Health Committee on April 1st, 2008

[Patricia Davidson, Conservative, Sarnia—Lambton, ON]

Thank you, Madam Chair.

Thank you to both presenters. You've certainly given us a different perspective on post-market surveillance today, talking about the gender issue and the issue with children and so on.

I find the gender-based analysis to be very interesting. I'm involved with a study on gender-based analysis and gender budgeting on another committee I sit on, so this is something that I find very pertinent. One of the things that is happening is that gender-based analysis for policies, programs, and risk management is already a part of the mandate of Health Canada. I think you're aware of that and I think you made some reference to that.

How would you build further on this mandate to ensure that post-market surveillance of these products captures the significant differences that could be there for different genders as well as different ages? Further to that, how would we get around some of the ethical issues that we've already alluded to here this morning regarding testing for young children or testing for pregnant women--those types of things?

Maybe you both could speak to those questions.

[Madeline Boscoe]

In a way I'm here because twenty years ago women sitting around this table and in the House thought that sex and gender mattered, and we needed to develop infrastructure and knowledge to help. Someone very wise, a mentor in my career, said, “Madeline, you've got to know that it takes a generation”, and I guess it does.

Why I think we need to see things like sex and gender in drug reviews in law is because it's hard to do, tough to do, and costs to do it. I'm working right now with the Canadian Cochrane Collaboration, which as you may know the CIHR has funded to help improve the analysis of evidence. One of the things we're finding is because the Food and Drug Administration in the United States requires sex as an issue in clinical trials, there are an awful lot of women in these trials, but no one's analyzing the data. It doesn't make any sense to me. You think you've done it, and you think you can go home and do something else, and you take another look and you realize.

So I think we're a long way away yet. We're building the case. We have some few researchers. The Department of Health supports a program called the centres of excellence for women's health, which I think was originally a multi-party initiative, which is helping build the data that I'm able to show you. So we can show not that this is a morally right thing to do, but it costs us not to do it. On the issue of including it in a regulation, I think we need training. I still think we need third-party analysis and audit processes to help advance that. These are skills that people are still learning, from a drug reviewer to a policy analyst. I think that those of us in the community need to help step up to the plate to help train and build capacity in the department.

My own feeling is that when we took women out of clinical trials because they might get pregnant, that was a somewhat paternalistic approach to a very complicated problem. It's true that we gave thalidomide to women when we didn't know anything about its effects on fetuses, and we've definitely learned the hard way. But I think women are much more sophisticated now about that. We have drugs on the market that do harm fetuses if women are pregnant, and they are taking them. Touch wood--except for a few examples, it's worked out well.

So I hope that's enough.

[Patricia Davidson, Conservative, Sarnia—Lambton, ON]

I still don't understand how you get around the issue of the testing part of it. How do you get away from the thalidomides and those types of occurrences, if you're actually doing the testing on a pregnant woman?

[Madeline Boscoe]

You need to first start in animal models, and animal models are very helpful on the toxic effects of drugs on fetuses. That's one of the ways. The other way is for women who are now in clinical trials, one of the agreements, for example, is that they don't become pregnant, and if they do become pregnant, they need to understand the risks. So those processes are in place.

Particularly, let's go back to the Gardasil example and testing with young children. I think this is a much more complicated area because of the intimate ways in which evidence is done. Fortunately, there are some new tests that are on the market now, for example, for HPV that are just starting out that we could use with this age group without exposing them to intimate examinations.

[Dr. Bruce Carleton]

I think the issue of how to ethically involve children and women in clinical trials when we know or might suspect that there is a problem depends on the question you're asking. It depends on what you want to study. If what you're trying to study is an effective anti-infective for a serious infection that occurs during pregnancy, then the ethical boundary you're crossing to treat women in a clinical trial to determine its effectiveness while exposing them to a potentially risky therapy can be weighed against the potential benefits of that therapy. I think how we get around the ethical issues depends on the question, really.

Anthracyclines destroy the heart. There's a 61% mortality rate. They also cure cancer. So they're effective drugs, and we can get around the ethical issue of using them if we demonstrate that the benefit is more than the risk of the presumed toxicity.

Then there is early clinical trial monitoring. Already mandated are data safety monitoring boards to ensure that interim results are reviewed. Any safety signals that occur early in a clinical trial halt the clinical trial until further evaluation can be done. So we minimize the exposure.

