Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 14 - Evidence - April 26, 2012
OTTAWA, Thursday, April 26, 2012
The Senate Standing Committee on Social Affairs, Science and Technology met this day at 10:30 a.m. for a study on prescription pharmaceuticals in Canada. (topic: Clinical trials)
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
The Chair: Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie, I am a senator from Nova Scotia. I will ask my colleagues to introduce themselves, starting on my right.
Senator Seidman: Judith Seidman from Quebec.
Senator Martin: Yonah Martin from Vancouver, B.C.
[Translation]
Senator Demers: Jacques Demers from Hudson, Québec.
Senator Verner: Josée Verner from Quebec City, Québec.
[English]
Senator Cordy: Jane Cordy from Nova Scotia.
Senator Merchant: Pana Merchant from Saskatchewan.
Senator Callbeck: Catherine Callbeck from Prince Edward Island.
Senator Eggleton: Art Eggleton from Toronto, and I am the deputy chair of the committee.
The Chair: I thank the witnesses for being here today. We are continuing our study on prescription pharmaceuticals in Canada, specifically in this phase with regard to clinical trials. This is our fifth meeting. We have three witnesses today. I will identify them as I invite them to speak. We will begin with Mr. Jack Corman, President of the Institutional Review Board Services.
Jack Corman, President, Institutional Review Board Services: Thank you, Mr. Chair and senators, for the invitation. I must say that I found the brief and the task as laid out in the invitation to be quite daunting. The subject of clinical trials is huge, varied and complicated and getting more and more so. Distilling comments down to a few moments and trying to pick the most important items from my perspective I found to be very challenging.
As I was scouting around, I talked to various people whose opinions I respect and was told one thing: Tell the truth. You will be able to say things from a perspective that possibly no one else has and no one else will say. I do not plan to varnish my comments, but some important things need to be said as Canada continues down this slippery slope of losing its competitive edge, which we have had for years but, in fact, is in decline. I will give one example of what can happen.
About 10 years ago or so, when the European Union brought in their EU Clinical Trials Directive, there was a report, I believe in The Times of London, that showed that within one year Germany lost 400,000 jobs. Today, they have managed to execute sufficient reforms to turn the corner. Canada used to be a strong number two, globally, with clinical trials. We have dropped down to number three or four. Germany and France have jumped ahead of us, and there are reasons for that. We do not have enough time to explore them all, but I certainly have opinions that I would be glad to share with the members of this committee.
I would like to hold up this one little tablet. This is a $1-billion tablet — rosuvastatin CRESTOR. It cost $1 billion to develop this product. Today it is $1.4 billion to develop new drugs, and most of that money goes into clinical trials and into meeting the increasingly stringent regulatory requirements, in effect to take a zero-risk-tolerance approach to the development of drugs. It is impossible to eliminate risk. Yet, increasingly, the public and the regulators believe it is their duty to eliminate risk. You cannot do that.
I would like to use the JUPITER study as an example. I do not know how many of you have heard of this study, which was a very large trial. After this drug was approved, it assessed the possible health benefits of a statin drug for people with an elevated CRP, which is a marker of inflammation. That study was stopped early because it showed that people who were given this drug, without other indications of cardiovascular risk factors, did a lot better. They did not get the heart attacks or the diabetes and so on. "Phase III trial" means that any physician who chose to prescribe this drug on the strength of this landmark study with 15,000 patients was, in fact, guilty of off-label prescribing. In the U.S. it would potentially trigger lawsuits and so on. The dissemination of the information by the sponsor of the study, the drug company of course, is forbidden because it is not an approved indication. We get into this off-label use, and I think it is really important to ensure that physicians have the room that they require to exercise their professional judgment in terms of what is best for their patients.
I would also like to say that this particular JUPITER study had something like 869 sites around the world, and Canada got 10 per cent of those. There were two in Alberta, six in New Brunswick and I believe eight in Nova Scotia. Why? It was because of the ability to use private research sites that were able to use central ethics review, unlike certain provinces that have enacted silos and have prevented that. I can give many examples as it is an area where I have worked closely. I have been involved for 10 years on the expert committee and, most recently, on the Canadian Institutes of Health Research harmonization activities and on the Canadian General Standards Board standards committee for research ethics boards.
