Scientific Advisory Committee On Respiratory and Allergy Therapies (SAC-RAT) Record of Proceedings - February 23, 2018

Committee members present:

Irvin Mayers (Chair), Donald Cockcroft, Myrna Dolovich, Alan Kaplan, Larry Lynd (by teleconference), Matthew Stanbrook, Bill Swan

Health Canada presenters:

Scott Appleton, Andrew Raven, Violina Thomas, Paul Wielowieyski

Health Canada staff observers:

Scott Appleton, Ian Dobson, Anna Edmison, Gail Grant, Larissa Lefebvre, Stephanie Parra, Conrad Pereira, Carl Poulin, John Patrick Stewart, Susan Stojdl, Ajaykumar Thaker, Violina Thomas, Emily Tung, Leslie Vrooman, Robin Zhang, Bruce Randall, Léo Bouthillier

Welcome and opening remarks (John Patrick Stewart)

The Director General of the Therapeutic Products Directorate welcomed the scientific advisory committee members. He provided context for the meeting, that is, to discuss and potentially finalize the scientific and regulatory requirements for establishing bioequivalence of subsequent market entry orally inhaled products containing corticosteroids, long-acting beta2-adrenergic agonists (LABA), long-acting muscarinic antagonists (LAMA), and combinations thereof, for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease.

He explained the process to be used for the meeting, and once again thanked the committee for their time and for providing advice to Health Canada. He then handed the meeting over to the Chair of the panel.

Chair's remarks (Irvin Mayers)

The Chair thanked members for participating in this meeting. He confirmed acceptance of the draft agenda for the meeting. He then led the panel members in a verbal update of declarations of affiliations and interests. No declarations required any restrictions on members' participation.

Presentations 1 and 2 (available on request):

1. Presentation: (No title) Violina Thomas, Allergy and Respiratory Drugs Division, Bureau of Cardiology, Allergy and Neurological Sciences

The presentation provided a general overview of current regulatory approaches for subsequent market entry orally inhaled products, revisions to the Health Canada draft guidance document for subsequent market entry ICS products for the treatment of asthma based on the March 2012 SAC-RAT meeting recommendations and clinical end-point study requirements outlined in the US-FDA product-specific guidances for generic Inhaled Corticosteroids (ICS)/LABA, LABA, and LAMA. The presentation concluded by reiterating questions posed to the committee

2. Presentation: Use of pulmonary bioavailability studies as an indicator of comparative efficacy, Paul Wielowieyski, Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences

The presentation provided an overview of regulatory approaches, including such topics as therapeutic equivalence; Health Canada, US FDA and EMA definitions of bioequivalence; US FDA's aggregated weight-of-evidence approach to establish bioequivalence and the EMA's step-wise approach to establishing therapeutic equivalence. Two objectives of pharmacokinetic studies of locally acting orally inhaled products, i.e., total systemic pharmacokinetics (as a surrogate for safety) and pharmacokinetic studies as a marker of pulmonary deposition (for efficacy) were also discussed. Finally, the issue of pulmonary pharmacokinetics as an indicator of comparative efficacy was discussed. The presentation concluded by reiterating questions posed to the committee.

Well-designed efficacy studies using drug deposition with radio-label could act as a surrogate for clinical trials of bioequivalence. If deposition can be seen to be the same then efficacy should be the same since these are the same molecules. However other considerations (device differences, excipients) would also need to meet criteria for safety and efficacy. This question is expanded upon below (Question 2; page 7).

Deliberations on the questions posed to the committee (all members)

Issues raised by the committee, in questioning the presenters and in discussion, included, but were not limited to:

• accounting for concomitant medications in the design of clinical trials
• cost of conducting clinical trials (Not a Health Canada mandate)
• regulatory approaches taken by other jurisdictions such as the European Medicines Agency and the United States Food and Drug Administration
• impact of Health Canada equivalence decisions for Provincial Formularies (not a Health Canada mandate)
• utility of different clinical endpoints in comparative trials
• ethics and feasibility of placebo-controlled trials in patients
• definition of the terms 'mild' and 'moderate' in the context of disease severity
• primary importance of ensuring products are safe, efficacious, of good quality and equivalent where applicable, but also providing guidance on the conduct of studies to facilitate approval
• importance of perception of equivalence of generics to the respective reference products
• applicability of demonstration of therapeutic equivalence in one population to a different patient population
• potential confounding effects of such factors as smoking or vaping, in clinical trials
• relevance of FEV1 in comparison of combination products
• feasibility of clinical endpoint studies for ICS-LABA combination products
• how to assess whether a pharmacokinetic study was well conducted.

