Health Committee on May 1st, 2008

[The Chair, Conservative, Joy Smith]

Order, please. I'd like to welcome everyone to the 14th meeting of the Standing Committee on Health. Pursuant to Standing Order 108(2), we are doing a study on post-market surveillance of pharmaceutical products.

Today we have a full complement of presenters, and we have a full complement of questions for all our presenters. We will give each organization 10 minutes to present. Following that, we will go into the questions and answers.

From Health Canada, we have Mr. Michael Vandergrift, Dr. Marc Berthiaume, Dr. David Clapin, and Mr. David Lee; from the Public Health Agency of Canada, Dr. Barbara Law; and from the Ontario Ministry of Health and Long-Term Care, Mr. Brent Fraser. Also on the list we have Dr. Bruce Carleton from the University of British Columbia. Welcome.

I will ask each organization to take 10 minutes. We look forward to hearing from you.

We will begin with Dr. Michael Vandergrift.

[Michael Vandergrift, Director General, Policy, Planning and International Affairs Directorate, Health Products and Food Branch, Department of Health]

Thank you very much, Madam Chair, for the opportunity to appear in front of this committee again.

We appreciate the opportunity to return to discuss the issue of post-market surveillance. I know this committee has heard from many excellent witnesses, and we're pleased to appear again to provide additional highlights of our work in this area and to respond to any questions you have.

I'd like to turn it over to Dr. Marc Berthiaume to take us through the opening comments. Dr. Berthiaume is director of the marketed pharmaceuticals and medical devices bureau in the marketed health products directorate at Health Canada. As such, he works on the front lines of post-market surveillance of pharmaceuticals and medical devices. In addition to his duties at Health Canada, Dr. Berthiaume is a physician who continues to practise medicine on a part-time basis.

[Dr. Marc Berthiaume, Director, Marketed Pharmaceuticals and Medical Devices Bureau, Marketed Health Products Directorate, Health Products and Food Branch, Department of Health]

Good morning.

All marketed health products have risks associated with their use. Prescription drugs, over-the-counter products, biological, vaccines, medical devices and natural health products all have risks. Some of these risks are known at the time of market authorization, but we also know now that additional information about risks can only become known once the product is more widely used. Regulators around the world, including Health Canada, are now working to build into the system improved capacity to gather and use this information to protect the health and safety of Canadians. This is not a failing of the system and these issues are not unique to Canada.

The strength of our post-market surveillance system, like others, is largely, and quite rightly, determined by how quickly it can identify new risks and how efficiently it can act to mitigate them. Significant improvements have been accomplished in the past few years in these two areas.

The risks of a drug should not be considered in isolation. It is important to always consider the balance between potential risks and potential benefits. This principle applies to the full spectrum of health products from over-the-counter medicines to prescription drugs.

Another important concept when analyzing adverse drug reactions is that they occur as an interaction between a drug, a patient, and the environment, which speaks to the fact that adverse drug reactions have more complex causes than just the drug by itself. For example, a study published in JAMA in 2006 concludes that cases of unintentional overdose or drug misuse account for more than half of drug-related admissions.

Most of the serious adverse events causing hospitalizations are known, well described, and associated with drugs that have been on the market for long periods of time, such as blood thinners, painkillers, insulin, and penicillin-like antibiotics. These potential risks are well known and factored into the decisions of practitioners when they prescribe that specific medication. According to the study mentioned earlier, 16 of the 18 drugs most commonly causing emergency visits for adverse drug reactions have been in clinical use for the past 20 years.

Appropriate prescribing also requires that the risk of a drug be weighed along with its benefits--for example, the number of lives saved or the number of years of increased life expectancy. If a patient has a sustained irregular heart beat, their likelihood of experiencing a stroke is 3% per year, which could lead to death, paralysis, or other serious outcome. To prevent a stroke, a powerful blood thinner called Coumadin is used; it has a known risk of 1% per year for serious gastrointestinal bleeding. The risks of this drug are real, and a significant number of hospitalizations due to life-threatening bleeding caused by Coumadin are documented every year, but this does not that mean that the risk is unacceptable, given the number of strokes prevented. Clearly, good population-level decision requires more than considering drug risks in isolation.

