Therapeutic Products Directorate Scientific Advisory Committee on Nonprescription Drugs (SAC-NPD) - Record of Proceedings

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November 16, 2012

Committee Members (present): Larry Lynd (Chair), Roberta Albert, Carole Bouchard, Bruce Cran, Dennis Gorecki, Margaret McQuaid, Shelley Stepanuik, Jeff Taylor, John Weber

Committee Members (by teleconference): Michael Rieder

Regrets: Jeannine Matte, Ruth Wilson

Health Canada Representatives:

• Director General's Office: Barbara J. Sabourin
• Bureau of Policy, Science and International Programs: Moira Messenger, Thea Mueller, Eric Ormsby
• Office of Business Transformation: Erica Harnett, Caroline Hunt
• Bureau of Gastroenterology, Infections and Viral Diseases: Jacques Bouchard,Susanne Geertsen, Taiwo Womiloju
• Marketed Health Products Directorate: Luna Al-Khalili, Margaret Zimmermann
• Natural Health Products Directorate: Shalini Dammous,Michael Steller

Observers: see Appendix I

Acronyms used in this record:

AU

Actual use

BPSIP

Bureau of Policy, Science and International Programs

HPFB

Health Products and Food Branch

LASA

Look-Alike Sound-Alike

LC

Label comprehension

MHRA

Medicines and Healthcare products Regulatory Agency

NCE

New Chemical Entity

NDED

Nonprescription Drug Evaluation Division

NHP

Natural Health Product

NPD

Nonprescription drug

OTC

Over-the-counter (nonprescription)

RCC

Regulatory Cooperation Council

Rx

Prescription

SAC

Scientific Advisory Committee

SS

Self-selection

TGA

Therapeutic Goods Administration

TPD

Therapeutic Products Directorate

US

United States

Welcome

The SAC-NPD Chair, Dr. Larry Lynd, welcomed members and brought the meeting to a start.

Opening Remarks

The Director General of the Therapeutic Products Directorate (TPD), Barbara J. Sabourin, opened the meeting by welcoming the members and thanking them for their time and effort in preparing for and participating in, this meeting. She reminded all in attendance of the importance of the SAC-NPD's recommendations to Health Canada's regulatory review and decision-making processes. She also reminded the members that the TPD's Observer Protocol would be piloted at this meeting; however, only one individual requested and was granted Observer Status.

Ms. Sabourin also provided an update on several items currently ongoing at Health Canada:

1. Schedule F - As announced as part of the Jobs, Growth and Long-term Prosperity Act (Bill C-38), there will be changes to Schedule F. To operationalize the changes, amendments to the Food and Drug Regulations are now required.
2. Cooperation with other jurisdictions - Two examples of where Health Canada is collaborating internationally:
   1. Regulatory Cooperation Council (RCC) - This is an initiative with the United States Food and Drug Administration. As part of the RCC, the Bureau of Gastroenterology, Infection and Viral Diseases (BGIVD) have been involved in determining the common elements of a monograph for a nonprescription drug.
   2. Regulatory Cooperation Initiative - This is an initiative with the Therapeutic Goods Administration (TGA) from Australia. The TGA is working to create monographs for over-the-counter (OTC)/nonprescription products and is collaborating with Health Canada on two specific monographs. It is expected that these monographs will be posted soon.
3. Regulatory Roadmap - This recent publication outlines the Health Products and Food Branch's (HPFB) framework regarding the regulations that need to be renewed and establishes the principles for the Branch.

Ms. Sabourin concluded by wishing everyone good and productive discussions.

Review of the Agenda, Affiliations and Interests Declaration

The Chair reviewed the agenda items with the committee indicating which sessions external observers would be present. An additional item was added to the closed portion of the agenda regarding an overview of the changes to Schedule F.

The Chair led the committee in declarations of Affiliations and Interests. Members did not disclose any new potential conflicts and all committee members therefore participated fully in the meeting.