We have a crisis, a lack of trust and a lack of ability in the public sector to figure out ways to work together harmoniously and to leverage what exists in the private sector. This is really for my main message. We already have powerful, effective, private sector clinical trial resources that are not given the credit they are due. For example, you may know that over $100 million has been committed by the Ontario government for the clinical trials Ontario initiative, which includes harmonization. I met with some colleagues of mine who work in the private sector and with people in the ministry. They had no idea that there were already networks of physicians and that there already was centralized ethics review and so on. We need to leverage what we have.
I will give you one more example. A U.S. teaching hospital has a large clinical trial of an old drug for a new indication that is funded by the National Institutes of Health. It has 700 sites in the United States and 50 to 70 sites in Canada; and we are the central ethics board for that. The real message is that we were asked specifically to help them find sites in the private sector because they did not want to go to the academic institutions. There is something wrong. These are facts on the ground.
How we leverage what each side has for mutual benefit remains a huge challenge. I hope that we can find a way to do that better. I do not think CIHR has necessarily risen to that challenge. I have been part of the clinical trial summit and have seen the press releases and other initiatives in B.C. and so on. We need to find a way to work together for mutual benefit.
In the interests of time, I could stop there. I have a lot of other things I could say about issues around the regulatory environment. For example, the European CRO Federation wants to expand into North America. I was asked to advise them on where to go: Canada or the United States. Culturally they have an affinity for Canada, but they are concerned about the regulatory environment because they have heard some things about it that gives them great cause for concern. We are still in discussions, but I think it is a legitimate concern. There is also this issue around networks; and some are great. In one instance, one network demanded up to $500,000 of changes to the protocol plus the $25,000 fee to assess it. The way that our networks are constructed, doing the right thing and the right way, caused this particular CRO to walk away from Canada. We need a way to build more accountability into the system. It is doable, but people of goodwill who have experience in the trenches need better and stronger representation.
As I say, there are many other things we could talk about, but this has been sufficient for the moment. Certainly, you are more than welcome to ask any questions you wish in any way.
The Chair: We will get there, thank you.
Our next witness is Ms. Helen Stevenson, President and Chief Executive Officer of the Reformulary Group.
Helen Stevenson, President and Chief Executive Officer, Reformulary Group: Thank you very much for the invitation to speak. I will give you a few remarks from the perspective of a payer. I was responsible for the large Ontario Drug Benefit Program and also for the program throughout the reforms that we did in 2006 and 2010. I bring you that perspective today as someone who was faced with many difficult decisions with respect to the evidence brought forward as part of the approval and submission process for drugs to be funded and the even larger issue around sustainability and affordability. I am now in the private sector and have the perspective of a private sector payer, too.
You have heard, no doubt, throughout the course of various submissions with respect to clinical trials about the varying levels or different types of trials done and the different levels and qualities of evidence that are brought forward and done in trials, right from big randomized control trials down to observational trials and even just trials in "N of 1" or one individual. I am speaking as a payer, not a clinician, and as someone who had to take into consideration evidence. In those kinds of clinical trials, a challenge we often face is that the trials were done in what would have been considered an ideal population — people who really did not have a lot of other illnesses, could take the drug in very controlled circumstances, and had no other issues, et cetera. In the real world, and certainly among many of the provincial drug programs across the country, a large portion of the population who are covered under the programs are either elderly, which would have been characteristic of the Ontario program, or have multiple issues. Therefore, you automatically no longer have the ideal settings and you have challenges such as whether the therapies are tolerated, et cetera. The absence of that kind of data creates a real challenge for payers with respect to whether the results from those trials can be replicated in a real-world setting.
I would like to present two main challenges. One is with respect to what is adequate, both as a regulatory body, for instance from a Health Canada perspective, and as a provincial body, where we are tasked with making decisions and often trade-offs with respect to funding certain drugs in a large number of the population versus funding drugs that may benefit only a very small population. The challenge from a regulatory perspective is to determine what is adequate with respect to the evidence that is coming out of the trials, what has been studied in the trials and, on the opposite side, what is feasible for pharmaceutical manufacturers to do in their trials. By the time the files have come to at least the provincial governments, it is virtually impossible to go back and start building in new factors to the clinical trials.