Pharmacovigilance and pharmacoepidemiology are rapidly evolving fields. The changes that Health Canada is proposing to the regulatory system are designed to bring Canada's regulatory system on par with the best in the world. Like other regulators, we are moving to add to the value provided by adverse reaction reports and work towards more systematic receipt and assessment of additional post-market safety studies and other data.

Over the course of this study, concerns have been raised about the need for independent post-market review. Since its creation in 2002, the marketed health products directorate within the health products and food branch has coordinated post-market surveillance and disseminated product safety information. MHPD scientists providing independent scientific evaluation are distinct from scientists who authorize products for market, and the directorate has a budget separate from those parts of Health Canada responsible for pre-market review while at the same time ensuring effective communication throughout the regulatory life cycle of the product.

Since its creation, MHPD has been providing independent assessment and consistency in safety standards, methodologies, and risk messaging to stakeholders; ensuring distinct resource use by dedicated post-market surveillance staff to optimize operational requirements and accountability; enabling patients to take more responsibility for their health product decisions through increased access to reputable and credible risk messages; and putting increased emphasis on post-market monitoring, review, and risk management.

Health Canada made a clear commitment to independent post-market surveillance with the creation of the marketed health products directorate. We have recently issued a five-year post-market surveillance strategy on the MedEffect Canada site on the Health Canada website, and copies have been provided to you today. This five-year plan outlines how Health Canada will continue to evolve post-market surveillance activities in line with new sources of credible safety information and in line with international standards.

The strategy includes a number of key objectives, such as integrating new sources of Canadian and international information, developing international and national partnerships to facilitate work sharing, and implementing a new state-of-the art information management system to improve signal detection and adverse reaction data analysis, including integration of adverse reaction reports throughout the product life cycle.

Within that strategy, one of our objectives is increased use of external expertise to supplement the scientific and medical expertise of Health Canada staff. Health Canada has created an Expert Advisory Committee on the Vigilance of Health Products, which provides advice on post-market policies and programs related to the vigilance of health products. The committee includes a mix of expertise and experience, with members representing patients, consumers, the health and industry sectors, researchers, and academia.

Health Canada also brings together external scientific advisory committees to contribute to the analysis of post-market safety issues on specific products or classes of products. This process was used recently to examine safety issues related to the product Avandia. We want to benefit from and contribute to the broad range of expertise available in Canada for the benefit of Canadians, and we are confident that in doing so the quality of the decisions we make about the risks and benefits of products will be enhanced.

I would like to take the opportunity to highlight three key operating principles that guide our work.

The first is the precautionary principle. This principle is incorporated into our decision-making and grounded in the integrated risk management framework. When we have a significant safety signal, we can and do take action, even in the absence of definitive evidence. A range of actions can be taken, from issuing risk communications to removing market authorization. The choice is determined by the seriousness of the risk identified, the potential for harm in the Canadian population, and the potential ability of the health care system to manage that identified risk if there are also potential lifesaving benefits.

The second operating principle is alignment with the best international practices. There is tremendous value in aligning our terminologies, guidances, and regulations. This facilitates our information sharing and work sharing with other regulators. In support of post-market surveillance, Health Canada has developed information-sharing memorandums of understanding with numerous foreign regulatory agencies and is active in many international initiatives, such as the International Conference on Harmonization, the Council for International Organizations of Medical Sciences, the Global Harmonization Task Force for medical device harmonization, and the WHO, to name a few.

Safety issues that occur in Canada are not typically different from those in other countries, and given the size of the Canadian population, new risks may not be identified in Canada first. Many signals are identified in international studies, as was the case for recent regulatory actions concerning Prexige, Vioxx, and other drugs. Our strong relationships with other regulators allows Canadians to benefit from timely global information sharing and response.

