Scientific Advisory Panel on Bioequivalence Requirements for Modified Release Dosage Forms (SAP-MRDF)

June 11, 2010

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact: Bureau of Policy, Science and International Programs Enquiries

Record of Proceedings

Therapeutic Products Directorate Note: Until such time as final recommendations are made and policy is developed and published, current bioequivalence requirements remain unchanged.

Panel members: Jake Thiessen (Chair), Robert Herman, Eugenia Palylyk-Colwell, John Parker, Philippe Robaey, Daniel Sitar

Presenters: Henning Blume, Shurjeel Choudhri, Murray Ducharme, Laszlo Endrenyi, Lily Hechtman, Dan Marshall, Joseph Massarella, Timothy Pollak, Russell Rackley, Arthur Straughn, James Swanson, Yu Chung Tsang

Health Canada staff: Andrew Adams, Scott Appleton, Kimby Barton, Harold Boudreau, Danielle Brule-Brown, Marilyn Davis, Christine Ficker, Larissa Lefebvre, Conrad Pereira, Cathy Petersen, Mary Raphael, Shagufta Sultan, Chantal Tremblay-Ruest, Lelsie Vrooman

The structure of this one-day workshop format was intended to allow for more direct stakeholder involvement and greater transparency in policy development. All stakeholders were invited to attend the presentations to the panel. Only two related questions were dealt with, in order to give adequate time to fully deliberate and address the issue. These questions were circulated and posted on Health Canada's website prior to the meeting so that they could be addressed in the presentations to the panel.

In the morning, accepted presenters made a series of short presentations to the panel. Panel members, and where time permitted, attendees, then posed questions to the presenters. In the afternoon, the SAP-MRDF deliberated in a closed meeting before making their final recommendations to Health Canada.

Morning Workshop - June 11, 2010

Welcome and Opening remarks (Ms. Barbara Sabourin)

The Senior Executive Director of the Therapeutic Products Directorate welcomed the expert panel members and various stakeholders representing industry (both innovator and generic pharmaceutical companies), academia, health professionals, patient interest groups, as well as several different levels of government. She explained the process to be used for the workshop, and thanked all the stakeholders for their time and willingness to make presentations and for sharing their expertise on this complex issue. She concluded by wishing them all a successful and productive meeting, and mentioned that comments on the day would be welcomed.

Chair's address (Dr. Jake Thiessen)

The Chair welcomed and thanked all the expert panel members for taking the time to participate in this very important meeting. He made some short introductory remarks regarding the issue at hand and advised the audience that he would be moderating the stakeholder presentations in the morning to ensure time-lines would be respected and all would have a chance to be heard and that panel members would have an opportunity for questions if necessary.

He explained that the afternoon in camera session would allow the members to consider what they had heard.  The focus of the deliberations would be on answering the two questions posed to them in order to make recommendations to Health Canada on the adequacy of current bioequivalence requirements for modified-release dosage forms.

Presentations

Note: * indicates that an electronic copy of the presentation is available upon request in both official languages.
** indicates that an electronic copy of the presentation is available upon request in English only.

1. Bioequivalence requirements for modified-release dosage forms (Dr. C. Pereira)*
2. [No title] Dr. J. Swanson**
3. Conventional bioequivalence criteria may not ensure clinical equivalence and, therefore, interchangeability for products with complex pharmacokinetic profiles (Dr. J. Massarella)**
4. Relationship between pharmacokinetic and clinical response for modified release methylphenidate formulations (Dr. A. Straughn)**
5. Bioequivalence criteria need to guarantee therapeutic equivalence (Dr. S. Choudhri)**
6. Bioequivalence (BE) regulations for MR products: necessity of single-dose fasted, food effect and multiple-dose studies (Dr. H. Blume)**
7. Mylan's nifedipine extended-release tablets, the generic equivalent to Adalat^® XL^® (Dr. R. Rackley)**
8. Scientific Advisory Panel on Bioequivalence Requirements for Modified-Release Dosage Forms (Dr. Y. Tsang)**
9. Are the current BE requirements for modified release dosage forms appropriate for all products? (Dr. M. Ducharme)**
10. Partial Area under the curve and other metrics for some modified-release drug products (Dr. L. Endrenyi)**
11. June 11, 2010 - Modified release formulations (Dr. T. Pollak)**
12. Modified release dosage format medications: clinical implications of current bioequivalence standards in Attention Deficit Hyperactivity Disorder treatment (Dr. D. Marshall)**
13. Concerns and recommendations regarding bioequivalence requirements for MRDFs (Dr. L. Hechtman)**

