Scientific Advisory Committee On Respiratory and Allergy Therapies (SAC-RAT) Record of Proceedings – November 2, 2018

Committee members present:

Irvin Mayers (Chair), Donald Cockcroft, Eugenia Palylyk- Colwell, Sharon Dell, Myrna Dolovich, Murray Ducharme, Alan Kaplan, Larry Lynd, Darcy Marciniuk, Matthew Stanbrook, William Swan, Harissios Vliagoftis

Health Canada presenters:

Paul Wielowieyski, Robin Zhang

Health Canada staff:

Scott Appleton, Mark Bustard, Jatinderpal Raj Deol, Ian Dobson, Anna Edmison, Gail Grant, Jenna Griffiths, Despina Miteva, Stephanie Parra, Conrad Pereira, Carl Poulin, Bruce Randall, John Patrick Stewart, Susan Stojdl, Andrew Tam, Ajaykumar Thaker, Chantal Tremblay-Ruest, Emily Tung, Leslie Vrooman, Kevin Young, Jun Zhang

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 the scientific and regulatory requirements, particularly with respect to the use of pulmonary pharmacokinetic (PK) studies, for establishing bioequivalence of subsequent market entry orally inhaled products (OIPs) for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. For purposes of the discussion, OIPs were considered to include inhaled corticosteroids (ICS), long-acting beta2-adrenergic agonists (LABA), long-acting muscarinic antagonists (LAMA), and combinations thereof.

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 welcomed members and thanked them for participating in this meeting. He asked panel members to introduce themselves individually. There were no objections to the draft agenda and no declarations of affiliations or interests that required any restrictions on members’ participation. The Chair then reviewed the questions posed by Health Canada, which were to be the focus of the discussion.

Presentations 1 and 2 (available on request):

1. Presentation: Comparative Pulmonary PK and in vivo Bioequivalence of Orally Inhaled Drug Products, Paul Wielowieyski, Bureau of Pharmaceutical Sciences

The presentation provided a brief overview of disposition characteristics of orally inhaled drugs in the lungs, with a view to establishing the relevance of PK comparison of OIPs. This was followed by a discussion of therapeutic equivalence and an overview of regulatory approaches of the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA), including the US FDA’s aggregated weight-of-evidence approach to establishing bioequivalence and the EMA’s step-wise approach to establishing therapeutic equivalence. Two objectives of PK studies of OIPs were presented: Systemic PK studies, as a surrogate for safety and Pulmonary PK studies as a marker of pulmonary deposition (for comparative efficacy). The presentation concluded by reiterating questions posed to the committee.

2. Presentation: Quality Considerations of Generic Inhalation Products (pMDIs and DPIs), Robin Zhang, Bureau of Pharmaceutical Sciences

The presentation provided a brief overview of existing guidelines and general quality requirements for OIPs. Some special considerations for subsequent-entry pulmonary metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) were also presented. These considerations related, for example, to qualitative and quantitative sameness of formulation, device attributes, physicochemical properties and in vitro performance, dose proportionality and use of a foreign-sourced reference product.

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

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

• Current and potential future regulatory approaches taken by other jurisdictions such as the EMA and the US FDA
• Requirements not only apply to subsequent market entry products but innovator products as well (e.g., line extensions, bridging studies, post-approval formulation changes)
• Extrapolation of equivalence decisions based on results of studies done in adults, to the pediatric population
• Extrapolation of equivalence decisions based on results of studies done in healthy adults, to various patient populations and whether it is biologically plausible to expect such extrapolation to be invalid
• Provision of clear information to the Provinces/Territories regarding the basis of equivalence decisions, to support their interchangeability decisions.
• Thoroughness of literature review in support of regulatory position
• Separation of observations due to product attributes from variability due to study subject variables
• Effect of device attributes on pharmacodynamics (PD)
• Relevance of clinical study conditions, for example the use of spacers, to labelled conditions of use or clinical practice guideline recommendations
• Ability to discriminate between drug product attributes using PK studies versus PD studies
• Relationship between drug concentrations in blood and concentrations at the site of action, and therefore the relationship between PK and PD
• Value of PD outcome measures, for example, forced expiratory volume (FEV1), in comparing OIPs
• Number of subjects required for a PD study
• Value and relevance of using charcoal block
• The dose-response relationship and its effect on detecting PD differences  

