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.
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.
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.
I'm with the Public Health Agency of Canada, and we actually do the post-marketing vigilance for vaccines that are used in humans to prevent disease.
With respect to the deaths in question, I think EMEA put out a press release on January 24, 2008, regarding a couple of deaths. Our action at that time was to contact them the next day, January 25, to ask specifically about their concerns in regard to these deaths. We were reassured by the EMEA officials that they felt that Gardasil was not implicated in the deaths.
Also, through the memorandum of understanding between Health Canada and us, as well as Health Canada and the European Medicines Evaluation Agency (EMEA), we were able to specifically request the reports, which we got by January 28 and distributed to Biologics and Genetic Therapies Directorate counterparts as well as ourselves, to reassure ourselves that there was nothing there that was of concern.
Every death is a concern, but there are actions undertaken. We felt that all the proper actions were taken. We communicated through proper channels with the people who knew about the deaths and we were reassured there was not an issue. Similar things had happened in the U.S., where there were nine deaths.
I think it's important to note that if you looked at the pre-licensure trials that included 10,000 women, not all 9- to 12-year-olds—and I'll come to that in a minute—but among the women who were studied in the 10,000, there was a group that got the vaccine and there was a group that got a placebo, but nobody knew who got which. There were an equal number of deaths in both groups, none of which were thought to be due to either the vaccine or the placebo.
The problem with any product like this that is used in mass programs is that deaths occur spontaneously due to other reasons. At least in a clinical trial, if it does occur, you have an opportunity to show there's no difference between the group that got immunized versus the group that got a placebo, which doesn't contain the active ingredient.
In post-marketing surveillance, you don't have that other group; you just have the report of a death, and you have to try to discern whether this would have happened because of the vaccine or some other reason. So our feeling was, in collaboration and communication with our colleagues both at Health Canada as well as internationally, that these were not due to the vaccine.
I don't know if you want me to address also the question about the children, the younger girls. In the trials that were done for the vaccine itself.... I think it was made evident earlier that any product that comes to market may have been tested, and with Gardasil, it was 10,000-plus individuals who were tested. That's a lot, but that's not enough to detect rare events, and that's why you need to have post-marketing surveillance. In rare events such as death, each one needs to be investigated and looked at.
In the pre-licensure trials that were done, they were unable to include large numbers of younger children, because of the need to do specific tests that were thought to be inappropriate to do on prepubertal girls. So the tests were only done for those 13 years of age and up. But they then tried to test whether the immune response the younger girls would have would be equivalent, and you don't need to have nearly as a big a number as that.
So from the point of view of the effectiveness of the drug, that was clearly studied. For the safety of the drug, you wouldn't have enough numbers even in the 10,000. So the smaller number, a few hundred of the 9- to 12-year-olds, clearly wasn't enough, but that's something that's followed in post-marketing surveillance.
I want to focus on the national pharmaceutical strategy and how all these issues are obviously both federal and provincial. So I want to know how the NPS is working in terms of the co-chairs' meeting, and working groups and all those things.
I understand that you are co-chair of the working group on real-world safety. Obviously there was a conference in September 2005. There was the invitational workshop on research projects. There was the consultant's report in 2007. Are you ending up in a two-way communication with the federal government in terms of responding to these kinds of things? What recommendations would your working group be making on this issue? Did you comment on progressive licensing? Have you commented on how you would recall a drug?
Some of the people have heard this before, but I used to do a lot of obstetrics and was sometimes up delivering a baby during the nightly news and I would receive a letter from Health Canada three days later to find that a drug had been recalled, but my patients were lined up the next morning worried about it. We seem to have a very old-fashioned way of communicating with physicians about risk.
Also, I want to know if your working group is dealing with any of the stuff around counterfeit medicine. If there has been an adverse drug reaction, how do you know it really was the medicine and not a counterfeit, as we look at the issues around heparin and the real problems coming from the States right now?
So, first of all, how is it going on the NPS? I understand there has not even been a federal co-chair appointed.
It's interesting that historically both drugs and vaccines were with Health Canada when the agency was still with Health Canada as the Laboratory Centre for Disease Control. Then drugs were separated off and vaccines stayed where they were originally, with the Laboratory Centre for Disease Control. That's just some historical perspective.