Review of previous recommendations

Taiwo Womiloju of the Nonprescription Drug Evaluation Division (NDED) provided a brief summary of how the recommendations from the previous meeting were used by Health Canada. Previously, the committee recommended that a time-interval be specified on the label for a wash and leave-on lotion, both containing benzoyl peroxide, co-packaged for acne treatment. Ms. Womiloju reported that this recommendation has, to date, been implemented for two submissions reviewed by the NDED. There are additional submissions for co-packaged products of salicylic acid and Benzoyl Peroxide products for which this recommendation will likely also be used.

The external observer, who also asked to present perspective on consumer health product switches in Canada, was welcomed into the meeting room.

Introduction of the issue - Draft Guidance of Switch Submissions including data and labeling requirements

Dr. Thea Mueller from the Bureau of Policy, Science and International Programs (BPSIP) provided a brief overview of the guidance document on switch submissions that TPD has drafted. Members were provided a copy of this guidance in advance of the meeting.

In addition to feedback on the draft guidance, TPD was also seeking the committee's input on the possible implementation of benefit-risk assessment model. Such a model, in particular that proposed by Brass et al (2011)^{Footnote 1}, has been suggested to Health Canada by industry associations. An important consideration, which was conveyed to the members for consideration, was that Health Canada is constrained by the Food and Drug Regulations to conduct only efficacy evaluations on the potential benefits of the drug and not economic benefits.

Following Dr. Mueller's summary, members inquired as to the details of a New Chemical Entity (NCE) switch, which was described in the draft guidance document. It was noted that a NCE was no different than a brand new product and may be treated under the New Drug Submission guidelines; however, consumer studies would also be required for these products. It was indicated that the inclusion of this type of submission (a NCE submitted under a New Drug Submission) is still under debate.

Opportunities for Switch - Presentation by Consumer Health Products Canada

Mr. Robert White from Consumer Health Products Canada gave a brief presentation to the committee members. This presentation summarized benefit-risk assessment and decision analysis tools. As well, Mr. White provided members with background information on possible switch submissions that may be considered globally over the next decade.

An electronic copy of this presentation is available upon request in English only.

Questions and Answers

Many opinions and questions were raised by various members of the group. Some of the questions were directed to Mr. White and Dr. Thea Mueller, for which responses were given.

The external observer left the meeting room.

Changes to Schedule F

Barbara J. Sabourin, the Director General of TPD and Moira Messenger, Policy Analyst, from BPSIP provided further details on the changes to Schedule F. Namely, they reported that the regulatory part of the process for Schedule F would be replaced by an administrative process and the schedule in the regulations an administrative list which will be maintained on Health Canada's website.

This project involves three tracks:

1. Regulations - Amendments to the Food and Drug Regulation are under development. These will follow the usual process and will be posted in the Canada Gazette with an associated consultation period. The amendments are required to replace the current scheduling process with an administrative process. The amendments will also include the principles that are considered in determining if a product should be sold pursuant to a prescription.
2. Guidance Documents - The new guidance documents will describe, in more detail, the principles and their associated factors for "Schedule F". These factors are largely, and fundamentally, the same as those which have been in use for decades.
3. Operational - The list will no longer be part of the regulations and, instead, will be maintained on Health Canada's website. The content will be relatively unchanged from the current list and will be an ingredient-based list. The format of the proposed prescription drug list will be different than the current Schedule F; the new list will include the drugs and classes of drugs divided into a more user-friendly format with a section for human use and one for veterinary use.

Ultimately, the new list will be the same as the previous list; however, the process will become more efficient (red tape reduction). The new list will be incorporated by reference into the new regulations such that all enforcement work remains supported by the regulations. As well, there are no changes to the scientific assessment of these drugs.

The name of the new list has not been determined. Members suggested that the list not be called The Prescription Drugs List.

The committee members asked to be notified when the new information was posted to Canada Gazette I for comments. Members were encouraged to comment. Further, if major issues were noted by members, they were asked to notify the Secretariat such that these issues could, potentially, be discussed a future SAC-NPD meeting.

Deliberation of Questions to the Committee regarding the draft Guidance document on Switch Submission

The below questions were posed and deliberated by the SAC-NPD members. Each is followed by the panel's final recommendations to Health Canada.
Prior to commenting on the questions, Dr. Jacques Bouchard of BGIVD described the types of products that are typically switched from Rx to OTC. Namely, these are products that have recently come off patent or will be off-patent soon. In some cases, a switch submission may contain only published data that has been obtained through other regulatory agencies.

