Scientific Advisory Panel on Diclectin (SAP-Diclectin)

Record of Proceedings

June 2, 2016

Panel members: Mitchell Levine (Chair), Karen Fung Kee Fung, Allan Donner, George Wells

Presenters: Adriana De Maria, Nadiya Jirova, Andrew Raven (Health Canada), Navindra Persaud (St. Michael's Hospital and University of Toronto), Michael Gallo, IIan Mattok (Duchesnay Inc.)

Health Canada staff: Kimby Barton, Marc Berthiaume, Léo Bouthillier, Anne Decrouy, Christine Ficker, Jenna Griffiths, Melissa Hunt, Nashwa Irfan, Nadiya Jirova, Beth Keeping, Adriana De Maria, André Molgat, Conrad Pereira, Co Pham, Andrew Raven, Supriya Sharma, John Patrick Stewart, Yinghua Su, Chantal Tremblay-Ruest, Leslie Vrooman, Shelley Wagner, Osama Wahid.

Welcome and opening remarks (John Patrick Stewart)

The Director General of Marketed Health Products Directorate, who was introduced by the Manager of the Office of Science, welcomed the scientific advisory panel members and presenters.  He provided context for the meeting, including brief mention of powers under Bill C-17, Protecting Canadians from Unsafe Drugs, and issues raised by Navindra Persaud following his re-analysis of data obtained under Bill C-17.  He explained the process to be used for the meeting, and once again thanked the panel for their time and willingness to provide advice to Health Canada.  He then handed the meeting over to the Chair of the panel.

Chair's address (Mitchell Levine)

The Chair reiterated the mandate of the panel and the questions posed to the panel by Health Canada.  He then confirmed acceptance of the terms of reference of the panel and the draft agenda for the meeting.  He explained that the presenters would address the panel only and there would be no discussion between presenters.  Following the presentations, the presenters would leave and the panel would deliberate on what they had heard, and formulate responses to Health Canada's questions.  He then 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.  No conflicts of interest were declared.  The Chair then asked attendees to introduce themselves before the presentations commenced.

Presentations

  1. Health Canada: The presentation included a summary of the regulatory history of Diclectin, Health Canada's review of Study DIC-301, the US Food and Drug Administration's review of Diclegis, Health Canada's view of Study DIC-301 in context, and Health Canada's safety review of Diclectin in pregnancy.

    Issues raised by the panel, in questioning the presenters, included, but were not limited to,

    • Definition of clinical significance for the purpose of this study, including discussion of different scales such as the Rhodes scale.
    • Potential for bias in using the last observation carried forward, in the statistical analysis.
    • Reasons for sample size being greater than required.
    • Instrument used for efficacy in the 1975 8-way efficacy study.
  2. Navindra Persaud:  The presentation commented on the design, outcome measure, analysis plan, results and sample size in study DIC-301, with a view to examining whether any clinically important or statistically significant difference between Diclectin and placebo had been shown.

    Issues raised by the panel, in questioning the presenter, included, but were not limited to,

    • Justification for sample size being larger than required.
    • Reasons for differential dropouts from the study.
    • Use of different statistical analyses such as the linear mixed model and generalized estimation equation approach.
    • Safety profile for drugs other than Diclectin that are used for nausea and vomiting in pregnant women.
    • Relationship between the Rhodes and Pregnancy-Unique Quantification of Emesis (PUQE) scales.
  3. Duchesnay Inc.:  The presentation included an overview of the regulatory history of doxylamine and pyridoxine combined, for the management of nausea and vomiting of pregnancy, an overview of the rationale and protocol development for study DIC-301, and a review of the results of study DIC-301, with an emphasis on efficacy.

    Issues raised by the panel, in questioning the presenters included, but were not limited to,

    • Implications of changes in drug labelling for marketing.
    • Basis for sample size calculation.
    • Definition of non-compliance versus dropout.
    • Reasons for subjects to withdraw consent to participate in the study.
    • Validation of the PUQE scale.
    • Effect size to consider as significant.

After the presentations, external presenters left the meeting.

Deliberation on the questions posed (All panel members)

The questions posed, to the panel, by Health Canada, were as follows:

  1. What is the most appropriate interpretation of the data from the DIC-301 study?
  2. Do you feel that the study results are relevant to practitioner and patient decision-making, and if so, how should the summary of data be presented to accurately convey the outcomes?

The discussion covered a variety of points, such as:

  • Clinical relevance of the results of the study.
  • Potential consequences for patients if, hypothetically, the drug were to be removed from the market.
  • Potential consequences of using the last observation carried forward in the statistical analysis.
  • Effect size used to assess clinical significance.
  • Appropriateness of the PUQE scale for the purpose of this study.
  • Relative safety of other drugs for nausea and vomiting.
  • Adequacy of study design

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 panel members)

Question 1: What is the most appropriate interpretation of the data from the DIC-301 study?

Recommendation:

  1. There are a number of concerns with the design and the analysis of this study:

    • The sample size calculation cannot be reproduced.
    • The reasons for dropout are not provided on an individual patient basis.
    • The details regarding the implementation of the last observation carried forward were not sufficient.
    • The confidence intervals for treatment effects of the components of the primary outcome and the secondary outcomes were not reported.
    • The psychometric properties of the primary outcome, the PUQE score, have not been fully established.
    • In summary, for the above reasons the results of the study are not definitive and consequently the interpretation of the DIC-301 study is problematic.
  2. The small effect size observed for the primary outcome is statistically significant, thus the difference observed is not attributable to chance.

    The primary analysis was statistically significant and some of the secondary analyses were also statistically significant. The direction of the treatment effect was consistent amongst all of the outcomes.

    The statistical significance was maintained when an alternative approach for missing data (Mixed-Effect Model Repeated Measure (MMRM)) was considered.

    For alternative analysis populations, i.e., Completer analysis per protocol, the results were not significant but in the same direction as the primary analysis.

  3. The clinical significance of the results obtained is uncertain due to no established Minimal Clinically Important Difference (MCID) for the PUQE scale. However, consideration of the secondary outcomes suggests a perceived clinical benefit, beyond the placebo effect, from the patient's perspective.

  4. In this study there are no safety signals that generate any concern. This is consistent with previously published data.

    In summary, we would conclude that there is a small statistically significant treatment difference of unclear clinical benefit.

Question 2: Do you feel that the study results are relevant to practitioner and patient decision-making, and if so, how should the summary of data be presented to accurately convey the outcomes?

Recommendation:

Due to the methodological concerns with this study we would not convey any alternative messages different from the Product Monograph (PM) regarding benefit or safety to patients or practitioners arising from the results.

In light of the historical demonstration of safety in pregnant women, and the lack of a safer alternative medication for this indication, we would not recommend any changes to the current labelling of this drug for the management of nausea and vomiting of pregnancy.

Closing remarks / Adjournment (Chair)

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

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

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