Workshop adjourned - Stakeholders leave

Afternoon Panel Deliberations - June 11, 2010

Affiliations and Interests Declarations (All members)

The Chair led the panel members in a short verbal declaration of Affiliations and Interests. He asked each member to briefly introduce themselves, and to stipulate if any changes had occurred since each had completed their written declaration as part of the membership requirements for this committee.

Upon completion of the declarations, it was unanimously agreed that all members could participate fully in the meeting and the Chair encouraged free and open discussion.

Deliberation on the questions posed (All members)

The questions posed by Health Canada were as follows:

1. Are current comparative bioavailability metrics and standards adequate for modified-release dosage forms?
2. If current metrics and standards are considered inadequate, what metrics and standards would you recommend and under what circumstances would they be applied? Proposals should be supported by scientific rationales and data.

The discussion covered a variety of points, such as:

• The evidence and supporting data presented by the stakeholders were not compelling in that no clear pharmacokinetic - pharmacodynamic relationship was shown between drug concentrations resulting from a specific release pattern and therapeutic response that would justify special bioequivalence standards for modified-release products.
• Dosing conversion instructions in the Concerta product monograph do not support the viewpoint that small differences in delivery rate and concentration are therapeutically important. For example, it is recommended that doses of the immediate release formulation of 5 milligram (mg) twice or three times per day or 20 mg sustained-release (10 - 20 mg/day), may be replaced by 18 mg Concerta once a day without any additional patient monitoring being required.
• If concentration nuances were very important, dosing would be done by weight and this is not the case for methylphenidate. It was, however, recognized that dosing by weight is difficult with growing children and dosage must be individualized.
• Any special bioequivalence criteria should take into consideration where on the concentration-response curve dosing is being done. A steep segment would be different than a shallow segment.
• The observed inter-subject variability was very high, making it more difficult to justify tighter standards.
• Reservations were expressed over adult (pharmacokinetic) information and data being used to justify results in pediatric patients.
• Claims of the importance of a unique modified drug delivery system should be supported by direct evidence that the specific timing of delivery of the drug is important for therapeutic response over the course of a dosing interval. Such claims should be described in the product monograph.
• Proof of principle studies are not compelling evidence. They are hypotheses generating and signal the need for further study to provide compelling evidence.
• Current bioequivalence standards are acceptable, with possible rare exceptions. While it is possible that for some drugs special bioequivalence standards may be necessary, currently there is insufficient evidence to support special standards for either methylphenidate or nifedipine. That is, there is no evidence that these two drugs are rare exceptions. While there may be some signals of special issues, it really falls to companies and investigators to produce definitive evidence.

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

Final recommendations (All members)

1. Are current comparative bioavailability metrics and standards adequate for modified-release dosage forms?

   Recommendation

   The current comparative metrics and standards are adequate, with rare exceptions, such as time sensitivity of drug release to elicit a therapeutically significant outcome.

   The evidence to support exceptions must be in the product monograph of the original product and changes in rate of drug delivery throughout the day must be reconciled with matching generally accepted and clinically relevant response data generated from a well designed randomized clinical trial program.

2. If current metrics and standards are considered inadequate, what metrics and standards would you recommend and under what circumstances would they be applied? Proposals should be supported by scientific rationales and data.

   Recommendation

   For the rare exceptions possible, the metrics and standards would need to be addressed on a case by case basis.

Closing remarks / Adjournment (Chair)

The Chair thanked the members for their participation.

Meeting adjourned

[Note: This record of proceedings was submitted and approved in English by the Chair of the SAP-MRDF.]