Canada. Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format. Public Works and Government Services Canada, 2004.

Health Canada. Guidance for Industry: Pharmaceutical Quality of Inhalation and Nasal Products. Public Works and Government Services Canada, 2006.

Jayaram, L., MM. Pizzichini, RJ. Cook, L-P. Boulet, C. Lemière, E. Pizzichini, A. Cartier, P. Hussack, CH. Goldsmith, M. Laviolette, K. Parameswaran, and FE. Hargreave. 2006. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur. Respir. J. 27: 483-94.

Lemière, C., P. Ernst, R. Olivenstein, Y. Yamauchi, K. Govindaraju, MS. Ludwig, JG. Martin, and Q. Hamid. 2006. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J. Allergy Clin. Immunol. 118(5): 1033-039.

Nair, PK., and FE. Hargreave. 2007. Airway disease, inflammometry and individualized treatment. In Polosa R, Holgate ST (eds), Therapeutic Strategies in Asthma: Current Treatments. Clinical Publishing, Oxford: 5-64.

Parameswaran, K., R. Leigh, PM. O'Byrne, MM. Kelly, CH. Goldsmith, FE. Hargreave, and M Dolovich. 2003. Clinical models to compare the safety and efficacy of inhaled corticosteroids in patients with asthma. Canadian Respir. J. 10(1): 27.

Pizzichini E., MM. Pizzichini, A. Efthimiadis, S. Evans, MM. Morris, D. Squillace, GJ. Gleich, J. Dolovich, FE. Hargreave. 1996. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid phase measurements. Am. J. Respir. Crit. Care Med. 154: 308-17.

Taylor, DR., MW. Pijnenburg, AD. Smith, JC. De Jongste. 2006. Exhaled nitric oxide measurements: clinical application and interpretation. Thorax. 61: 817-27.