Record of Proceedings - March 29, 2011, Scientific Advisory Panel on Opioid Analgesic Abuse (SAP-OAA)

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Contact: Bureau of Policy, Science and International Programs Enquiries

Health Canada - Health Products and Food Branch (HPFB) Bilateral Meeting Program

Panel Members Present: Edward Sellers (Chair), Nady el-Guebaly, Andrea Furlan, Raimar Löbenberg (via teleconference), William Pryse-Phillips, Beth Sproule

Health Canada Representatives:

• Director General's Office: Supriya Sharma
• Office of Science: Isabel Brazeau, Colette Strnadova
• Bureau of Cardiology, Allergy and Neurological Sciences: Kimby N. Barton, Lisa Kelly, Cathy Petersen, Joanne Goh (via teleconference)
• Marketed Health Products Directorate: Tanja Kalajdzic, Lucye Galand

Observers:

• Linda Rheaume, Emile Geoffroy (Bureau of Cardiology, Allergy and Neurological Sciences [BCANS])
• Hanan Abramovici, Nathan J Isotalo (Healthy Environments and Consumer Safety Branch [HECSB])
• United States Food and Drug Administration (FDA) (via teleconference)

Acronyms used in this record:

• BCANS = Bureau of Cardiology, Allergy and Neurological Sciences
• CDSA = Controlled Drugs and Substances Act
• CMP = Canadian Product Monograph
• DAWN = Drug Abuse Warning Network (United States)
• FDA = Food and Drug Administration (United States)
• MAH = Market Authorisation Holder
• MHPD = Marketed Health Products Directorate
• NOUGG = National Opioid Use Guidelines Group
• OAA = Opioid Analgesic Abuse
• SAP = Scientific Advisory Panel
• USP = United State Pharmacopeia

1. Opening Remarks from Director General (S. Sharma, Therapeutic Products Directorate)

The Director General opened the meeting by welcoming the members. Dr. Sharma indicated that the members will be consulted on issues concerning safety and abuse of new formulations of prescription opioid analgesics. Specifically, the questions posed to the panels members will revolve around pre-market evidence requirements for the inclusion of tamper-resistance claims in the product monographs and on post-market risk management strategies for new and existing opioid drug products. Dr. Sharma thanked all Panel members for their time and effort in participating in this meeting and wished everyone good and productive discussions.

2. Opening Remarks and Welcome (E. Sellers - Chair of the SAP-OAA)

The Chair opened the meeting and welcomed the members on site and those participating via teleconference. Dr. Sellers invited the panel members and the meeting participants to introduce themselves.

3. Review of the Agenda and Conflict of Interest declaration

The agenda was accepted as established. It was noted that during the course of the meeting the agenda might be slightly altered to accommodate members' schedules.

Verbal Affiliations and Interest declarations were completed. Members were asked to disclose any conflicts that might arise as the meeting proceeded. No members had conflicts that would preclude their participation.

4. Review and acceptance of the Terms of Reference

The members accepted the Terms of Reference by signing an acceptance form.

Dr. Löbenberg joined the meeting via teleconference.

5. Presentation from the Bureau of Cardiology, Allergy and Neurological Sciences

(L. Kelly, BCANS)

Health Canada made a short presentation to give background information to the panel members for the deliberations to follow.

Additional informative material was distributed to the panel members (FDA Epidemiology Advisory Committee Meeting - Clinical review of Purdue and Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee.) This information was discussed during the presentation.

The presentation is available upon request.

Before starting the discussion, the Panel members sought clarification from the working group members on the questions and on Health Canada's regulatory processes (for example [e.g.], update of the Canadian Product Monograph [CPM].)

Question 1

Regarding the pre-market data in support of the characteristics of the product:

a) Based on your knowledge and experience in the field of opioid abuse, and the current status regarding pertinent study designs (as per the background package), what are the Panel's thoughts on the pre-market evidence requirements for endorsement of the facts about the tamper-resistance characteristics of the product?

The Panel members noted the importance of taking into consideration the characteristics of a product that can deter abuse or confer tamper resistance. They felt it would be helpful to the prescribing physician to know the physical characteristics of the product that led to its purported tamper resistance. The impact on the pattern of abuse could be different depending on the drug in question. As an example, the panel members mentioned Immediate Release (IR) formulations versus Extended Release (ER) formulations.

