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

Record of Proceedings

October 26, 2012

Committee Members Present:

Irvin Mayers (Chair), Don Cockcroft, Myrna Dolovich, William Racz, Matthew Stanbrook, William Swan, Harissios Vliagoftis

Regrets:

Parameswaran Nair, Susan Waserman

Participants from the Scientific Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology Present:

Kwok Chow, Elizabeth Vadas

Health Canada Representatives:

Director General's Office: Barbara Sabourin
Office of Business Transformation:Erica Harnett, Caroline Hunt
Bureau of Policy, Science and International Programs: Bob Li, Eric Ormsby, Conrad Pereira
Bureau of Cardiology, Allergy and Neurological Sciences: Kimby Barton, Gail Grant, Dominique Heon, Ajaykumar Thaker, Violina Thomas
Bureau of Pharmaceutical Sciences: Mark Bustard, Stéphanie Parra, Craig Simon

Acronyms used in this record:

BPS:

Bureau of Pharmaceutical Sciences

DGO:

Director General's Office

FDA:

United States Food and Drug Administration

MDI:

Metered dose inhaler

PK:

Pharmacokinetic

SAC-PSCP:

Pharmaceutical Sciences and Clinical Pharmacology

SAC-RAT:

Scientific Advisory Committee on Respiratory and Allergy Therapies

SME:

Subsequent market entry

Opening Remarks (Barbara Sabourin, DGO)
Barbara Sabourin, Director General of the Therapeutic Products Directorate at Health Canada opened the meeting by welcoming the participants and thanking them for their time and effort. Ms. Sabourin also mentioned that members of Health Canada's scientific advisory committees are often called upon to serve on other important consultations for the Directorate. She then introduced the new core SAC-RAT member, Dr. Harissios Vliagoftis, as well as two members of the Scientific Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology (SAC-PSCP), Drs. Kwok Chow and Elizabeth Vadas, whose expertise in pharmaceutical formulations were deemed critical to the discussions.

Introductions, Affiliations and Interests Declaration (Irvin Mayers, Chair)
The Chair led the committee in round-table introductions. Members introduced themselves, provided brief summaries of their backgrounds and indicated any potential conflicts of interest.  No conflicts were identified and all members were allowed to participate fully in the discussions.

Introduction of issues (Craig Simon, BPS)
Dr. Simon from the Division of Biopharmaceutics Evaluation within the Bureau of Pharmaceutical Sciences provided an overview of the issue which the committee discussed.  Specifically, Dr. Simon indicated that BPS had reviewed an application for a subsequent market entry (SME) budesonide suspension for inhalation using a suitable nebulizer. He reported that this was the first application for a product of such a unique nature, whereby the sponsor proposed an alternate approach for the determination of bioequivalence for this product; namely that extensive in vitro data rather than in vivo data be used. The Bureau of Pharmaceutical Sciences was seeking the committee's recommendations on the appropriateness of this approach in the approval of this specific product due to its unique formulation, packaging and delivery characteristics. This approach was described in the United States Food and Drug Administration's (FDA) response to AstraZeneca's Citizen's Petition^{Footnote 1}, which was provided to the members in advance of the meeting.

The committee members discussed several items with Dr. Simon as follows:

• The uniqueness of this product: Many nebulizer products are solutions rather than suspensions. The composition of this particular suspension is simpler compared to other pharmaceutical suspensions in that the only ingredient that is not fully dissolved is the active pharmaceutical ingredient. Further, this suspension requires the use of a nebulizer for administration. The nebulizer is not included as part of the product itself, nor is a particular brand of nebulizer specified for use with this budesonide suspension. Instead, the patient or health care provider may select and use any appropriate air driven jet nebulizer (see package insert), with the exception of ultrasonic nebulizers. It is well known that the efficacy of the drug product can be influenced by the performance characteristics of the nebulizer selected (efficiency of delivery of aerosol (emitted dose of drug and respirable fraction of the aerosol)).
• Health Canada regulations and in vitro data for bioequivalence testing: Health Canada regulations with respect to SME drugs allow for the approval of these drugs and a declaration of their equivalence based on in vitro testing (pharmaceutical properties) alone. It is not always necessary to have clinical studies. This is the current Health Canada practice for solutions.
• This is a precedent setting product: This is the first application for a suspension for inhalation that is to be administered via a nebulizer.
• The number of nebulizers to be used as part of the in vitro tests: As currently, presented in the FDA's response to AstraZeneca's Citizen's Petition1, a single brand of nebulizer is to be used for all the testing. Requesting that testing be conducted with more than one brand of nebulizer is a possibility for Health Canada.
• Characteristics of different nebulizers:
  • Different brands of nebulizers may not produce the same droplet size. Further, newer nebulizer products have higher drug delivery capabilities than older, disposable nebulizers. In fact, the newer nebulizers may be upwards of 60-70% more efficient. When either using a newer nebulizer delivery device or switching between nebulizers, calculations/dose titrations need to be conducted in order to equalize the drug delivered to that of the innovator suspension product/nebulizer delivery system.
  • Most marketed nebulizers are based on two technologies; jet nebulizers use an airstream, while ultrasonic nebulizers use vibrational energy.
• The qualitative and quantitative identicality: The generic and the innovator products will have the same salt. The excipients must be qualitatively identical and quantitatively very similar.