1. Does the committee have any recommendations regarding the minimum success criteria (threshold) that must be achieved in these studies [consumer use studies: label comprehension (LC), self-selection (SS) and actual use (AU)]:
   1. for primary communication objectives/endpoints

      The committee members were not in favour of recommending a threshold to be applied to all products. As a guideline, the Committee agreed that a 90% target might be an appropriate goal, acknowledging that this target should be flexible and could vary depending on the product, the target population, the endpoint and the associated risk. It was also suggested, however, that these thresholds could be identified in a pre-submission meeting with Health Canada. However, many consumer use studies are conducted in other countries, making it difficult for Health Canada to critically analyze the results in the context of the Canadian Non-Rx environment. For this reason, members also discussed whether there should be a requirement for Canadian consumer use studies. Members suggested that the requirement for a Canadian study be established at a pre-submission meeting.

      Members also indicated that Canadian studies may be particularly important to address issues that are germane to the Canadian context, including the provincial formularies. Data from foreign studies may be acceptable provided the populations are comparable; specifically, literacy rates should be similar to those in Canada.

      Members identified the following items which might trigger the need for Canadian-specific data:

      • The drug is first in class to be switched
      • The drug is proposed for use in a new target population (exempli gratia(e.g.) pediatrics)
   2. for secondary communication objectives/endpoints

      Members agreed that secondary communication objectives/endpoints generally would not be required to attain the same threshold as the primary communication objectives/endpoints. Instead, there should be an evaluation of secondary outcomes that are deemed important for a particular product. This is in keeping with the draft guidance document which states:

      "Label comprehension (LC) studies may address secondary communication objectives that are less critical to the safe and appropriate use of the drug such as recommended life-style changes. Pre-specified threshold levels do not need to be defined for these types of objectives."

2. Does the committee have any recommendations as to which communication objectives should be assessed as primary endpoints versus secondary endpoints in these studies ((e.g., dosage and administration (how to use this medication properly); contraindications (when not to use this medication); drug interactions; side effects (when to consult a physician)..... et cetera (etc)).

   The committee members suggested the following items as primary endpoints:

   • Primary indications;
   • Contraindications (who should definitely not use this product);
   • Dosage regimen (how to use, when to take, when not to take, how much to take, how long to take);
   • Common side effects and when to seek professional care.

   The committee members agreed that primary endpoints should:

   1. be product specific; and
   2. take precedent over the secondary endpoints.
3. Does the committee have any recommendations as to how to proceed if most but not all key messages/communication objectives are successfully met? Is it sufficient for the sponsor to revise labeling in an attempt to clarify statements on the label (id est (i.e.) with an assumption the revised text will be better understood) or does the committee recommend that Health Canada require the sponsor to conduct an additional study to test the revised label?

   In the event that most but not all, key messages/communication objectives are met, members suggested that an assessment on how to proceed should be done on a case-by-case basis. Furthermore, if there is a deficiency in the comprehension of any of the above-listed four primary endpoints in an LC or SS study, and the label was revised, members recommended that a second study be required to ascertain whether the changes are adequate. A second study would not be expected if a compelling rationale were provided to explain why such a study would not be needed.

4. Should LC and SS studies be based exclusively on the exterior package labeling or should they also be based on the package inserts (e.g, Part III of the Product Monograph in the case of Canadian products)?

   The committee recommended that these studies be conducted using both the exterior package labeling and the package inserts.

5. For Actual Use (AU) studies, does the committee have any recommendations regarding the minimum acceptable level of compliance with directions for use? Should the same level of compliance apply to all at-risk subgroups including those with low literacy? Please consider the following areas of compliance with dosage and administration instructions when answering:
   1. appropriate use (e.g. they don't meet any contraindications or are taking other medications which may interact with the product...etc);
   2. dose (e.g. number of pills/dose);
   3. frequency of dosing (e.g. number of doses per day);
   4. duration of use.