The Panel members concluded that the basic pre-market evidence requirements for the endorsement of tamper-resistance characteristics of products with a potential for abuse should be:

1. Description of the product
   • Chemistry, manufacturing, pharmacokinetic and pharmacodynamic properties of the products
2. Comprehensive and appropriate in vitro studies to demonstrate the properties of a tamper-resistant product
   • For example: extractability, dissolution, etc.
3. Clinical laboratory studies to support the in vitro data and to assess the potential of abuse of the drug in its tampered and non-tampered state (demonstrate the tamper-resistance properties)
   • Studies should be performed with recreational drug users
4. Comparative studies with regular and tamper-resistant products
   • Studies performed with consumers to document what they would do with the product, how they would alter it and which product they would choose (preferred product)
5. Data regarding abuse in other countries should also be evaluated

The panel members noted that it is difficult to establish a threshold for each evidence requirement because opioids are all different. However, they did suggest that perhaps different levels could be established based on what data had been collected.

b) Based on your experience of the impact of prescribing information on the various affected communities (e.g., physicians, patients, addicts), do you think it is reasonable that Canadian Product Monographs (CPMs) carry similar language regarding pre-market data, to that found in the examples from pertinent United States Prescribing Information?

The panel members agreed that is would be reasonable and acceptable to include a scientific statement regarding the tamper-resistance of a product in the Canadian Product Monograph (CPM) or even on the label. However, the statement should not be presented as a claim regarding decreased abuse liability.

Question 2

Regarding the post-market data regarding real-world benefits of the product:

a) Given that Canada does not currently have in place the various national systems that the United States has for collection of relevant post-market data (e.g., rates of emergency room or medical examiner mentions from the Drug Abuse Warning Network (DAWN), as per background package), is it conceptually reasonable to accept United States data as the basis for a Canadian claim of demonstrated real-world benefit in reduction of addiction harm?

The Panel members concluded that it is reasonable to accept United States data. They also noted that any good data from foreign sources (e.g., European studies) are worth evaluating. However, relevance to the Canadian population should be taken into consideration and United States and foreign data should be, as much as possible, a supplement to Canadian data: foreign data should not be the only source of information.

b) Regardless of whether the post-market database is United States or Canadian, there must be a consistent bar established for Health Canada endorsement of a claim regarding real-world consequences of the tamper-resistance characteristics. Based on your knowledge and experience in field of opioid abuse, and on the current status of measures and databases currently available (as per the background package), what are the Panel's thoughts on the evidence requirements for endorsement of the possible real-world consequences of the tamper-resistance characteristics, in terms of reduction in abuse-related harms?

The Panel members expressed concerns about having an explicit claim about tamper-resistance (abuse deterrence) within the CPM. They suggested that the tamper-resistance characteristics of a product should be presented as a factual statement in the CPM, rather than as a claim. In addition, it was noted that likely only one or two manufacturers would have a substantial enough amount of patient data to be able to demonstrate any decrease in abuse with a new formulation. The Panel members noted that it would be impossible for smaller manufacturers of drugs that are new to the market to provide evidence of decreased abuse, as they would have no historic baseline against which to measure.

c) If the Panel feels that United States data are not an acceptable basis for a Canadian claim regarding reduction of real-world abuse-related harm, what are your thoughts on establishing Canadian databases?

The Panel members previously concluded that is was acceptable to use United States data. They felt that Health Canada could benefit from promoting the creation of a widely available framework to coordinate efforts and to share foreign data.

Health Canada was advised to collaborate with the United States Pharmacopeia (USP) to promote standardised methodology for in vitro testing of tamper resistant products).

Question 3

Regarding potential claims from post-market data in support of real-world benefits of the product's characteristics:

Currently, there is no precedent, in either the United States or the European Union, for the step of translating a demonstrated decrease in real-world, abuse-related harm into an actual claim in the prescribing information (e.g., wording in the indication).

a) What are the advantages and disadvantages of allowing such a claim (that is [i.e.], reduction in real-life, abuse-related harm) to appear in the Product Monograph, given that the target audience is the prescribing clinician and/or the patient who is taking the medicine for pain management? Are there other fora that are better suited for claims about mitigation measures aimed at abusers of the drug, rather than patients using the drug for treating pain?

The Panel members wanted to clarify the wording of the questions by explaining that the population of prescription drug abusers is very heterogenous and that all types of people could abuse these medications, including people with pain. Therefore, the mitigation measures aimed at abusers of the drug include also people with pain.

The Panel members agreed that the CPM should communicate scientific facts and describe how the product is intended to be used, for both the prescriber and the patient. Statements concerning reduction in real-world abuse liability do not belong in the CPM. The Panel felt this may be useful information, but the CPM is not the best place for it. There are other venues where that information could be communicated.

The Panel members reiterated that abuse-deterrent characteristics should be documented within the CPM, and should appear as scientific statements rather than as claims.

b) If the Panel agrees that such claims should appear in the Canadian Product Monograph, what are your thoughts on the optimal language for such claims?

The Panel members advised Health Canada that such claims should not be allowed in the CPM.