Going forward, these are issues from a payer perspective that need to be addressed with respect to how we can go back into the very origins of the trials to try to influence them and build in things like comparators. Much of what a payer would look at is a particular drug compared to existing treatments both from a clinical and a cost-effectiveness perspective.
The second challenge, which would resonate with many people in the room, is with respect to sustainability. It was a constant theme. The Ontario program was the largest one in the country and quite generously funded but never funded enough. When you look at the different programs and funding across the country, there is the issue of affordability. It may be that a drug is safe and effective, but is it affordable in a particular province? That is a consideration as well. It might sound like a bit of a leap from the notion of clinical trials but, as trials come forward, we need to build in much more on the comparative side. As a payer, it comes down to a lot of trade-offs — in the public interest, am I providing the greatest good for the greatest number, or should we focus on providing funding for people who are vulnerable, and do we have the data to support that?
I am happy to answer any questions.
The Chair: From the Canadian Stroke Consortium, we have Dr. Mukul Sharma, Chairman of the Board.
Dr. Mukul Sharma, Chairman of the Board, Canadian Stroke Consortium: Good morning, senator. Out of respect for your ears, I will keep my comments in English.
I am an academic stroke physician at the University of Ottawa and newly elected Chair of the Canadian Stroke Consortium. Our organization is the leading stroke research and education organization in the country. We were founded in 1994 and have participated in 72 clinical trials amongst many other clinical research projects. We currently have about 160 members across the country.
I want to tell you about how we go about organizing trials, what the organization does, why it was created and the elements of clinical trials. It was founded in 1994 by a generation of physicians older than I who saw the need for collaboration to get clinical trials rapidly going in multiple sites across the country. There is no way that one or two centres have the resources, manpower or indeed the number of participants necessary to show benefit or harm with any new treatment. That was the reason for founding it.
The second reason was so that one approach went to the sponsor in terms of issues we had with design, the ethics of a trial, and indeed of the feasibility of running it in Canada. All of that has worked remarkably well, although there have been some issues recently, which I will come to later.
The trials we look at come from multiple sources: pharmaceutical companies and sponsors, investigators who are members of the consortium, or other investigators, often international, who approach us because of our track record in carrying out clinical research.
The process of that ensues as follows: The initial thing that happens with the consortium is it is presented to the chair, who makes a decision as to whether the concept is developed enough to go for a formal review. We like to be involved early in the development of trials so that we have some input on the design of the trial. It is difficult, if a trial protocol has been written, to actually change things and get them into the Canadian context or address concerns we might have, scientifically or with regard to the safety.
The review is conducted based on all of the information provided by the sponsor about the agent and about the proposed design of the trial. A committee is struck, the documents are reviewed, there is a one-day meeting usually, after which a report is issued by the chair of the review committee. One of the reviewers is always a member of the ethics committee who issues a separate report as to whether there are any ethical concerns related to the conduct of the trial. If it is accepted and approved by the board, it then goes out to the sites. We provide ongoing support to the sites in terms of conduct of the trial, monitoring and assistance as needed.
Our second mission is education. We have taken it upon ourselves to increase the capacity and density for clinical research and clinic trial capacity in the country in the field of stroke. We do so by training and mentoring young researchers, neurologists and physicians. Before we started this, for three years we had zero neurologists graduating and entering the field of stroke medicine. As of last year, we had 22; so some persistence certainly did pay off.
The growth of that population is jeopardized for a number of reasons, some of which Mr. Corman has alluded to.
I want to talk to you about why we do clinical trials and the elements of the design that are critical and important to ensure that a trial protects participants and results in a valid result that is as broadly applicable as it can be. Why do a trial? Is it not the case that after education, training and experience, I, as a physician, know what is right? The straight answer to that is no. Each of us, as human beings, is influenced by our biases and past experience, and physicians are no different in that. I can point to any number of examples that would have been thought of as no-brainers in terms of treatment but which did not work out when subjected to a trial.