   While the desire of the committee was to establish a threshold, all agreed that a minimum level of compliance with directions for use could not be specified. There is currently no available data to support the selection of a specific threshold. Thus, any mandated threshold would be arbitrary. This may change in the future as more data become available.

   Members also discussed the possibility that compliance rates may be lower for AU studies than for LC or SS studies, particularly in certain subgroups (e.g., low literacy).

6. Given the current differences in the information provided on exterior package labels in the United States and Canada, are United States (US) based consumer studies acceptable for:
   1. Label Comprehension studies?
   2. Self-Selection Studies?
   3. Actual Use Studies?

   Or should Health Canada require that companies perform these studies (some / all) in Canada with Canada specific labels?

   The committee discussed not only studies from the US, but also international studies. Members agreed that Canadian studies would be required if the labeling information differs from what would be available to a Canadian patient. A decision on the acceptability of data from a foreign country would depend on whether the study was representative of the Canadian environment.

   Members also agreed that, in the event there were data from Canadian LC and SS studies, with international AU data, the need for a Canadian AU study might be less important. However, it may depend on the country of origin of the AU study being reviewed, since these data will reflect the labeling and SS habits of that particular country.

   The committee acknowledged that the packaging is often different for the same product when marketed in Canada versus in the US. For this reason, it was suggested that the two labels be directly compared prior to determining whether Canadian-specific studies are required.

   If the information listed on the exterior package does not cover all that which is included in the package insert, additional (Canadian-specific) SS studies should be required. The messaging on the exterior of the box is crucial for SS and should accurately reflect key information that is included on the package insert. Furthermore, Health Canada may consider requesting that additional information be moved from the package insert to the exterior packaging, acknowledging that this may be difficult with space restrictions and the need for information to be printed in both official languages. Additional factors to consider in this context is that often generic drugs do not have a package insert and that some older products were approved when package inserts were not required.

7. It has been recommended that TPD adopt the benefit-risk model proposed by Brass et al (2011)^{Footnote 1}. Please comment on the applicability of this model when making decisions to reclassify a product from prescription to nonprescription status. Of particular interest is the suitability of the benefit domains that have been identified in this model. Are there other models that should be considered by TPD for inclusion in the switch guidance document?

   Committee members agreed that the Brass et al (2011)^{Footnote 1} benefit-risk model should be omitted from TPD's guidance document on switch submissions and should not, at this time, be adopted by Health Canada. Instead, it would not be unreasonable for sponsors to incorporate this type of model into their submissions should they wish to do so.

   The committee discussed that there were many possible benefit-risk models that could be used. In fact, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are considering including a model in to their new drug approval process. The Brass et al (2011)1 model was recommended to Health Canada by industry. This model has been adopted by the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom. It was noted however that the MHRA takes a different approach to Rx to OTC drug switches.

Prior to beginning discussions of the day's second topic, the committee members briefly discussed specific comments on the draft guidance. Members were encouraged to share their comments directly with the TPD via Dr. Thea Mueller.

Revised Guidance for Industry: Review of Drug Names for Look-Alike Sound-Alike (LASA) Attributes - Presentation

Mrs. Margaret Zimmermann from the Marketed Health Products Directorate gave a brief presentation to the committee members. This presentation summarized the contents of the revised guidance for industry on the review of drug names for LASA attributes.

The following were discussed during and following the presentation:

• The revised guidance document includes information on the review of Rx drug names for LASA attributes. Natural Health Products (NHPs) are not included in this revision. The committee members agreed that the NHPs are technically OTC drugs and were disappointed about their exclusion from this guidance. Members acknowledged that, in practice, there is confusion with these products as well.
• Confusion exists regarding abbreviations (e.g., Benylyn DM). Products currently on the market will not need to be changed. Instead, the revised guidance will be applied for new products such that a new abbreviation may not be permitted.

An electronic copy of this presentation is available upon request in both official languages.

Deliberation of Questions to the Committee regarding the revised draft Guidance for Industry for Look-Alike-sound-alike (LASA) attributes and product line extensions

The below questions were posed and deliberated by the SAC-NPD members. Each is followed by the panel's final recommendations to Health Canada.