There will always be a risk to using any drug in human life. There will always be risk, much like driving a car entails the risk of accidents. We can make them safer, much safer. I think understanding gender differences is important. Age-related differences are important. But I really believe that the serious effects we're talking about are largely genetically mediated, and that's where the heart of much of the science will push all of us. We'll be followers in this in the coming years.

[The Chair, Conservative, Joy Smith]

Thank you, Dr. Carleton.

We'll go to Mr. Temelkovski.

[Lui Temelkovski, Liberal, Oak Ridges—Markham, ON]

Thank you very much, Madam Chair and both presenters.

I find this fascinating, Dr. Carleton. You mention a different sort of monitoring, which is genetic. You just finished by saying that we may be followers. Who would we be following? Are there other jurisdictions around the world that are much more advanced?

[Dr. Bruce Carleton]

I meant that you'll be following science. The science is there, and it's already been done. Warfarin genetic testing is being done now. Carbamazepine, a very well-used and well-accepted anti-seizure medication also used in some mental disorders, has a genetic test available to predict a rare reaction called Stevens-Johnson syndrome, which causes your skin to fall off. There are about 80 or 90 drugs that can cause that particular reaction. There is a genetic test now for people of Han Chinese descent, which is very important in Vancouver, to predict that kind of testing. This is already being done, and increasingly we'll see more and more of that.

It's not really a jurisdictional issue. It's really the science.

[Lui Temelkovski, Liberal, Oak Ridges—Markham, ON]

You also mentioned earlier that mandatory reporting doesn't work. I think that's why we're studying it, to make it, maybe, hopefully, more effective or to make it work.

Would more reporting of adverse reactions and, as you mentioned earlier, of no adverse reactions help?

[Dr. Bruce Carleton]

The system is 95% incomplete, so there has to be a massive increase in reporting, and the quality reports have to be there.

I favour a model in which we train clinicians, who are responsible for the recognition and reporting of adverse reactions, to do the work, and not just increase public awareness of reporting. It's great to have consumer reporting; there's nothing wrong with that, and I encourage it. But to get the substance of the reports we need, we really need dedicated professionals to monitor and evaluate drug responses. That's the information that will be most helpful.

In Spain it is a criminal misdemeanour to not report an adverse drug reaction, but it hasn't changed reporting. Vioxx was removed from the market because of Merck's own trial that confirmed the cardiovascular risk. No surveillance system in the world--mandatory or voluntary--picked up that risk, despite the fact it was the most frequently prescribed drug in the history of the world.

I suggest that surveillance systems run by governments traditionally haven't accomplished the goal of helping us identify significant risk in many cases. They can help in many ways, but I think we have to look to science to help us understand better ways to informed solutions. If we can have safety solutions we'll get reporting, because clinicians want safety solutions.

When I started my work I went to the oncologists at the Children's Hospital in Vancouver and told them what I was proposing to do. The head of the medical oncology unit said, “You know, it's an interesting study looking at the genetic basis of adverse drug reactions. We don't have adverse drug reactions in oncology.” That's either a sign of ignorance or arrogance, but it's neither; it's nomenclature. She doesn't think about reactions that are expected, like hearing loss and heart toxicity, as being adverse. She thinks of them as being a consequence of using the drug.

Now that they see that we can actually predict in whom the most serious toxicities are likely to occur, that's where reporting, funding, and support comes from. That's the way to get reporting. Maybe it's to mandate it, but it's to get individuals who are responsible for capturing these reports and individual institutions.

[Lui Temelkovski, Liberal, Oak Ridges—Markham, ON]

You mentioned that you've reported some of your studies and they're not yet published. Is there a filtering system there, from reporting it to publishing it?

[Dr. Bruce Carleton]

Right. We take all of the data we've collected and begin to go after specific reactions that we think are genetically mediated. We found three in the first six months, and we stopped looking at our data. We are still collecting and accumulating data, but we have a limited budget and limited resources. So we've concentrated on bringing these first three into a solution approach.

Instead of continuing to show a link between the drugs and genes, we're trying to bring these into a viable safety solution strategy for clinicians and patients who use those particular medications. So we started with serious morbidity, mortality reactions, drugs that are used in millions of patients a year, and risks that are at least threefold or more higher because of this gene trait.