One of the best of these in the field of stroke was a Canadian trial for a surgical treatment to prevent stroke. The most common type of stroke occurs when blood flow to a part of the brain is cut off and that part of the brain dies if blood flow is not established very rapidly. The major arteries that supply the brain are in the front — the carotid arteries. They are subject to atherosclerosis, so-called hardening of the arteries, which narrows and occludes them. In the 1980s, it was commonly thought that when there was narrowing and occlusion here if one bypassed the site of occlusion by an elegant procedure connecting one of the skull arteries internally to the brain, one would prevent stroke. Certainly, this worked well in the heart. It turned out that it did not work at all. One thing we learned was that restricted blood flow was not the cause but rather debris from the side of the narrowing that was transmitted distally. Years passed and just this year a second trial was published. People said, "Well, that is fine, but what you need to do is select a population where the cause actually is restricted blood flow." There was a trial where the vessel was completely occluded, so there was no possibility of debris passing, and measurements were taken that demonstrated that blood flow in that hemisphere was lower than normal. Guess what: That trial failed as well and mortality was higher with the treatment. We do trials because we cannot guess and we should not guess as to what treatments are effective and what are safe until they have been rigorously tested.
Any treatment is only good or worthwhile in comparison to something else. That something else is usually the standard of care, which in some instances is a placebo or no treatment.
How do we go about ensuring that the results of the trial are valid and applicable? A lot of this has to do with the design of the trial, and there are two elements that go into it. The first is methodology, common to all trials, and the second is expertise in that specific content area.
We want to avoid error and to avoid mistakenly thinking a treatment is effective when it is not; and vice versa, we want to avoid mistakenly thinking something that is valuable is ineffective. There are two general sources of error. The first is the random error, which accompanies all scientific measurements or all measurements in general. Just as in a chemistry lab, if one has a scale and weighs something, one writes down the weight with a plus or minus because that scale has some limitations as to how precise it can be. This would be true of any measurement we might make as an outcome in a clinical trial.
The second type of error, which is peculiar to medical research and clinical trials, is bias. I do not mean bias in the sense of the ordinary English term but rather bias in terms of a systematic error. That kind of error can be made if the design is incorrect and, for instance, participants are selected in a way that results in the participants not being representative of the population to which you want to apply the results. The other sources of bias have to do with measurement of outcome. For instance, and this is true just about always, if the investigator or the physician feels that the new treatment is effective — and, if you think about it, one really would not go into the time and effort to do these sorts of things if the treatment was felt to be ineffective — then one may have a tendency subconsciously to rate outcomes better for individuals who are on the new treatment. Some design elements are done to prevent you from knowing who is on what treatment; this is called "blinding." We go to great lengths to ensure that blinding occurs.
In one of the trials we undertook in acute stroke patients, it turned out that the trial agent, which was delivered intravenously, had a slightly yellowish tinge compared to the placebo. In that instance, we ensured that when the bag and the intravenous line were set up in the pharmacy by one of the pharmacy staff tasked with that, they were wrapped in tinfoil, which was impermeable to vision, brought to the bedside, and plugged to the intravenous line by a member of the treating staff who had no association with the trial, who then left; and then, the trial staff entered after all of this was done.
The second way that one wants to ensure that bias is minimized is in evaluating outcomes. There are some outcomes where it is hard to be biased; for instance if death is an outcome, it is relatively easy to decide if death has occurred. However, if the outcome is subjective — how one feels, if one has more energy, if headaches or pain intensity have decreased, then often the individual who makes the assessment clinically has no other contact with the patient or the trial apart from doing that assessment. When I do this as an investigator, it is called "blind evaluation." I walk into a room with a participant I have never met. I go through a set evaluation. The participant is instructed not to discuss things with me beyond the weather and how the Senators are doing — the less important Senators. The evaluation is done in a very standard format and put in. I have no knowledge of the patient's presentation or what sort of treatment or intervention they underwent.
The other issues critical to these successful interpretations of results are randomizations. There may be factors unknown to us that can influence outcome. The only way of controlling that is to not know which treatment that individual participant is going to get or what treatment the next participant will get. That is called "allocation concealment." Let us say that we are testing a surgical treatment. I have a feeling that this will work, but I am concerned that the next participant will not have a good outcome from surgery because they are frail or there are other issues that make me concerned. If I know they will be randomized at treatment, subconsciously I may not enter them into the trial, out of a desire to protect them. Allocation concealment is critical. All of these design elements in modern clinical trial reporting are specified. The journal will not accept it if those are not spelled out as to how they were done.
