Scientific Advisory Committee on Respiratory and Allergy Therapies (SAC-RAT)

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Record of Proceedings

November 13, 2009

Committee Members Present:

I. Mayers (Chair), D. Cockcroft, S. Dell, M. Dolovich, A. Donner, F. Hargreave, A. Kaplan (via teleconference), E. Lui, R. Moqbel, P. Nair, M. Patterson, W. Racz, R. Schellenberg, M. Stanbrook

Regrets:

M. Desrosiers, L. Lynd, D. Sin, S. Waserman

Health Canada Representatives Present:

S. Appleton, B. Li, J. Moore, A. Thaker, V. Thomas, P. Wielowieyski, J. Zhang

* Acronyms used in this record (in alphabetic order):

ARDD

Allergy and Respiratory Drugs Division

AUC

Area under the curve

AUC_t

Terminal area under the curve

BCANS

Bureau of Cardiology, Allergy and Neurological Sciences

C_max

Maximum concentration

CI

Confidence interval

COI

Conflict of interest

COPD

Chronic obstructive pulmonary disease

CTS

Canadian Thoracic Society

FEV1

Forced expiratory volume in one second

GOLD

Global Initiative for Chronic Obstructive Lung Disease

ICS

Inhaled corticosteroids

LABA

Long-acting beta-agonists

MCID

Minimal clinically important difference

NDS

New Drug Submission

PK/PD

Pharmacokinetics/Pharmacodynamics

QoL

Quality of Life

QTc interval

a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, corrected for heart rate

SAC-RAT

Scientific Advisory Committee on Respiratory and Allergy Therapies

SME

Subsequent Market Entry

TOR

Terms of Reference

TPD

Therapeutic Products Directorate

T/R

Test to reference ratio

Preamble

In October 2007, the Scientific Advisory Committee on Respiratory and Allergy Therapies (SAC-RAT) met in order to provide recommendations to Health Canada on clinical requirements for innovator products in the treatment of Chronic Obstructive Pulmonary Disease (COPD). Today's meeting will focus on initial discussions concerning data requirements for Subsequent Market Entry (SME) long-acting beta-agonists (LABA) used to treat COPD.

Opening Remarks and Overview of Agenda

The SAC-RAT Chair, Dr. Irvin Mayers, opened the meeting by thanking Committee members for their continued efforts in the development of science-based clinical recommendations for Health Canada regulators. Dr. Mayers also gave an overview of the day's agenda, introducing a new meeting format, which would allow the Committee to deliberate and formulate direct responses to each of the questions posed by Health Canada.

Introductions and Conflict of Interest (COI) Declarations

The Chair led the Committee in round-table introductions and conflict of interest declarations, encouraging a free and open discussion. Upon completion of the declarations, it was unanimously agreed that all members could participate fully in the meeting. Maureen Patterson, a COPD patient advocate from Edmonton, was welcomed as a new member of the Committee.

Review of Revised Terms of Reference (TOR)

SAC-RAT members accepted the revised TOR.

Progress Update

Dr. Ajaykumar Thaker, Manager of the Allergy and Respiratory Drugs Division (ARDD) in the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS), gave a brief update on the status of the two Guidance Documents developed in consultation with the SAC-RAT.

In August-September 2007, the draft Guidance Document for Industry: Data Requirements for Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma was posted to Health Canada's website for external consultation. Significant comments were received and thoroughly reviewed by the SAC-RAT and ARDD. The revised draft version of this document is to be posted on Health Canada's website for a second round of stakeholder comments in the upcoming months.

During the August-September 2007 consultation period, a small number of comments were received concerning the draft Guidance Document for Industry: Data Requirements for Subsequent Market Entry Steroid Nasal Products for Use in the Treatment of Allergic Rhinitis. This Guidance Document was reviewed by the SAC-RAT and ARDD and a final version is to be posted on Health Canada's website in the upcoming months.

Health Canada Questions and SAC-RAT Responses: Data Requirements for Subsequent Market Entry (SME) Long-Acting Beta-Agonists (LABA) in the treatment of COPD

Health Canada's questions and the Committee's responses are outlined below. [Note: Though he was unable to attend the meeting in person, Dr. Don Sin (a COPD specialist on the SAC-RAT) reviewed the questions and provided his responses to the Chair in advance of the meeting. Dr. Sin's written responses were distributed to Committee members for consideration in their deliberations.]

Part 1: General Questions

1. What are the basic data requirements for SME LABA products? Is it appropriate to have the same requirements as for SME Inhaled Corticosteroid (ICS) products? (that is [i.e.], a pharmacodynamic [PD] / therapeutic equivalence study and a pharmacokinetic [PK] study for safety)?