The above list is by no means exhaustive and is intended only to give a sense of the type of issues discussed by the panel.

Recommendations

In response to the questions posed by Health Canada, the committee provided the following recommendations :

Note: Questions 1-5 relate to the ICS draft guidance document.

Question: 1

Does the Committee agree that baseline adjusted pre-dose FEV1 at the end of the study period is acceptable as the primary efficacy endpoint for the therapeutic equivalence study for subsequent entry ICS products for the treatment of asthma?

Yes for mild, not moderate, population. Difference in baseline FEV1 must be adjusted to account for baseline variability. Trial duration should be short (at least 4 weeks) after washout.

Question: 2

Does the committee consider that it is necessary for the patients to be steroid naïve (not used steroids for at least 6 weeks prior to study) if the primary end-point is FEV1?

Alternatively, is a 2 week run-in period sufficient if the patients had been stable on their asthma treatment for at least 4 weeks prior to screening?

For the FEV1 endpoint, patients do not need to be steroid naïve.

A 2 week run-in period IS sufficient if patients have been stable.

Question 3:

Does the committee consider it necessary to provide more detailed inclusion and exclusion criteria in the guidance?

If so, what specific criteria should be included?

• Inclusion Criteria:
  • adult (18 and over) subjects with mild asthma
  • current non-smokers of tobacco products and less than 10 pack-year history of smoking
  • no current use of other inhaled, smoked or vaporized products, not including inhalers for the treatment of asthma
  • no beta-blockers
  • reversibility of FEV1 at least 12% and 200ml after SABA (e.g. salbutamol 4 puffs)
  • asthma stability is measured by Asthma Control Questionnaire (ACQ) less than or equal to 0.75
  • stable on maintenance asthma medication for at least 4 weeks prior to washout
  • able to discontinue current asthma medication for duration of study
  • asthma medications using only short acting beta-agonists (less than 4 doses/week) and inhaled corticosteroid less than or equal to 200 µg beclomethasone hydrofluoroalkane equivalent (HFA)
• Exclusion criteria
  • life-threatening asthma
  • patients with other pulmonary diseases
  • history of any significant co-morbid disease
  • hypersensitivity to the active pharmaceutical ingredients or excipients
  • patients receiving oral or systemic corticosteroid therapy in the last 6 months
  • viral or bacterial upper or lower respiratory infection in six weeks prior to enrolment.

Question 4:

Does the Committee consider that statistical significance (p<0.05) of Test and Reference over Placebo for the primary end-point is sufficient to show study sensitivity in view of the proposed study population?

or

Should clinical superiority of >12% from baseline for both T and R also be expected?

Yes, clinical superiority of >12% from baseline for both T and R should also be expected. As the SAC-RAT recommended on 14 March 2012, if a sponsor chooses FEV1 a therapeutic equivalence outcome, they will need to first show a mean change of at least 12% (reversibility) from pre-bronchodilator FEV1. A difference in the mean FEV1 of at least 12% is considered to be the standard definition of reversibility and would be considered clinically significant.

Question 5:

Does the Committee agree with the proposed therapeutic equivalence criteria, i.e., 90% CI of T/R to be contained within 80-125% for log transformed FEV1 and within ± 20% for non-log transformed FEV1?

Yes, As the SAC-RAT recommended on 14 March 2012, The draft guidance document currently states: "To demonstrate the bioequivalence of the test (T) product compared to the reference (R) product, the 90% CI of the T/R ratio of mean change from baseline of the primary efficacy endpoint (e.g. FEV1) should be within 80-125% based on log transformed data.

The committee proposed that:

1. for normal data, the log should not be used
2. a revisions to the text in the guidance document might be necessary according to the following statement:

The criterion for equivalence will be satisfied if the 90% confidence interval of the difference in absolute mean counts is entirely within + 20% of the reference's mean.