The final key operating principle that governs our work is shared responsibility. Health Canada is only one player in a complex, interdependent, integrated health care system. I would highlight that scientists of the branch are working with various organizations, such as the Canada Health Infoway and others, to leverage advantages in the Canadian health system regarding gaining usable access to the future electronic health record as a source of adverse reaction and other related information, for example.

As you are aware, health care in Canada is delivered by the provinces and territories. Therapeutic choices are made daily by health care providers and Canadian consumers. Health Canada does not regulate the practice of medicine, but strives to provide timely information on the risks associated with marketed products to facilitate the best therapeutic choices, as well as regulate the industry that has a responsibility for selling safe and effective products and informing stakeholders about information concerning the products they sell.

In giving life to these operating principles in our work, our goal is always to better respond to safety issues when they arise, and to fulfill our fundamental role in safeguarding the health and safety of Canadians.

I would like to thank the committee for the work it is doing to support us in this regard. We would be pleased to provide clarification and answers to questions from the committee, and we look forward to the committee's recommendations.

[The Chair, Conservative, Joy Smith]

Thank you so much, Dr. Berthiaume. I appreciate your insightful comments.

We'll now go to Mr. Brent Fraser.

[Brent Fraser, Director, Drug Program Services Branch, Ontario Ministry of Health and Long-Term Care]

I would like to thank the Standing Committee on Health for the opportunity to discuss post-market surveillance in the pharmaceutical sector.

I am the director, Ontario public drug programs, with the Ministry of Health and Long-Term Care, and I assist in managing the Ontario drug benefit program, a drug reimbursement program primarily for seniors, social assistance recipients, and individuals with high drug expenses in relation to income.

I am also the co-chair of the national pharmaceutical strategy working group on real-world drug safety and effectiveness. Part of the mandate of this NPS working group was to look at opportunities to build upon post-marketing surveillance in Canada and the body of evidence that is being done in various research sectors to determine if there are opportunities to coordinate this work and improve collaboration across Canada.

Direction is still being sought from ministers regarding the NPS work. Therefore, the focus of my comments today will be primarily from a provincial drug plan perspective.

As noted in the terms of reference for the standing committee's study on post-market surveillance, there are a number of key issues that are very important with respect to the reimbursement of drug products as benefits under a provincial program, including monitoring a drug product's use, consumer safety, public access to information, and adverse drug reaction reporting.

Products are listed on the Ontario drug benefit formulary based on recommendations from the Canadian Expert Drug Advisory Committee, part of the common drug review; and the Committee to Evaluate Drugs, Ontario's expert advisory committee. Final decisions are made by the executive officer, Ontario public drug programs.

One of the key areas that are raised during a drug product's review by our clinical experts is how the product will be used in a real-world environment, compared to published studies that are often the basis of their recommendations. Drug studies are controlled environments, and there are many restrictions, including when and how the product is administered, patients who are eligible for the trial, and limits on what other medications the patient may receive during treatment.

This environment limits the ability of our experts to make recommendations on what is the appropriate place of therapy for a new drug product or indication. Very few studies do head-to-head trials with other drug products, so we do not have a clear understanding of the overall effectiveness and safety profile compared to other products that may be used to treat similar conditions.

In addition, this does not tell us how the product will be used in the real world. For example, are there higher risks associated with the product in certain patient groups, or is the product more effective for some individuals? Is it better to try other medications first, before moving to other products that have less solid evidence of clinical effect?

Some of the newer products coming to market may rely on surrogate markers as evidence of effectiveness. These markers are often used as a proxy. It may be assumed that a change in a marker is an indicator of clinical effect or outcome. This is particularly challenging because we often do not have the evidence to show the direct linkage between the surrogate marker and the outcome that's presumed.