   Yes; however, the following tests should also be included:
   In vitro analysis of the characteristics of the particles in the device as well as the delivery device as outlined in the TPD "Guidance for Industry: Pharmaceutical Quality of Inhalation and Nasal Products" (Health Canada, 2006).

2. What are the essential safety requirements for SME LABA in the treatment of COPD? Given the safety concerns with LABA, is a 1-year safety study required for all products?

   A one-year safety study is not necessary for SME LABA products indicated for COPD. Once a generic product has been proven bioequivalent to the innovator product, Health Canada's usual standards of evaluating SME products should apply.

   For SME products submitted to Health Canada as a New Drug Submission (NDS), a one year study is required.

3. Can we approve a LABA for the treatment of COPD when it is not approvable for the treatment of asthma? What could be the potential consequences of an SME LABA product approved for COPD only?

   Yes, a SME LABA product can be approved for COPD indication only. There are now clear data demonstrating that COPD and asthma patients respond differently to LABA mono-therapy. For instance, LABA mono-therapy is not associated with an increased risk of mortality, hospitalization or exacerbations in COPD, whereas such concerns are still present in asthma. For SME LABA products approved for COPD only, concerns of off-label use were noted, but as physicians are well aware of the risks associated with LABA mono-therapy for asthma, such risks should be minimal. All SME LABA products indicated for COPD should have the same black-boxing warning for asthma as the innovator product. SME LABA products indicated for COPD only should not be a substitute for asthma in the provincial drug formulary.

Part 2: Questions for PD (therapeutic equivalence) study

1. COPD diagnosis and classification requirements have been discussed for an innovator product (see SAC-RAT meeting minutes October 2-3, 2007). Should the same criteria be applied to SME LABA?

   Yes. The Canadian Thoracic Society (CTS) has published  guidelines (PDF Version - 212.4 K) on the diagnosis and classification of severity of COPD.

2. Inclusion and exclusion criteria, and stratification by COPD severity and smoking status have been discussed for an innovator product (see SAC-RAT meeting minutes October 2-3, 2007). With respect to SME LABA, what inclusion and exclusion criteria should be considered for the PD study? Specifically, what patient population is considered most appropriate to study efficacy and safety of an SME LABA product?

   A fairly uniform population is considered most appropriate (stable, requiring no intervention in the preceding six weeks, stage 2-3 severity according to the Global Initiative for Chronic Obstructive Lung Disease [GOLD]) in order to show that both drugs behave the same. A good representation of gender, age (40+ years of age) and smoking history (current or past, for 10+ pack-years) should be captured.

   COPD and asthma are complex diseases that overlap significantly, and although some members recommend that asthmatics be excluded from such studies, no consensus was reached by the Committee. This issue will be re-visited at the next meeting.

3. Is it appropriate to request that the proposed COPD population (for example [e.g.], chronic bronchitis and/or emphysema) and the proposed indication(s) (e.g. improving airflow obstruction, symptom relief, modifying/preventing exacerbations, or modifying disease progression) of a SME LABA product be consistent with what has been approved for the innovator LABA product in Canada? What if the evidence does not support all indications that have been approved for the innovator drug?

   If the SME LABA product is bioequivalent to the innovator LABA product for COPD indication, it should have the same claims (e.g. improved airflow limitation, Quality of Life [QoL], symptoms and reduced exacerbations, and so on [etc.]) as the innovator product.

4. Should the primary efficacy endpoint of the PD study be determined according to the proposed indication(s)? The primary efficacy endpoints have been discussed for an innovator COPD product (see SAC-RAT meeting minutes October 2-3, 2007). Is there anything special regarding efficacy endpoints with respect to SME LABA products?

   As a primary efficacy endpoint, the area under the curve (AUC) of the forced expiratory volume in one second (FEV1) is recommended. To show equivalence, both the area under the curve and the shape of the curve (as assessed by the peak and trough) over a 12-hour period should be significantly different from Placebo but similar for the Test and Reference drugs. Secondary endpoints were not recommended.

5. What is the most appropriate study design that intends to demonstrate clinical equivalence of a SME LABA in comparison with a Canadian reference LABA product? Should the PD study be a randomized, double-blind, placebo-controlled trial? Should three arms be required (test, reference, and placebo)? Should a parallel or a cross-over design be preferred?

   A randomized 3-arm (Test, Reference, Placebo) cross-over, single-dose design with a washout period of 72 hours to eliminate the carry-over effect of the long-acting bronchodilator and an adequate run-in period (e.g. 7 days) is recommended. A cross-over design was preferred over a parallel design to reduce the number of subjects required. A single-dose study was preferred over a steady state in order to reduce the length of the study.