The following questions were posed and deliberated by the participants. Each is followed by the committee's final recommendations to Health Canada.

1. Is the in-vitro data package, as described in the FDA's November 18, 2008 response to AstraZeneca's Citizen's Petition^{Footnote 1} (pp. 22-23), adequate in lieu of clinical data to demonstrate bioequivalence of such a drug product?

   The committee members agreed that the in vitro data package described by the FDA in their response to AstraZeneca's Citizen's Petition^{Footnote 1} is potentially acceptable. It is possible to approve this budesonide suspension for inhalation using a nebulizer as a SME drug provided it meets stringent physical and chemical criteria such that pharmaceutical equivalence is shown. This would be in keeping with similar approaches in place at Health Canada for use with other types of products (example: solutions). Members further suggested that additional in vitro tests of both available strengths of the budesonide suspension must be conducted. Further, in vitro tests of the suspension using additional brand of nebulizers should also be conducted. Members agreed that these tests should be conducted using the same brand of nebulizers as used by the innovator (that is (i.e.) the same brand of jet nebulizer as specified in their new drug submission) as well as a vibrating mesh nebulizer or a micropump nebulizer. In addition, all dose strengths should be tested with all specified nebulizers. When testing the SME drug with a different nebulizer delivery device, calculations/dose titrations will need to be specified in the package insert in order to equalize the drug delivered to the innovator suspension product/nebulizer delivery system.

   By contrast, the members did express some unease in approving a drug that had not been tested clinically, particularly since this drug would be used to treat a pediatric population. It was agreed, however, that a clinical trial may not be feasible in the intended population for scientific and ethical reasons. Further, it was concluded that a clinical trial of this product may be influenced by considerable variability making it difficult to observe a difference. Pharmacokinetic (PK) studies may be possible and may provide additional insight regarding the drug's dissolution at the lung; however, members could not provide a strong rationale to support conducting these studies or pharmacodynamics studies. Ultimately, it was concluded that concepts which are generally used for inhalation solutions would, simply, now be extended to include inhalation suspensions and approvals based on the in vitro performance of the product.

   Members also felt very strongly that this particular budesonide suspension for inhalation using a nebulizer is a uniquely different product and that decisions made for this product should not influence future decisions for other products like metered dose inhalers (MDI) or dry power inhalers.

   Prior to arriving at this recommendation, the committee discussed several topics including the following:

   • Rate of dissolution;
   • Particle size;
   • Narrow target population;
   • Consistency of SAC-RAT recommendations;
   • Differences from MDIs;
   • Drug approvals based on pharmaceutical evidence alone at Health Canada;
   • Drug delivery using a nebulizer and the associated variability;
   • Algorithm to be followed in the event in vitro testing fails;
   • Lung exposure, systemic bioavailability and PK measurements;
   • The in vitro tests proposed by the sponsor (and described in the FDA's response to the Citizen's Petition).

   Since members agreed that the in vitro data package was acceptable in question (a), recommendations in response to the following questions were not necessary.

2. If not, are there additional in-vitro tests that would render the in-vitro data package adequate in lieu of clinical data to demonstrate bioequivalence of such a drug product?
3. If it is recommended that an in-vitro data package is not adequate in lieu of clinical data, please provide an explanation detailing the reasons why it is not adequate.

Next Steps, Closing Remarks, and Adjournment of Meeting
Committee members were thanked for their valuable time, productive discussions and recommendations.

Meeting was adjourned.

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