The final elements have to do with the way things are organized in and around the trial. Adverse events are collected systematically and reported to two bodies independent of the trial. The Ottawa Hospital Research Institute Ethics Board currently oversees 1,500 trials — a large volume of work. All of the adverse events are reported to the REB. In addition, all of the large trials we conduct have a separate advisory body called a data and safety monitoring board, DSMB. This is independent of the trial investigators and has access to all the data and can request any data or analysis during the conduct of the trial.
The primary responsibility is to ensure that participants are safe. Things may happen in the trial that are not visible for a conscientious investigator. If you are running a trial of 15,000 participants and you enter 80 at your site, you may not notice an increase in adverse events of a few per cent, which could be significant and important. That is the reason for the existence of the DSMB.
All of the trials that the consortium participates in are registered. The most common spot we register them is the American site, ClinicalTrials.gov. This was established in 1990, so it is 12 years old. As a physician and investigator, I do not think we should ever do trials that are not registered and where the results are not known. This results in harm to all of us. First, it is our money, either public money through CIHR or money that we pay in costs for pharmaceuticals, that paid for that trial.
Second, it is us as citizens, as Canadians, as patients, and as physicians who have volunteered their time and efforts and, indeed, themselves to produce the results, and we do have an ownership in that.
Third, it is a well known fact that, in terms of publication in journals, negative trials are far less likely to be published, especially if they are small. I think the concern that large trials, which are driven by pharma, will not be published if they are negative really does not exist. They are so large. As a pharmaceutical company, if you want to participate in the biggest market in the world, the U.S., you have to register. No one would conduct it without registering beforehand.
Also, in all of the trials we participate in — all large trials — ownership of data resides not with the company or the sponsor but with the investigator. It is the scientists — the investigators — who own and publish the data. Small trials that are negative may not be published, in many places in the world, for all sorts of reasons. Those do need to be registered.
We would encourage Health Canada to look at the options and stipulate a requirement for registration. As a researcher, it would help me enormously to know what was done, what worked, what did not work, and what the outcomes were.
I want to finish briefly with where we have been and the challenges we now face. Historically, in stroke research, Canada has been a very important player. It was Dr. Henry Barnett, at the University of Western Ontario, who did some of the seminal work that resulted in treatments we use to this day, things that seem as obvious as the effectiveness of aspirin in preventing heart attacks or strokes. It needed to be proven, and that was done by Canadian-run trials. So was carotid endarterectomy, standard treatment for stroke prevention. In every trial we have participated in, we have been complimented internationally for the conduct of the trial, the quality of the data, and our adherence to good clinical practice. We have been an important contributor to all trials.
We are, however, facing a number of challenges. First, the number of trials that we are participating in is declining. It is declining by decade. As an example — and this is a published paper in circulation — if you look at trials for stroke prevention, which I would argue is by far the most effective way to deal with a disease of this magnitude, in the 1990s, 24 such trials were conducted. In the 2000s, six were done and published. The number is declining.
The second thing that is happening is that there is a shift away from large pharmaceutical trials. Because of the complexity and the cost of what is required, this is the only way we will achieve new treatments such as prescription drugs, and it has decreased. Within the consortium, the number of pharma-funded trials we currently run is less than 50 per cent. Others are smaller, investigator-driven or publically funded trials. The complexity of what we do has increased. If we are conducting a trial with 30 sites, there are 30 separate ethics review boards that we need to go through and 30 separate contract reviews. I want to emphasize one thing. I do not have an objection to regulatory oversight. I welcome it. I think that it is important to know that things are conducted to a standard, in this country, that protects participants and protects the validity of the data. We will get into big trouble very fast if we leave those principles aside.
The problem is that the density of the environment has increased to a point where our timelines have become non- competitive. We go through, in Ottawa, at the University of Ottawa, the research ethics board and then the contract review. It may be six months before we are able to even start the site-initiation visit, start training our staff, and the rest of it. What we have seen is that the personnel time devoted to strictly regulatory issues has increased and is now over 40 per cent of the total time our people spend. The time spent with each trial participant, where our skills are most valuable, has decreased correspondingly, and the cost has increased. The cost of personnel has increased. We are in an environment currently, within the consortium, where we are doing fewer trials that are less well funded, at an increased cost and complexity. The trials are increasingly multinational. The numbers of participants are much greater outside Canada, and I think that there is a real risk that we will no longer be able to participate.
