Scientific Advisory Committee On Metabolic & Endocrine Therapies - Record of Proceedings

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: Policy Bureau Enquiries

---

Therapeutic Products Directorate
Scientific Advisory Committee on Metabolic & Endocrine Therapies (SAC-MET)
(2007/11/15-16)

Record of Proceedings

Committee Members Present: Peter Walker (Chair), Heather Dean (Day One only), Robert Dent, Dale Quest, Ehud Ur, Lili Wang, George Wells, Colleen Fuller, Irene Hramiak, Peter J. McDougall, Ronald Sigal, Michael Wheeler (Day One only)

Health Canada Representatives Present: Barbara Rotter, Chris Turner (Day One only), Suzanne Bailey , Patrice Tremblay, Melissa Hunt, Colette Strnad, Eric Ormsby, Andrew Raven, Marilyn Davis, Amanda Rappak, Sylvie Lefebvre, Nancy Berg, Evette Beschay, Nadia Roufaiel, Leanna Malone, Rania Mouchantaf

Sponsor Presenters: GlaxoSmithKline (Day Two only)

* Abbreviations used in this record:

HC - Health Canada
SAC-MET - Scientific Advisory Committee - Metabolic and Endocrine Therapies
T2DM - Type 2 Diabetes Mellitus
COI - Conflict of Interest
GSK - GlaxoSmithKline
IGT - Impaired Glucose Tolerance
IFG - Impaired Fasting Glucose
ICH - International Conference on Harmonization
FDA - Food and Drug Administration

At this inaugural meeting of the Scientific Advisory Committee on Metabolic and Endocrine Therapies (SAC-MET), two topics were discussed. Day one focused on obtaining external advice on definitions and clinical trial requirements for the prevention of Type 2 Diabetes Mellitus (T2DM). Questions and background documentation on this issue were formulated by Health Canada (HC). Stakeholders were given an opportunity to consider these questions prior to the meeting and to submit written comments to HC.

The day two agenda addressed post-market cardiovascular safety issues associated with the anti-diabetic drug, rosiglitazone ("Avandia"), manufactured by GSK. Further to Health Canada's review of the benefit-risk profile of rosiglitazone, the Canadian labelling of rosiglitazone has been updated. Health Canada asked the Committee to ensure that labelling revisions are adequate to manage current safety concerns. GSK attended a portion of the meeting and made a presentation to the Committee, and then the Committee met behind closed doors in order for the members to formulate recommendations to Health Canada.

Day One - November 15, 2007

Opening Remarks

Dr. Chris Turner, Director General of the Marketed Health Products Directorate (MHPD), opened the meeting. Dr. Turner thanked members for their participation at this inaugural meeting and emphasized that the Committee mandate was broader than treatment for diabetes. Following this he turned the meeting over to the Chair.

Introductions & Conflict of Interest (COI)

The Chair led the Committee in round-table introductions and conflict of interest declarations, encouraging a free and open discussion. No members declared any changes from their submitted statement of interest and affiliations. Upon completion of the declarations, it was unanimously agreed that all members could participate fully in the meeting.

Overview of Terms of Reference (ToR)

An overview of the mandate including issues surrounding indemnification, conflict of interest and compensation was presented. The ToR was accepted by the SAC members.

HC Presentation: Regulatory Review Process
*This presentation is available upon request.

The presentation provided a high level overview of Health Canada's drug review process as it pertains to the Food and Drugs Act legislation. Topics included federal responsibilities, the prohibitions and enforcement of the selling and advertising of drugs and, especially in the case of new drugs, evaluating conditions of drug use in terms of safety and effectiveness.

Question Period

Health Canada answered questioned from the SAC members regarding International Conference on Harmonizaton, review times and cost recovery.

For the drug review process, HC prioritizes a balance of safety, efficacy and quality, assessing the risk-benefits on a case by case basis. HC puts the drug in question under extensive assessment using information submitted by the sponsor as well as from wide-scale searches, published and peer reviewed sources. Canada's regulatory time-lines are comparable to other international standards. There is no strict rule, but generally companies go to United States, Europe, and then Canada for drug approval. Simultaneous filings are occurring more routinely, so additional information that arises out of the approval in one jurisdiction is often not available for analysis during the review process. The sponsor is responsible for committing to a specific timeframe for submitting data and documentation for submission review. The International Conference on Harmonization (ICH) is the body which outlines the technical requirements for sponsors when preparing their submission for pre-market assessment by the regulators.