We do the post-marketing surveillance for preventative human vaccines. The biologics and genetic therapies directorate, which is part of Health Canada, are the pre-market regulators, but they also have post-marketing responsibilities. One thing that's different about vaccines and some biologics versus other drugs is that every new lot of a vaccine has to be studied and given a release for marketing, and BGTD does that.
We interact with BGTD on a number of different committees. They have a committee for risk management, so when an issue comes up related to a vaccine we sit at that table and work with them. We have our National Advisory Committee on Immunization, and they sit at the table there. The committee provides expert recommendations on vaccines and updates vaccine safety information as part of the immunization guide. Different technical documents are produced when a new vaccine comes out--statements on the vaccine.
We run a vaccine vigilance working group. It is a federal-provincial-territorial committee that has members from all the provinces and territories, with a co-chair from the provinces and a co-chair from us. It looks specifically at vaccine vigilance, develops the form we use for reporting, and works on national case definitions and standard national operating procedures for adverse event reporting. We work with the provinces and territories in conjunction with them, and BGTD sits at that table.
We also have an advisory committee on causality assessment. It looks at the serious adverse events, some of which have been mentioned. They include deaths, hospitalizations, anything that prolongs hospitalization, anything that's life threatening, and anything that causes residual damage or potential congenital defects. We pull those reports and, to the extent possible, review them. We can't always get all the information we need for a committee to review them. BGTD sits at that table as well.
So those are all formal interactions. Then we have a number that are informal, ad hoc, as needed, when an event comes up, like the Gardasil deaths that were reported. They weren't Gardasil deaths; they were deaths following. They were temporal associations that were reported to EMEA. When we got that information, we met with our colleagues at BGTD. So we work with them very regularly--not every single day, but several times a week.
Thank you for your question.
Off-label use of a therapeutic product is basically when a product is used outside of the approved product labelling. It might be a different dosage or different route of administration, or outside of the indication for which the drug was initially approved.
The issue of off-label use is partially under the control of the physician. Sometimes it's the practice of medicine to use drugs outside of their recommended indications. The control or oversight of such off-label practice mostly resides with the provincial colleges of pharmacists and physicians who regulate the activities of their members.
In Canada it does happen sometimes, of course, in the pediatric population. There is some off-label use occurring there due to the fact that often there is a therapeutic need to handle some medical conditions. As well, there is not necessarily a solid body of knowledge that has been routed through the regulatory authorities and approved to basically grant an indication. Off-label use occurs also in certain subpopulations, such as cancer patients and AIDS patients. As I said, it's a reality that basically involves the practice of medicine.
We do, as a regulator, take action when we are aware of an off-label use that generates safety concerns, but we cannot regulate off-label use; it's outside the scope of our authority. As I said, it falls within the competencies of the different professional associations in Canada.
First of all, there are perhaps several misunderstandings around the term “progressive licensing”, which was not intended to mean, in our view, the same thing as moving drugs out earlier.
What we meant by that is that we really want to make sure that as our knowledge about a drug grows over time, we take the best advantage of that information. There is a traditional way of doing pre-market studies, and we didn't want to change that. However, in the United States there are ways by which a handful of drugs can come out “earlier”, meaning earlier in the pre-market study phase. Proportionally, in Canada, we've looked at 32 drugs that way, as compared with the 9,000 generally marketed; and those drugs were for very small populations, where people usually have an unmet medical need, so it's very narrowly confined.
The experience in the United States has really been to make sure that people follow up on studies. We've tried to explore this concept very responsibly, because people in these situations who are taking these therapies need to know the context they're in and that the study can be completed. Europe also has models they're working on in this respect.
So it's how you take responsibility for that handful of drugs—and these are not the general market authorizations that we would see in the life cycle for most drugs. In fact, for the vast majority of drugs there's no change in the pre-market data required. It's just for this very small handful.
Then the question you're going to is that you really want to make sure these commitments are met. So as we've been thinking this through and talking to many groups, there's a very strong insistence that.... For example, the provinces have told us that they want to see most issues resolved, that we have to deal with this responsibly. So again, making sure these commitments are followed up has been a very serious policy that we've looked at extensively.