[The Chair, Conservative, Joy Smith]

Thank you, Dr. Carleton.

Mr. Brown.

[Patrick Brown, Conservative, Barrie, ON]

Thank you.

Do you have any information on how other jurisdictions in the world deal with this in terms of females and children? Is there any evidence that systems are being adopted abroad that Canada could learn from?

[Dr. Bruce Carleton]

Sure. I'll start this time.

On the issue of other jurisdictions, in the United States the National Institutes of Health has a program called the pediatric pharmacology research units, or PPRUs. These were a result of modernization of the food and drug regulations, the FDAMA, the Food and Drug Administration Modernization Act, and a pediatric rule that was created particularly to allow for more testing. They created, really, an incentive for pharmaceutical manufacturers to do more pediatric testing early on in the drug development, and that has created a bunch of research units across the country to help produce better information about the kinetics of drugs.

Unfortunately, it's very much limited to the pharmacokinetics of drugs, pharmacokinetics being the way the drugs are absorbed, distributed, metabolized, and excreted from the body. It doesn't link in genetics at this point, although there's interest in doing that.

I think where Canada can add value to other jurisdictions is in areas like pharmacogenomics, in which we clearly are leading. I know we're leading because FDA came to see us in October. Along with seven of the major pharma companies, they formed a non-profit in the United States called the serious adverse events consortium.

Drug safety is one of those issues that pharmaceutical manufacturers definitely want to take on, now that Vioxx has been removed from the market. The reason they want to take it on is that they recognize it's a risk to their products and to their financial viability if drugs are pulled by them or by governments and safety concerns are identified. If they see a solution-directed approach, they seem to be interested. That's what they've created with the FDA: this way of taking all of these patients they have heard about or they may have collected information on and collectively look at whether there's a genetic reason or other common reasons that might be responsible.

They came to look because we have this embedded national network and they're interested in how we've done that. They can't do that in the United States. In the United States the hospitals compete with each other, even within the city. The international review team, when we began our work, told us that we'd never get this network set up even in Canada, and if we did we wouldn't find any biomarkers of drug risk. Well, we stopped looking after six months because we found three.

We did get the network set up. It took 18 months, but we did it. We feel with all the privacy issues, all the ethical concerns across the country, that every ethics review committee at every hospital and university in every province has to approve this, and that's all been done.

I think we have a unique value here by embedding such networks in the health care system that we can add to other jurisdictions, which other jurisdictions just simply can't do.

[Patrick Brown, Conservative, Barrie, ON]

One thing we've heard before at this committee has been testimony on the progressive licensing framework. How would you suggest that gender- and age-based specific tests be incorporated into that?

[Dr. Bruce Carleton]

I'll start, and then I'll let you comment, Madeline.

Very quickly, I've spent a lot of time working with Health Canada, many years, and also the provincial governments. I have been profoundly shocked, perhaps, on the lack of progress in many issues. We seem to have the same meetings with the same discussions time and time and time again.

There was a meeting in March, a stakeholder consultation, a Health Canada round on progressive licensing. I missed that. I told them I would come to talk to them about what I've done. I met David Lee, the lead senior counsel there, and Maurica Maher, who's head of the progressive licensing framework. I actually think those guys have the right attitude to this, but what they need to do is focus on solutions. It's great to have a framework, a legislative framework, but it has to be solution-directed.

If you want safer drugs for women, pick a drug, pick a group of women to test the safety and the new surveillance system on. It's the same with children, the same with men—let's not forget men. These safety issues are for all patients and are important. There are gender and age issues that are important, but it's important that we look to decide which safety solutions we would like to come up with first. So have solutions in place that you're aiming for, not just a framework for licensing. It's great, but it looks a little bit like a Cadillac from, frankly, a car dealer who hasn't ever really built anything like that before.

They need to recognize that we need to have very specific objectives to improve the safety. Maybe it's about a vaccine like the HPV vaccine, to understand the determinants of the deaths that have occurred or other risks that exist. There are many, many drugs and many reactions to choose from. We just need to pick two or three and get our feet wet.

[The Chair, Conservative, Joy Smith]

Thank you, Dr. Carleton.

Monsieur Malo.