   To the extent possible, trials should be blinded with respect to the investigator, the subject and the evaluator. Double-blind double-dummy design is recommended.

6. If a cross-over study is allowed, what would be an adequate washout period?

   To ensure adequate washout, 72 hours between doses (a minimum of 6 half-lives) is recommended.

7. Is a placebo arm always necessary? If an equivalence study without a placebo is proposed, how should the assay sensitivity be established?

   A placebo arm is needed for the recommended study design.

8. The duration of efficacy trials for an innovator COPD product is determined by the proposed indication (i.e., 3 months for improving airflow obstruction, 6 months for symptom relief, 1 year for COPD exacerbation, and 3 years for modifying disease progression). Should the duration of the PD study for the SME LABA also depend on the proposed indication(s)? What is the appropriate study duration for the PD study for each indication? What is the minimum duration for the PD study?

   The recommended study design and study duration for a SME LABA for COPD is outlined in the answer to Part 2: Question 5. As per the Committee's response to Part 2: Question 3, it is appropriate to transfer all claims of the innovator LABA product for COPD indication to the SME LABA product for the same indication.

   For a SME submitted as an NDS, the study duration should follow the respective indications as noted in the question (i.e., 3 months for improving airflow obstruction, 6 months for symptom relief, 1 year for COPD exacerbation, and 3 years for modifying disease progression).

9. Is one dose (i.e. the lowest LABA dose approved for COPD in Canada) sufficient to show efficacy?

   Yes. One dose, the lowest dose marketed by the sponsor of the Canadian reference product, should be used to determine efficacy. The following dosing is recommended: 12 micrograms (µg) for Formoterol, and 50µg for Salmeterol.

10. How should the study sample size be determined?

    Standard sample size calculations should be used as determined by confidence intervals.

11. The minimal clinically important differences (MCIDs) for specific efficacy endpoints have been discussed for an innovator COPD product (see SAC-RAT meeting minutes October 2-3, 2007); should those MCIDs be considered as clinical efficacy criteria for SME LABA too?

    As requested by the SAC-RAT, ARDD will provide additional data. This question will be re-visited at the next meeting.

12. The therapeutic equivalence criterion for an SME ICS product is that the 90% CI of the T/R ratio of mean change in the primary efficacy endpoint be within 80-125%. Should SME LABA comply with the same therapeutic equivalence criterion?

    Yes.

13. What specific safety parameters should be studied (i.e., measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, corrected for heart rate [QTc interval] - Bazett or Fredericia corrected, serum potassium, glucose, adverse events, vital signs, etc.)? What should be considered as clinically relevant changes in the safety parameters for COPD?

    The PK data is the primary safety signal. Secondarily, the subjects would be studied for QTc interval, heart rate, serum potassium and glucose levels.

Part 3: Questions for PK study

1. Is a pharmacokinetic study evaluating systemic exposure sufficient to demonstrate the safety of an inhaled LABA? If not, then what other information is required to demonstrate equivalence in safety?

   See answer to Part 2: question 13.

2. What would be a recommended study design (i.e., single-dose cross-over, steady-state or other) and an appropriate dose to use in a PK safety study for SME LABA in COPD?

   The PK study should be a single dose crossover study at the upper limit of the dosing range (i.e. the maximum labeled adult dose: 24µg for Formoterol, and 100µg for Salmeterol).

3. What subject selection criteria would be appropriate for a PK study on the safety of SME LABA in COPD (i.e., healthy volunteers or patients)?

   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) indicates that adult healthy volunteers are preferred. However, some members suggested that for a PK safety study of SME LABA for COPD, data should be collected on COPD patients (see answer to Part 2: question 2) as well as healthy volunteers/controls (typically 18-45 year-old males).

   It was suggested to collect samples for PK and safety analyses during the therapeutic equivalence study. However, initial changes in both pulmonary function and blood levels occur rapidly, requiring multiple measurements to be captured in succession during the rising phase of the curve. This succession of measurements may not be feasible in a single study; therefore, separate pulmonary function and PK studies may be necessary. If a single study is feasible, COPD patients should be used. If separate studies are done, healthy volunteers should be used.

4. What are appropriate equivalence criteria for a PK study on the safety of SME LABA in COPD (i.e., equivalent or lower systemic exposure based on determination of the terminal area under the curve [AUCt] and maximum concentration [Cmax])?

   As per 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 standards should 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 between 80 and 125%.

Closing remarks

Committee members were thanked for their valuable time and initial recommendations on SME LABA therapies in the treatment of COPD. Discussions on this topic will continue following the receipt of additional data provided by Health Canada and SAC-RAT members.

Prepared by: Jackie Moore
Next Meeting Date: To be determined