There are some centres at universities in this country, within our consortium, who can no longer participate. The reason was that their funding fell below the level where they could employ staff. It is not a quantity that can be dialed up. I cannot say to research staff, "We only need 70 per cent of you now, and you will be paid correspondingly less." As soon as it drops below a full-time equivalent, we end up laying off staff. That kind of expertise is hard to recreate in two or three years if opportunities come along.
I will stop there.
The Chair: I will open the floor now to my colleagues, starting with Senator Eggleton.
Senator Eggleton: Let me clarify a couple of things here. Does the fact that we are into a decline in clinical trials — there are fewer of them, you mentioned — does that mean, at the end of the day, that drugs are not coming to this country that people need, or does it mean that we are becoming more reliant on what is being done in other places, the United States or Europe or wherever?
Mr. Corman: I would like to first build on what Dr. Sharma said to give the broader landscape, which leads into the reply. Seventy per cent of the research is actually done in Canada in a private setting, not an academic setting. The barriers that exist with contracts and with central ethics review do not exist to nearly the same extent in the private sector.
We are a pretty good bellwether of what is going on. In fact, I think we are not just seeing fewer studies, but it will also lead to fewer drugs in this country. Again, it is a whole matrix of things to do with how we approve drugs and how we approve studies. In the regulatory soup, if you will, so much thickener has been added that it no longer flows. It is a real barrier and getting worse, and I include the inspector with that.
We talk about market access in the industry, and that is the pricing of drugs and the payer position. There is a reasonably direct relationship between decisions that drug companies make to market drugs in friendly jurisdictions, if you will, versus in unfriendly ones.
The Chair: I will get you to come back to the turf. That is a major issue, but it is not part of what we are dealing with. Could you come back to pure clinical trials?
Mr. Corman: Fair enough. I will simply say, with respect to that, that it is the comparative clinical trials and the pharmaco-economic analysis that we can do and need to do here in this country. We are losing out on both sides.
Senator Eggleton: What do we do, in terms of the regulatory framework, to get us back on track? You said, Mr. Corman, that we are at zero risk tolerance. You are dealing with people's lives. If we have risk aversion in this country, some people think it is more in the public service than anywhere else. Where do we draw the line here? Where do we make the changes in the regulatory environment to get us back on track so that we can get these clinical trials here to get the drugs here, without becoming too careless about this and while still trying to avoid error?
Dr. Sharma: Thank you for your question, senator. I think, in answer to your first question, that the answer is both. As the cost of drug development has increased, the number of pharmaceutical companies has collapsed. Due to the financial risk inherent in embarking on a course of development, fewer and fewer agents are being developed. That is the first thing.
The second thing is, we are more reliant on international trials, and I see that not just as a threat but as an opportunity. There is no reason a priori why we cannot lead international trials. We have the expertise and the skill set here. We do need to develop collaborations, at international levels, that permit us to do that. For instance, funding agencies — NIH, CIHR, and the European agencies — are all very parochial, if you will. They want the money spent within their jurisdiction. That is good as far as it goes, but it will kill us, in the future, if we are not able to develop those collaborations.
In terms of your second question as to where we go, as a physician, a citizen, and a person who deals with people who are suffering, I do not want to increase the chance that we will do harm. I appreciate what Mr. Corman said. We have to be honest that any time we do anything new, there will be unknown occurrences. It is not practical or possible to reduce that to zero, but the truth is anything that is foreseeable we should do our best to prevent.
What we can do are a couple of things. I think a lot of work needs to be done to avoid duplication. Why does the same protocol have to go through 30 different REB processes, where it is reviewed, questions are answered and different questions are answered? This is daily work for us in the consortium. Why is it that we need 30 different contract processes so that it takes years, over 30 sites, to actually get a trial going at all sites?
The other thing is I think we need to think seriously about a way to promote good clinical practice rather than adopting the punitive methods we have to date. The punitive methods are these: These are the regulations. You will be audited, and you will be punished if you have not met them.
Promoting good practice is especially good for centres that are smaller. I have the advantage of working in an institution where a lot of expertise is available to me. I see no reason why we could not develop networks to share that expertise with smaller centres and investigators.