To conclude the morning session, the Panel members agreed that no claims regarding reduction in abuse of a product should be allowed in the CPM. They noted that such information could be included in the CPM as a scientific statement only. The Panel members also noted that having new tamper-resistant formulations on the market will generate a lot of scientific data. These data (e.g., results of in vitro and in vivo studies and comparative studies) could be summarised, but not explicitly stated in the CPM. The Panel members agreed that the product monographs should contain information such as the indication of the product, how it is meant to be used and update on adverse events and safety information. However, explicit results of in vitro and in vivo studies and comparative studies should not be included in the CPM.

6. Presentation from the Marketed Health Products Directorate

(T. Kalajdzic, MHPD)

Health Canada made a short presentation to give background information to the panel members for the second portion of the discussions.

The presentation is available upon request.

During and after the presentation, the Panel members sought clarifications from the working group members with regards to the information that was presented and the questions to be posed.

Question 4

How to improve current approaches to monitoring and assessing the risks associated with opioid abuse in Canada.

a) In the context of current safety surveillance activities in Canada, what other methods could be used by the Market Authorisation Holders (MAH) that would be considered effective by the panel for the monitoring of the real-time abuse and off label use (e.g., in pediatrics) of opioids in Canada?

The Panel members discussed the different programs and databases established in several provinces across Canada. They also discussed the monitoring situation in other countries.

The Panel members agreed that patient registries and prescription monitoring programs would be useful in monitoring abuse in the post-market setting. As examples of monitoring sources, they noted: admission data to addictions facilities, emergency room statistics, records of physicians' prescribing habits and records of "double doctoring" (patients' visiting multiple doctors to get prescriptions). The Panel members discussed the need to evaluate the effectiveness of monitoring programs in achieving the goals of reducing abuse. They also noted that medication guides, lock boxes, and pill counts may also be useful tools for minimizing the risks.

During the discussions, a Panel member made a reference to the National Opioid Use Guidelines Group (NOUGG), which produced a document entitled Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain. These Guidelines give specific information on opioids and their classes. For example, the guidelines address topics such as storage information, patients' responsibilities, prescribing information, etc. The Panel member noted that the NOUGG received absolutely no funding from the pharmaceutical industry and that it was a non-biased source of information.

b) How could these methods be adapted to provide information on the time trends (i.e., changes in the abuse pattern over time)?

The representative from the Healthy Environment and Consumer Safety Branch gave an overview of the Controlled Drugs and Substances Act (CDSA). The Panel members agreed that a drug regulated under CDSA would receive sufficient monitoring through CDSA Scheduling.

c) What guidance should be provided to the MAHs regarding the optimal design of comparative studies (when these are deemed necessary for regulatory purposes)?

The Panel members made reference to existing and evolving electronic databases, in which records could be analysed and compared. A National strategy would certainly be required, especially to allow linking studies.

Question 5

In the current context, how could the existing risk-minimisation approaches be optimised?

a) What other risk management strategies do you recommend Health Canada to consider in order to mitigate the potential risks associated with these products?

The Panel members noted that several opioids are currently on the Canadian market. They suggested that Health Canada encourage the manufacturers planning to introduce new opioids on the Canadian market make the products less crushable and less abusable that the comparable (equivalent) already on the market. Health Canada pointed out that as of yet, no "tamper-resistant" formulation has been definitively demonstrated to reduce drug abuse, and therefore it would be difficult to make tamper resistance a regulatory requirement moving forward.

b) Should the proposed risk-minimisation approaches be standardized across the entire class (i.e., opioids)?

The Panel members noted that general risk-minimisation approaches could help address product-specific issues; however, risk-minimisation strategies need to be customized on a case-by-case basis to address the problems identified with particular products.

c) What methods do the panel recommend to assess the effectiveness of the risk-minimisation approaches?

The Panel members recognised the importance of:

• electronic databases;
• registries;
• promoting collaboration (e.g., Federal/Provincial initiatives);
• supporting community-based initiatives;
• revising the regulations to improve and extend regulatory authority.

The Panel members noted that the Inflexxion, NaviPro System is an excellent tool. Unfortunately, there is currently no framework available to incorporate systems like this, unless there is a Federal/Provincial initiative to give it a higher political importance.

d) What is the threshold for increasing the intensity of the risk-minimisation tools?

The Panel members did not recommend any threshold for increasing the intensity of the risk-minimisation tools. They recognized the difficulty of implementing risk-minimisation in Canada and the limited armamentarium of tools available for this purpose.

To conclude this last portion of the meeting, the Panel members encouraged Health Canada to promote and expand their regulatory authority to impose post-marketing risk assessment and mitigation strategies upon stakeholders. However, the Panel recognised that Health Canada might be limited by their mandate and by political and legislative considerations. Health Canada was encouraged to focus on those risk-minimisation strategies that are within their jurisdiction.

7. Next Steps, Closing Remarks, and Adjournment of Meeting

Committee members were thanked for their valuable time. The Panel members and Health Canada representatives concluded that the discussion had been very productive and that there would be no need for a second meeting.

Meeting adjourned.