1. The scope of the revised guidance has been expanded to include OTC products. Do you have any comments with respect to this evolution?

   Committee members were strongly supportive of the evolution of this guidance document. They further indicated that there is significantly greater concern for product name confusion with OTC/consumer access products than with products prescribed by a healthcare professional. Concern was expressed regarding the fact that NHPs were not included in this document. There is considerable confusion among consumers regarding the brand names for NHPs. There are many more NHPs than OTC products currently on the Canadian market. Name confusion with NHPs and OTC/consumer access products is also of concern.

2. Within the scope statement a list of exceptions has been included. Do you agree with these exceptions?  Should anything be added or removed?

   In general, committee members were in agreement with the list of exceptions included in the guidance document. It was noted, however, that longer names can often not be accommodated in the data entry fields of systems at hospitals/pharmacies. Thus, shorter names or a limit on the number of characters would be desirable.

3. What are your views on the practice of product-line extensions?

   Committee members agreed that product-line extensions, where the active ingredient is not the same should be prevented, even though the therapeutic indication is different. This is to ensure patient safety.

   In cases of name extensions with a common prefix (e.g., Tylenol-N), the committee agreed that the screening criteria specified in the draft guidance document need to be evaluated and met prior to granting exceptions.

   Consumer use studies may not be sufficient to justify a particular name choice for a product which uses a similar brand name, but contains a different active ingredient to the original product (e.g., Tylenol-N, which contains naproxen in place of acetaminophen).

4. Under what circumstances do you think that product line extensions are acceptable?

   The committee members agreed that a product line extension would be acceptable provided the product contains the same primary ingredient and has a different indication (e.g.¸ Tylenol with acetaminophen for vaginal candidiasis would be acceptable).

   Further, members confirmed that there should not be any deviations from the above recommendation, even if consumer use (AU or SS studies) data are available. Label comprehension or SS studies may support the switch of a product from Rx to OTC but, if there are other marketed products with similar names or graphics, it would not be appropriate to approve a product-line extension.

5. Are there circumstances that would make a product line extension unacceptable to you?

   While the committee members felt that this question had been addressed in questions 3 and 4, they felt that it also should be noted that misleading or deceiving consumers is a risk factor for product line extensions. This should be avoided.

   Over-the-counter drugs, which have the same root name as their Rx counterpart (e.g., Pepcid and Pepcid AC or Lamisil and Lamisil OTC), were felt to be acceptable by the committee members given that these products contained the same active ingredient. There may be some language considerations regarding the translation of "OTC" to French. However, it was indicated that for the average consumer these may, regardless, simply be letters with little meaning/significance.

Next Steps, Closing Remarks, and Adjournment of Meeting

Prior to adjourning the meeting, members were reminded to send general comments on the draft guidance document on switch submissions directly to Dr. Thea Mueller.

A brief discussion regarding the date of the next meeting and possible agenda items was held. Committee and working group members agreed that a meeting in May 2013 would be appropriate. The committee secretariat will poll members for their availability to confirm a specific date. In the interim, the NDED will assess their list of priorities to establish agenda items for this meeting.

Committee members were thanked for their valuable time, productive discussions and recommendations.

Meeting was adjourned.

Appendix I:

List of external observers:
Consumer Health Products Canada - Mr. Robert White

Following the meeting the below publications were shared with members:

1. Brass EP, Shay LE, and A Leonard-Segal. 2009. Analysis of Multiple Endpoints in Consumer Research in Support of Switching Drugs from Prescription to Over-the-Counter Status: The Concept of End-point Hierarchies. 85(4): 369-374.
2. Leonard-Segal A, Shay LE, Shetty D and J Schiffenbauer. 2009. Unique Role of Consumer Studies in nonprescription Drug Development. Journal of the American Pharmaceutical Association. 49: 670-673.
3. Soller RW, Chan PV and C Shaheen. OTC Considerations for Expanding Access to Nonprescription Medicines: A Critical Synthesis of Questions from the Food and Drugs Administration to its Advisory Committee on Rx-to-otc Switch. Selfcare. 2(5) 117-138.