Mr. Corman: There are two things that need to be thought through and implemented quickly in terms of regulatory reform. It is also legislative reform. The current Food and Drugs Act governs the sale of a drug. When you are talking about clinical trials, it is for the purposes of a clinical trial. The authority of Health Canada is limited to the sponsor, really. I think that is not enough. If you are going to have effective oversight, you need to have all the players under that oversight umbrella. That includes investigators, and it includes research ethics boards, which are presently outside of Health Canada's purview. I think the act needs to be amended to recognize that there is this additional requirement.
I think also, as with everything else, that the devil is in the details, in the implementation. I will give you an anecdote, a true story. Two years after a clinical trial was completed at a major Canadian academic institution, an inspector walked in, found a sandwich in the refrigerator in the clinic, and cited the sponsor for being non-compliant with the regulations, which reverberated all the way down to headquarters in the United States. This had never been seen by any other inspectorate in the world, and I can give you more examples like that. It is how we do our business, not only the regulatory framework.
I would also add one thing. Academic centres — and I do not want this to be us versus them because it really needs to be brought together — have historically not been compliant with regulations. They do not allow industry sponsors in to conduct audits, and — back to legislative reform, perhaps — Health Canada is not permitted to reveal the results of any of its inspections. The United States is maybe a little too transparent, but have you to let a little light in. We have to find a way to do that.
Senator Eggleton: Perhaps hearing from Ms. Stevenson, could you clarify the word "payer" because, in the context you intended here, that has not come in front of us yet. That is the first time I have seen the word "payer" being used.
Ms. Stevenson: I use the term "payer" to describe the organization, or, in this case, the government, who is essentially reimbursing, making the decisions with respect to what to fund. They are the payer, the one actually paying for the pharmaceuticals, although there is a reimbursement flow within that. That is what I use to describe it. More specifically, it is linked to the fact that, in that case, we were the ones who made the decisions of what we were willing to pay and what we were willing to fund and not fund.
My perspective around clinical trials is rather narrow from the perspective of having all the data presented to us as an organization that makes the decisions with respect to which drugs to fund for the beneficiaries that we covered.
The clinical trial data is a challenge that perhaps has to be backed up into the process from the very beginning. We will be asked to fund drugs on an exceptional basis, for a population of children, for instance, when the drug has rarely, if at all, been studied in children. I took very seriously, although I am not a clinician, the responsibility of assessing harm versus benefit. Even administering drugs, for instance, can sometimes create quite a bit of harm, especially with some of the specialty drugs. Our expert committee commented repeatedly how the clinical trials simply did not have the evidence for the specific indication — how the drug was going to be used — that they were applying. In the absence of that kind of evidence, it is difficult to make decisions. Then, it leads down the path around access and whether we are denying access, et cetera.
[Translation]
Senator Demers: Based on your experience, what steps can be taken to attract more clinical trials, without contravening the partners' rights?
[English]
Mr. Corman: I think we are on the right track. FATE has initiated a marketing effort, which I think is good. It is just a beginning. We need to do more of that. There is the talk about a concierge service — a central agency or office that, in effect, markets Canada. I was part of a group that went to Belgium a few years back, supported by the Quebec government, as a matter of fact, to try to interest Belgian companies and some French companies to come to Canada. We need to do more of that. We need to find ways and means to get the message out because we have been, as a nation, typically diffident in extolling our virtues. As we organize, remove some of these barriers, streamline certain things, and rationalize the regulatory environment, we have to tell the story and do it really well, which we have not done before.
Dr. Sharma: Thank you for the question, senator. I wish I had a clear, concise answer to that. There are a couple of things we can do. First, once again, we have to look at this as an opportunity to run and direct international trials, and we have to look at ways in which our funding agencies can collaborate with NIH, with the European Medicines Agency and with the Australian agencies, where we have academic contacts, to facilitate those occurrences.
The second thing we have to do is to think very carefully about the business model and the barriers to entry. Here, I am thinking in terms of pharma. If you are looking at a process that will cost you over a billion dollars to develop an agent, you want to make that as efficient as possible. I think there are some things you can do, such as consolidating multiple reviews, where the cost is reduced. I should point out that the members of the consortium, all of us, receive no compensation for this work or for our work as officers of the consortium. It is a labour of love in that sense. It is an important professional obligation we have.