If there is more reliance on this type of information to support access to new drugs and the drug approval process, post-market evaluation will become increasingly more important. la addition, there will be a need for long-term outcome studies to validate the clinical effects.

Once a product comes to market, manufacturers seem reluctant to complete these types of studies. As a result, we are often caught in a situation where the expert advisers do not have the right information to make recommendations for listing on the formulary, and manufacturers are not encouraged to complete longer-term studies to validate the initial findings upon gaining market approval.

It is imperative that data collected to support post-market research is beneficial for federal and provincial bodies. Although our roles are different, there is often a common link in the type of data that is required to assess drugs post-market. We would encourage manufacturers to continue to work in this area, as this is critical information that will be used by all sectors.

There are many examples of drug therapies that have had unexpected or negative effects when introduced to market. Some of these effects may be seen as a result of persons taking products for prolonged periods of time, well beyond the typical clinical research study period. In addition, these types of experiences will help validate some of the clinical effects that may have been assumed during the review process for new drug products and listing on provincial formularies.

Data collection and analyses are often done individually within different research centres across Canada, and the results of this work may not be communicated broadly. At this time, no organization has been given the mandate to collect and analyze these data. There may also be a lack of individuals who are trained in this area.

Funding to support research programs and linkages among those programs may help to reduce or eliminate duplication of research. It may also help to enrich the data that is collected by including a broader range of participants in the studies. This could be considered as an initial step to funding a larger centre and may help ensure that functions to support these programs and linkages to other national bodies involved in the drug review, funding, and monitoring processes are established with minimal overlap of functions. At this time, some stakeholders are looking at these opportunities to see how some of these networks could be established in Canada.

It is also important for us to clearly understand what information should be collected. Observational data is important for us to understand how broadly products are being used, and they may point to certain risks or concerns. But it may not be specific enough for one to know the actual impact of the drug, and this can create confusion within the marketplace.

The establishment of complex registries to collect data may provide the detailed information required to fully assess a drug post-market, but it will have a significant impact on resources required to collect this information.

The other important factor is timeliness of information. It is not enough to collect this information if the results are not disseminated in a timely manner so previous decisions regarding reimbursement of a drug can be re-evaluated if necessary.

In conclusion, as this work is developed it will be important to consider the impact on all stakeholders, including patients, health care professionals, manufacturers, researchers, governments, and others. A balance needs to be created to ensure that data is collected in a timely and accurate manner but does not overburden the health care sector.

Once again, I would like to thank the standing committee for allowing me to address you on this important issue.

[The Chair, Conservative, Joy Smith]

Thank you very much, Mr. Fraser, for your presentation.

We will now go to Dr. Carleton.

[Dr. Bruce Carleton, Senior Clinician Scientist, Child and Family Research Institute, BC Children's Hospital, University of British Columbia]

Good morning, Madam Chair and members of the committee. Thank you again for the opportunity to speak to you.

I would like to reiterate a couple of brief points that I made the last time, but I won't dwell on those. I'm hoping that you read the transcript of comments instead.

The first point is that adverse reactions are a major public health issue, but our regulatory system does in fact prevent most unsafe drugs from being on the market. The difficulty is in heterogeneic responses to drugs, the differences in the variability in response that we all have. I believe last time I presented the example of a skin reaction in which the skin of this young baby fell off as a result of ibuprofen--Motrin, Advil. This is a product that is used repeatedly by people without any particular trouble--I use it myself without problems--but some people do have such a significant reaction. The difficulty in improving safety is that these reactions are not necessarily predictable and they don't occur in large numbers. Finding solutions to these safety problems and allowing drugs to continue to be used when they're effective and they're not unsafe is really the crux of the problem. Addressing this public health issue requires an understanding of response heterogeneity and understanding that we have different responses.

An article published in the Journal of the American Medical Association in 1998 suggests that adverse drug reactions not due to error or abuse are in fact the fifth leading cause of death in the United States. This is a very significant problem, and we need ways to address it.