HC Presentation: Definitions and Clinical Trial Requirements for Prevention of Type 2 Diabetes Mellitus (T2DM)
*This presentation is available upon request.

The questions outlined in the background documents were reviewed.

Tabling of Stakeholder comments on questions to be discussed (T2DM)

At this time, a tabling of stakeholder comments was provided and the Committee was reminded to take responses into consideration during discussions.

Committee Discussions: Question 1

1. (a) For the purpose of evaluating pharmaceutical interventions for the prevention of Type 2 diabetes mellitus (T2DM), what should be the definition of "prevention"?

The Committee acknowledged the difficulty in assessing "prevention claims" from sponsors, given that the continuum of diabetes development is such that patients may not ever manifest Type II disease symptoms. The pre-diabetic status definition was described as based on risks predicting the patient's condition will develop into T2DM.

The Committee agreed that a sponsor could ostensibly claim:
"A reduction in the incidence of the development of Type II diabetes".

The Committee supported further development of oral anti-diabetes drugs for indications of reduced incidence in the development of T2DM, based on a theoretical prevention of micro and macrovascular complications. They supported claims made about the reduction in incidence of T2DM if supported by meaningful clinical trials. These claims would require sufficient long term studies where the development of diabetes is a pre-specified outcome. The Committee believed that prevention of diabetes with drug intervention requires well designed, appropriately powered trials demonstrating a statistically significant reduction in the incidence of Type II development.

(b) If delay of onset of T2DM is considered to be a valid "prevention" indication, what would be a clinically meaningful "delay"?

Setting a threshold value for a meaningful delay time, such as one year, was considered to be very difficult when relevant parameters and costs must be factored in. The Committee was concerned that setting a threshold would be too proscriptive, but believed a statistically significant reduction in overall incidence would typically signify important benefit. Committee members noted that the acceptable magnitude of delay would depend on the risks associated with the product but that delay is not a valid prevention indication. The Committee was not in favor of using either the term "prevention" or "delay", but preferred "reduced incidence".

It was pointed out that more benefits would accrue if T2DM could be delayed until after reproductive age, or if the chronic form of the disease could be prevented in children. When the outcome in adulthood is long term (or chronic), then delaying the onset of T2DM for only a few weeks may not be significant to patients. This important question was deemed worthy of further consideration, but a more in depth literature review for different groups and perspectives would be required. The Committee objected to a "delay" being a primary outcome when it is so important to consider the risks associated with each drug versus the possibility of reducing incidence of developing T2DM.

Committee Discussions: Question 2

2. Based on the agreed-upon definition(s), how should clinical trials be designed in order to investigate the safety and efficacy of a drug for the "prevention" indication?

In particular, the following features of the study design should be defined:

2.1 study population (i.e. key inclusion and exclusion criteria)

The Committee reached a consensus that taking a global view of patients to include children as well as adults is most appropriate. The concept of "delay" was found to be an ambiguous definition to use in the instance of drug treatment for diabetes. Socioeconomic, ethnic and education status were acknowledged as relevant factors in the development of T2DM. It was recognized that criteria for pre-diabetes will also show regional differences. Obese persons were identified as one of the groups at highest risk.

No regulation is available to request certain populations to be included in clinical trials but the Committee felt that all at-risk populations should be included, including ethnic groups. The point was made that discussions are pertinent to populations of 13 years old and up and that the inclusion of adolescents in clinical trials for new drugs would need to be studied but probably in a smaller study of that group and not in a main trial based in an adult group. It was appropriate to the Committee that a smaller trial in adolescents would be necessary for approval in that age group but could not be part of the main trial for a variety of reasons.