[Luc Malo, Bloc, Verchères—Les Patriotes, QC]

Thank you, Madam Chair.

Thank you to our witnesses for coming today.

Dr. Carleton, in light of the evidence we have heard, I had the impression that considerable information was available on the adverse effects of drugs. What I hear you saying is that in the end, very little is received. You said that only 5% of results were published or made available. Why?

My second question is a bit of a follow-up on the previous one. You also told us that the 5% of available data often contained incomplete information. Was it incomplete due to the type of study you were doing on the human genome or was it incomplete because of the comparisons that could be made?

[Dr. Bruce Carleton]

Sure. Good questions.

There are two points. One is the incomplete nature of reporting, and the other is the quality of the reports, which is what we're talking about.

So the first is incomplete reporting. Why don't people report? There are lots of reasons that people have cited. I believe, after having studied this for 20 years, that the reason people don't report is that there's no reason to report. What happens if I report an adverse reaction? Health Canada already knows about that one. This is well accepted. Those are some of the things that I hear from clinicians. They're not reporting reactions because they recognize that somebody already knows about them. They don't understand the purpose of surveillance. The purpose of surveillance isn't to uncover whether a drug is responsible. It really should be to uncover whether there's a solution to the drug safety problem that can be produced as a result.

In 2004, a group of researchers in Toronto in Canada found that for toxic epidermal necrolysis, the most serious form of skin reactions that occur from drugs like Bactrim or cotrimoxazole, actually where the skin turns black and falls off in very large sheets--it's largely fatal in most cases, an awful condition--most of the patients end up in Canadian burn centres. There is almost no non-drug reason for that particular reaction to occur. So they went to Canadian burn centres and said, “How many of these cases have you treated in the last five years?” I think that was the length of time. They found only 4% of those cases were actually reported to Health Canada.

So I think part of the problem is that people don't see a reason to report in terms of helping them find a solution to these problems. It's just another report of a reaction that's idiosyncratic, from the Greek idios meaning “compound” or “mixture” of reasons. We don't know why. So I want to find a reason why.

The second question you asked was about the quality of reports. Why are the reports that come in not complete? And it's not just my reports. It's the ones in Health Canada, the ones I've seen through the Canadian pediatric surveillance program, the ones I've seen for the network I've built in the United States. The reason they're not complete is the physicians tell you the information they think you want to know. So if they think the purpose of reporting is to link drug and reaction, they'll report “Paxil: suicidal thinking”, and then sign their name. They don't provide all of the other information that's useful to determine the biological reason for the response, because they don't understand how you're going to use that information or how it's being used.

So I think that's part of the problem. We have to do more than just sell clinicians on reporting for the public good. We have to show them why it's useful--because we can get solutions.

I found when I built the network across the country that oncologists didn't want to participate in it initially. But once you start showing high odds ratios, high risks associated with a particular gene trait, they start to listen. The arms become uncrossed and they begin to listen and move to the edge of their chair and provide funding. Once they see a solution possibility, they begin to report. So I think those are the reasons why.

[The Chair, Conservative, Joy Smith]

Did you want to make a comment on that, Ms. Boscoe? You sort of raised your hand, so I wondered.

[Madeline Boscoe]

Is that okay?

[The Chair, Conservative, Joy Smith]

Please go ahead, absolutely.

[Madeline Boscoe]

I want to link it to the other question too. There are elements that we can learn around surveillance that I think Bruce has alluded to that have been a standard in public health. We do select doctors and nurses and pharmacists to report. We train them up. Sometimes it's on how much measles is going on or how much pneumonia they're seeing. What we haven't done is train up our professionals to do this in such a robust way. It's partially because people don't see a circle. They see a black hole.

The other piece that I think you've had before you is the proposal for the drug research and effectiveness network, which would be tasked with the job of developing how to synthesize this information, how to do the follow-up studies of the kind that Bruce is involved with and developing a hierarchy of needs. But I just can't stress enough that we need a framework going into it that will make sure that we're covering off the bases so that we are including sex and gender and we are including data on age at the beginning, otherwise we won't have it at the end and we'll be back here again just repeating the wheel.

I think those processes are in the planning stages, and I would urge you to bring Dr. Lee back.

[The Chair, Conservative, Joy Smith]

Thank you, Ms. Boscoe.

Mr. Tilson.