How do we address a problem that occurs in some and not in all? Every drug is different. Some people have reactions to one drug and not another. I believe that a key in this is to understand the role that human genetics play in the difference in response, and that's the context in which I'm speaking to you today.

My work and the work of Dr. Michael Hayden, the geneticist I work with, is about understanding drug response and linking clinical pharmacology and human genetics. When drugs enter the body, there are four basic steps that they go through: they're absorbed, they're distributed, they're metabolized into active or inactive constituents, and they're excreted. Those four steps are controlled by genes. If we understand which biotransformation step results in a toxicity problem--in an adverse effect--we can also understand what genes might be responsible for allowing that particular occurrence. In fact, as I reported last time, Dr. Hayden and I have discovered the genes for three serious and fatal reactions.

We believe this work has tremendous value worldwide. These are drugs that have been used for many years, as my colleagues from Health Canada have stated. The drugs that are currently on the market are also a problem. It's not just the new drugs that are a problem; it's the ones we've been using in cases for 50-some-odd years. What we want to do is to use this new science of pharmacogenomics, combining clinical pharmacology and human genetics, to understand drug response, and then to use that to develop predictive tests to prevent adverse reactions in people who are most likely to experience them--or at least we should know, before we begin therapy, in whom the most serious reactions are likely to occur. If we do this properly, it will happen one drug and one patient at a time.

The technology is rapidly decreasing in cost. The research is building to show this is of value. The Food and Drug Administration in the United States is already recommending genetic testing for at least three drugs and three specific reactions, one of which was our discovery, as part of the network that was funded with Genome Canada money that developed this work, and we're very excited to move this particular area forward.

I'd like to say, finally, that all Canadians, all stakeholders in this process--from pharma, government, and industry to patients, clinicians, and academics--want safer drugs. Everybody wants that. This is an opportunity for us to move forward with a common goal, and we have the national health system to support this. I can't emphasize enough the work that I do internationally with different groups who suggest that in their countries they just can't do what we're doing. We have created an opportunity here. We've embedded our work within the health system in Canada. We've used clinicians to find reactions. By the end of this year we'll have more than 10,000 adverse drug reaction reports and controls that are critical to understanding the differences between people who respond negatively to drugs and those who don't. That work will allow us to move forward on a great many other targets to begin the development of predictive diagnostics to help clinicians make better choices for safer drugs for Canadians in the future.

Thank you very much.

[The Chair, Conservative, Joy Smith]

Thank you, Dr. Carleton.

We will now proceed to our questions. We will begin with Mr. Thibault.

This is a seven-minute round, Mr. Thibault.

[Robert Thibault, Liberal, West Nova, NS]

Thank you. Please advise me when there are only 10 minutes left.

[The Chair, Conservative, Joy Smith]

I'll advise you when there are five minutes left, Mr. Thibault.

[Robert Thibault, Liberal, West Nova, NS]

You've given me a lot to go on and a lot to follow up on. It's very difficult to do it in seven minutes, or even in one session.

I'm pleased to have you with us again, Dr. Carleton. You have brought to the committee one of the few solutions we've seen. A lot of people have shown us what the problems are, and I think we understand them. Some people, including you, have brought us elements of a solution.

I was watching some broadcasts on TV this week that were showing what Ontario is doing in the genetics of cancer. They're trying to be the world leader in getting the cancer genome and are suggesting there's more data in that set than in the whole human genome process. Once they can hold that information and make it available to the world, it might speed up therapies for cures for cancer.

What you're talking about reminds me of something similar that could be done that way. If we could have a proper network, with the work being done internationally and everybody doing bits of it, we could come to a pharmaceutical genome in time. Is the backbone being created internationally?

[Dr. Bruce Carleton]

The backbone is being created. A number of countries are interested in this in the European Union, of course, and in United States and Canada. International cooperation is important to progress, and we can divide and conquer these particular problems independently as well. There isn't really a need for these large international trials to uncover this.