The Committee concluded that a study on anti-diabetic drugs should use a patient population enriched for risk factors in order to have realistic statistical power and well defined criteria. The population should include anyone who meets the criteria for being "pre-diabetic" (and thus indicating a high risk of T2DM), as well as candidates from groups with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), metabolic syndrome and obesity.

While a lifestyle intervention is the principal treatment method, the Committee focused on pharmaceutical interventions.

2.2 primary endpoint(s)

The Committee recommended a primary endpoint as the incidence of developing T2DM. This was seen as a pre-specified outcome in a clinical trial with adequate statistical power performed in an appropriate population.

2.3 important secondary endpoints

Secondary outcomes will be useful for tracking cardiovascular disease and adjudicating results unique to diabetes risk reduction during treatment. Macrovascular disease should be tracked and adjudicated as a secondary endpoint (such as composite MACE, or major adverse cardiac event endpoint, consisting of myocardial infarction, stroke and cardiac death). Other useful secondary endpoints include body weight, waist circumference, lipids, blood pressure, and other informative parameters with respect to cardiovascular risk factors.

The Committee strongly encouraged monitoring microvascular disease, quality of life and socioeconomic factors in accordance with an acceptable level of safety of specific drug effects.

The choice of secondary endpoints should be customized for each drug on the basis of the underlying mechanism. Secondary endpoints would be different for studies assessing incidence reduction indications than for studies examining treatment of diabetes because of differences in the risk tolerance level.

2.4 study duration:

The Committee recommended a minimum of three years for study duration to show reasonable degree of incidence reduction.

2.4.2 placebo run-in, if any

A placebo run-in phase was considered to be optional. Any run-in phase should be clearly described, as well as the inclusion /exclusion criteria that were used to determine eligibility for the active treatment phase. The Committee raised the question of whether a placebo run-in phase would have to be reflected in subsequent instructions for use of the drug product.

2.4.2 blinded treatment phase

The blinded treatment assessment was recommended to last at least 3 years.

2.4.3 open-label extension, if any (e.g to further assess safety and maintenance of efficacy)

Although the open label extension was not considered to be necessary by the Committee members, it was recognized to have potential value for the collection of additional adverse event data. Furthermore, the availability of an open label phase can often be an incentive to patients in a clinical trial, as those receiving active treatment have the option of continuing, and those randomized to placebo, subsequently have the opportunity to try the active drug. The willingness of patients to continue active treatment can be informative. Open label extensions are generally not informative with regard to efficacy.

2.4.4 post-treatment washout period, if any (e.g. to evaluate sustainability of effect(s) after treatment withdrawal)

The Committee felt that a post-treatment washout period would be highly desirable for at least one clinical trial and must be of an appropriate duration according to the mechanism of action of the drug. Failure to include a washout period in a clinical trial would have to be supported by a detailed rationale.

2.5 standard therapy (e.g. lifestyle recommendations for all randomized subjects)

The Committee acknowledged that lifestyle plays an important role in managing diabetes and reducing risks, so it was considered necessary to offer lifestyle advice in pamphlet form as per standard practice and an active lifestyle program could be additionally offered.

Committee Discussions: Question 3

3. Depending on the nature and magnitude of the benefit, what level of risk is acceptable for an agent intended for a healthy population (i.e., not yet manifesting disease)?

What safety information should be required:

a) pre-approval?

The safety information collected on the drug prior to approval should include the standard safety parameters assessed in clinical trials. A risk management plan should also be provided.

While an agent may offer benefits, the risk must be interpreted proportional to the magnitude of the benefit. If the potential harm caused by a drug and its cost are sufficiently low, it becomes reasonable to expose an "at risk" population to a preventative intervention of proportionally low efficacy or exposing proportionally lower risk individuals to that intervention for a longer period of time.

b) post-approval? (within what timeframe?)

Post market surveillance including follow-up on participants post-approval is strongly recommended for a three year follow-up for safety and efficacy.

Committee Discussions: Question 4

4. Should drugs for the prevention of T2DM be approved in the absence of demonstrated reduction in cardiovascular, renal, retinal and other serious health consequences of diabetes?

The Committee strongly encouraged a heightened surveillance system for voluntary reporting of adverse drug reactions.