This would not be precedent-setting, as + 20% is a generally accepted range in bioequivalence studies."

Question 6:

Does the committee agree that the Clinical Endpoint Study Requirements outlined in the US-FDA's product-specific ICS/LABA, LABA, and LAMA draft guidances are acceptable to establish therapeutic equivalence for the similar Canadian products?

No, for an ICS-LABA product clinical study requirement is not one we would recommend to Health Canada. Clinical trial endpoints are not feasible in Canadian population. The committee was concerned that the FDA uses a placebo controlled RCT rather than an active control. The data in COPD from multiple studies shows benefit of long acting bronchodilators. Few, if any, Canadian respirologists would agree to having their patients in a 1 year trial where short acting bronchodilators would be mandated as the only treatment. Therefore depriving patients of superior treatments over a full year is not ethical. It is also considered to be unethical to do these studies in other countries where the standard of care is short acting bronchodilators (i.e. subjects cannot afford good care).

Yes, for LABA or LAMA monocomponents, clinical outcome study using FEV1 would be acceptable.

Question 7:

If the US-FDA draft guidances are not considered acceptable, then what alternative approaches for the clinical endpoint studies of SME ICS/LABA, LABA, and LAMA products would the Committee recommend?

(To be discussed in more detail. This is a conditional response) For an ICS/LABA trial, an alternative is a well done PK trial. Then the LABA component of the fixed-dose combination can be tested using FEV1 as an outcome measured in an appropriate population.) The ICS component of the fixed-dose combination can be tested using an agreed upon inflammatory marker (e.g. sputum eosinophils). These trials should be conducted in mild asthma population.

Presentations 3 and 4 (available on request):

3. Presentation: Population Bioequivalence, Andrew Raven, Office of Science, Bureau of Policy, Science and International Programs

The presentation gave a brief overview of the concept of population bioequivalence as described in US FDA guidances in the context of orally inhaled and nasal drug products.

4. Presentation: Data Requirements for Strengths of Orally Inhaled Products Not Administered in In Vivo Studies, Scott Appleton, Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences

The presentation provided a brief overview of Health Canada's policy on Bioequivalence of Proportional Formulations for Solid Oral Dosage Forms as background for discussion of potential parameters, such as spray pattern and plume geometry, delivered dose, aerodynamic particle size distribution and dose proportionality, for assessment of proportionality of orally inhaled products. The presentation concluded by reiterating questions posed to the committee.

Question 1:

Does a pulmonary bioavailability profile reflect the extent and pattern of deposition in the lung?

A well done, well administered trial could give a reasonable reflection of deposition versus bioavailability. Need to demonstrate a differentiation in the delivery of the drug. Using differential inspiratory flows may enhance deposition separation for delivery of inhaled products and would, ideally, require two different study days. In vivo PK study in healthy subjects can be used to show that a change in inspiratory flow rate (IFR) could affect regional lung distribution. In vitro testing would use two different operating flows through a cascade impactor.

Question 2:

Are pulmonary PK studies (when GI absorption is blocked or negligible) a valid approach to establish comparative efficacy of orally inhaled products?

Only In vitro testing is not sufficient to establish comparative efficacy. To pass in vitro only for an ICS LABA, a well-designed PK only can be appropriate for some products as PK can be more specific than BE. The alternative is a "stand-alone NDS". Using in vitro testing by itself may not be sufficient to establish bioequivalence. The field is evolving and the committee came out on both sides of the question. There might be times when a well done PK study would be sufficient. It is more difficult to perform bioequivalence studies with combination products since both components must show bioequivalence e.g. area under the curve FEV1 for the LABA and trough FEV1 for the ICS. The PK study following concentration time for each component might be better but the committee thought this approach was still problematic.

Q1 & Q2 discussion to be completed at next meeting.

Next Steps

• The draft guidance document Data Requirements for Safety and Effectiveness of Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma can now be finalized and published.
• Given the difficulties associated with demonstrating equivalence between ICS-LABA combination products in clinical studies, further discussion is required.

Closing remarks / Adjournment (Chair)

The Chair and Health Canada thanked the members for their participation. The meeting was adjourned.