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:

Question 1:

Does the SAC-RAT have any concerns with the approval of subsequent entry OIPs and changes to or line extensions of innovator products on the basis of in vitro and PK data (efficacy: comparative pulmonary PK and safety: systemic PK)?

Recommendation:

In summarizing the discussion, the committee indicated that they would not be concerned about the assumption that pharmacokinetics reflects pharmacodynamics for drugs with reasonable systemic bioavailability from lung absorption. They would be concerned with drugs known to have low systemic bioavailability from lung absorption.

They would not be concerned if there is evidence to conclude that equivalence shown in PK studies in healthy adult subjects implies equivalence in various disease states and different age groups as is customarily done in the determination of bioequivalence. Although there does not appear to be enough evidence to definitively make this conclusion for OIPS, there is also no evidence, or biological plausibility, to the contrary.

There is evidence to conclude that pharmacokinetics will detect small variations in particle distribution that result in differences in lung absorption.

There was discussion that the sameness of the device would need to be shown in the target populations. The details of how sameness would be assessed, was not fully defined.

The majority of committee members concluded that it is acceptable to demonstrate the equivalence of a subsequent-entry orally inhaled product (including line extensions or changed innovator products) based on in vitro testing, including sameness of device, coupled with comparative PK study. It is not necessary to carry out pharmacodynamic or therapeutic equivalence comparisons in patient populations.

Question: 2

What should be taken into consideration with respect to the design and applicable standards of the comparative pulmonary PK studies?

Considerations for the design and standards of comparative pulmonary PK studies

1. Study design and considerations
   • Design: 2-way cross-over or replicate
   • Study population: healthy adult volunteers
   • Tested Strength
   • Charcoal Block: validation of the effectiveness for each API
     • when required i.e., when the contribution to concentration levels in the systemic circulation from the GI tract is not negligible
   • Time point selection
     • proper selection of early time points to reliably characterize very rapid rate of absorption (e.g. tmax ≤ 5 min)
   • Early bioavailability approach (truncated AUCs)
     • validated for each API and formulation, and will depend on particular PK characteristic of each API
2. Criteria for demonstration of bioequivalence:
   • AUCT: The 90% confidence interval of the relative mean AUCT of the test to reference product should be within 80.0-125.0%.
   • Cmax: The relative mean measured Cmax of the test to reference product should be within 80.0-125.0%.

These standards must be met on log transformed parameters calculated from the measured data.

Recommendation:

• In general, current Health Canada guidances and recommendations for bioequivalence studies, with respect to study design and bioequivalence standards, would be applicable to comparative pulmonary PK studies.
• Two-way crossover studies, under fasting conditions, should be done whenever possible.
• Studies may be carried out with healthy adult volunteers.
• The highest strength should be tested if the formulation is proportional across the range of strengths. All non-proportional strengths should be tested.
• In general, there does not appear to be a need to use charcoal block.
• Blood sampling should be timed to capture both lung absorption and absorption from the GI tract, where absorption is expected through both routes.
• Bioequivalence standards may be applied to (early) truncated area under the curve where this parameter has been shown to be appropriate based on the PK of the active ingredient and the formulation.
• It is not necessary to use a spacer in the PK study, unless the reference product labelling indicates that the product is to only be used with a spacer.

Next Steps

• Health Canada will proceed with development of a draft guidance, for stakeholder consultation, on requirements in comparative PK studies for subsequent-entry OIPs.
• A new topic, potentially for discussion at the next SAC-RAT meeting, was mentioned

Closing remarks / Adjournment (Chair)

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