If so, should sponsors be required to provide studies establishing the long-term clinical benefits post-approval?

The Committee highly recommended the provision of studies from sponsors to establish the long-term clinical benefits post-approval of a drug.

Committee Discussions: Question 5

5. Based on the agreed-upon definition(s) of prevention of T2DM, what would be
acceptable label claims for drug products with demonstrated safety and efficacy?

Based on definitions of prevention, acceptable label claims could be that:
Drug "x" as an adjunct to diet and exercise is indicated for reducing the incidence of T2DM in patients with impaired glucose tolerance and/or impaired fasting glucose (depending on study design.).
Furthermore:
Drug "x" demonstrated an "y" % reduction in the progression to type 2 diabetes mellitus in patients with IFG and/or IGT vs. patients treated with a comparator and an "z" year period.

Day 1 Adjournment

Day Two - November 16, 2007

Opening Remarks

Introduction - Rosiglitazone

*A presentation was given by Health Canada, however due to proprietary information, it will not be available for distribution.

Sponsor Presentation - Rosiglitazone

The Sponsor presented data on clinical outcomes and macrovascular safety issues and risks of cardio adverse events.

Questions from the Committee

The Committee asked for clarification on meta-analysis and criteria for assessing long term trials.

HC Presentation - Rosiglitazone

Questions from the Committee

Sponsor Leaves
After the departure of the Sponsor representatives, the Committee was left to deliberate on the questions posed by Health Canada.

Q1:  Are the planned label revisions for rosiglitazone-containing products adequate to manage current safety concerns associated with rosiglitazone?

The Committee was asked to offer advice as to whether the changes to the drug product labelling adequately respond to the safety issues in question. This is in accordance with fulfilling its regulatory mandate to intervene and respond to public concern by releasing information in a timely manner.

The Committee expressed concern that the risk data on rosiglitazone were inconclusive.

Some members felt that Health Canada should be cautious and respond to the signals. HC agrees that the evidence is not conclusive, but is acting according to their precautionary principle by reporting these signals, even in the absence of conclusive data.

Although the data presented was inconclusive, the Committee concluded to err on the side of caution and supported the requested changes to labelling. The Committee felt label changes were adequate but indicated that the findings from trials and the literature review were inconclusive on its macrovascular effects.

Concerns for other agents in the same class of drugs was expressed. Thus the Committee suggested the safety of pioglitazone should be subjected to similar scrutiny.

The Committee favoured the approach taken by the Food and Drug Administration (FDA) who indicated that the data was inconclusive in the changes they made to the labelling on November 14^th, 2007 with respect to the usage of rosiglitazone:

A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared AVANDIA to placebo, showed AVANDIA to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 patients), comparing AVANDIA to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive.

Q2: If not, what additional risk management approaches would you recommend to address the current safety concerns? For example:

a) Market withdrawal or further restrictions of use, such as:

• restrict use to defined patient subpopulations
• contraindicate use in defined patient subpopulations.

The Committee did not recommend further restrictions or market withdrawal.

b) Other labelling approaches, such as:

• strengthen warnings and precautions in the Product Monograph

The Committee identified a need for better and longer designed trials that would provide more safety and efficacy data.

Q3: What type of information would help further assessing the issue. How can that information be generated?

The Committee recommended that cardiovascular clinical outcome trials be started earlier as part of a risk management plan. The need for formal adjudication of the adverse events should be stressed. The Committee emphasized the importance of public education regarding the management of diabetes.

The Committee recommended that positive reinforcement should be available to industry to conduct pre-specified outcome studies and make the results known. HC responded that meetings with the manufacturers help to communicate requests for more studies. The Committee indicated a greater need to mandate manufacturers to provide long-term studies and clinical trials with pre-specified outcomes supporting HC's commitment to safety, in addition to efficacy.

Review of recommendations and rationales

Next Meeting Date

Committee members were agreeable to a group teleconference if needed to deal with additional questions. Early May 2008 seemed preferred.

Lunch / Thank you

Meeting Adjourned: 12:30 p.m. Friday, November 16th, 2007
Prepared by: M. Davis & A. Rappak
Next Meeting Date: Spring 2008