[Robert Thibault, Liberal, West Nova, NS]

That's not my suggestion. My suggestion is that if you are doing five classes of drugs and the Swiss are doing three, all of a sudden you have 20 classes of drugs.

[Dr. Bruce Carleton]

Exactly.

[Robert Thibault, Liberal, West Nova, NS]

Thank you very much. I look forward to learning more about it and seeing it progress.

I was looking at the document by Health Canada, and it shows signal detection and assessment. I know we have good expertise within the Health Canada organization for this. I've had an opportunity to visit GPHIN at public health, which is similar, but it's working in the area of epidemiology worldwide. Do we have the ability in Canada now to detect and see where the problems are happening in pharmaceuticals generally in Canada--if there is a lack of pharmaceuticals or a lack of supply?

[Dr. Marc Berthiaume]

So your question is about whether we can identify emerging safety signals in pharmaceuticals.

I think tremendous progress has been accomplished in the past few years in that area, especially very recently with the creation of the Canada Vigilance online database. It is a new database that will enable more efficient collection of spontaneous adverse drug reactions. It will also have a built-in data mining capacity--some kind of software that will help us identify if there are disproportional numbers of certain types of adverse events with certain drugs.

[Robert Thibault, Liberal, West Nova, NS]

We've heard a lot about the question of the information getting back to practitioners in a reasonable way. The suggestion has been made by practitioners that they would voluntarily inform Health Canada or anybody of adverse events if the information could flow both ways--if they could learn from the same screen as they're informing. Are we moving in that direction? Is this data getting out there in a usable form?

[Dr. Marc Berthiaume]

I think it's an area in which we're making step-by-step progress. A recent improvement is the ability to submit spontaneous adverse drug reaction information electronically. There is also now the capacity to search the spontaneous adverse drug reaction database online.

Although it's very difficult to have immediate retroactivity for the person who's reporting, they can have more of a population--

[Robert Thibault, Liberal, West Nova, NS]

I see the potential. I can't imagine that this can't be done. If a client has a certain reaction to heparin and I type that in, it should automatically come back and give the comments, alternatives, and problems. As the database is built, it should feed back quite quickly. The technology seems to be there to do it.

[Dr. Marc Berthiaume]

The technology to give some estimation of the numbers of adverse events that have been reported to Health Canada for a specific drug and/or a specific adverse event is in place now. There's a delay because the adverse events reports have to be processed, looked at by a specialist, and then entered into the database.

[Robert Thibault, Liberal, West Nova, NS]

Certainly there will be a delay, but when a practitioner inputs the problem he's having that day, the information known to date could be given to him in usable form. You'd think with Infoway and the work we're doing, that potential would be there. I hope we get there in the future. It's been suggested--

[Dr. Marc Berthiaume]

We use the Canadian Adverse Reaction Newsletter as one way of identifying clusters of cases. It's distributed to all physicians in Canada with the Canadian Medical Association Journal. So we have different ways to go back to the physician to--

[Robert Thibault, Liberal, West Nova, NS]

But I'm sure that newsletter is part of a pile of documentation that goes to a man or woman who's already working long days and doesn't necessarily always have time.... It's not the same as getting the information at the pertinent time.

Mr. Lee.

[David Lee, Director, Office of Patented Medicines and Liaison, Therapeutic Products Directorate, Department of Health]

Just to clarify, we've been having a lot of very good discussions with the various practice communities--nurses, doctors, and so on--who really need this information. We're finding that the needs vary depending on the disease they may be treating. Some patients are on quite a few therapies long term, so there are different information needs for them. If you're taking something for a short time, how do we get the best information out there?

To Marc's point, we're really trying to develop what we need there. I think it's a very important discussion for this committee.

[Robert Thibault, Liberal, West Nova, NS]

Do I have any time left, Madam Chair?