The other costs, which are ancillary to it, do need to be done. There is a need — and CIHR is moving forward with this — to support networks of researchers like ours. Unless we have some substantial changes or some other way of recouping our finances, I do not think we will survive beyond five or six years as an organization. We will be fragmented, as we were in the early 1990s.
Senator Merchant: I think it was Ms. Stevenson who mentioned this. When you look at the clinical trials and new medicines, you try to get value for your money. Are all the clinical trials run against a placebo, or are there trials — and maybe Dr. Sharma can tell us this, too — where you compare the efficacy of one medicine against another, whether or not one is much better than what is already on the market? You said you might not be prepared to fund a medication unless there is proof that it improves the value added.
The Chair: You mentioned it specifically during your remarks.
Ms. Stevenson: I did. I will give you a short answer from our perspective. I am speaking from the experience of the drugs that have come to us to be reviewed and funded, so my perspective might be more limited than, for instance, Mr. Corman's. There was quite a large variation in trials. Some actually did what we called head to head — one drug versus another drug. Others were done the more traditional way of drug versus placebo. There was quite a big variation in the trials that we saw.
Mr. Corman: I would like first to address the placebo question in the context of the purpose of the trial. Registration studies to get a drug approved by a regulatory agency have to produce what is called level 1 evidence. Typically, the gold standard is the randomized, placebo-controlled clinical trial. Increasingly, that has run into some serious ethical issues. However, there are regulatory agencies, like the EU and the FDA, who essentially demand such a design. They are not designed to compare effectiveness or cost-effectiveness, one treatment versus another; they are just designed to prove that they work and are sufficiently safe for a particular indication. You have this double, maybe triple, layer of review — Health Canada with the marketing — and then you have the provincial review that is looking again at the same information. That is why, I guess, we — for good reason — put the Common Drug Review into place, which has an important role.
It is really important to understand the distinction between the two. I would also say that Canada — Health Canada — has a reputation for being excessively hard on placebo-controlled trials and is at some odds with other regulatory agencies. I would like to introduce at this time the notion of the harmonization of regulatory approaches. I will leave it at that, but I think we have a lot of work to do in that area as well.
Dr. Sharma: That is an excellent question, senator. In general, the principle in our field is that the comparator needs to be the standard of care. If it is the case that no treatment is available, it will be a placebo. If, however, no treatment is available, we would not enter into a trial where there is a placebo for the simple reason that we are, for 50 per cent of the participants, behaving unethically. We are not treating them properly.
Senator Merchant: I have one more question, if I may. Again, it came out of your presentation, Dr. Sharma. You said that sometimes adverse events are not reported. I thought that was maybe in smaller studies or something. Is there something that the government can do to mandate that reporting for the sake transparency and ethics?
Dr. Sharma: I think there are two elements to that question. First, how does one know that adverse events have occurred during the course of a trial? The answer to that is that all participants in our trials are evaluated on a set schedule, with a set series of evaluations. They can be blood tests or questions and are actually quite exhaustive. This prevents biased reporting of trials. Let us say that this or that occurred. All of that, everything that has occurred, is then are sent to REB, the sponsor, and the DSME, and records of hospitalization are reviewed as to what has occurred.
What I was referring to was publication and reporting of trial results that are negative, including adverse events. I think that what needs to be done is to take a position similar to that taken in the U.S. ClinicalTrials.gov — where, by the way, we put all of our trials — where it is stipulated for all clinical research done in the U.S. involving human subjects. I see no reason why we cannot follow a similar process here. We do not need to invent a separate website. That one already has international standings. There are currently 125,000 trials registered at ClinicalTrials.gov. It is publicly available, so you can go and see it. There are two phases to it. First, you register the purpose and the design, and then there is the results phase. The results phase includes adverse events that have occurred, so even if the trial is not published in a journal, all of that is available. You know what has happened.
Mr. Corman: I would like to speak from the regulatory side, first with respect to adverse drug reactions or suspected reactions. There are a number of different terms — serious adverse events and so on. There is an absolute immutable regulatory requirement to report all safety information. Where it is a regulated clinical trial, there is no doubt that adverse information is captured and reported.
I believe that, where it is publicly funded research — let us say that is not a regulated clinical trial under Health Canada or even the FDA — they follow the same rules. That is pretty much standard. I do not think it is a matter of escaping the reporting obligations. It is a big issue around interpretation and over-interpretation, and that is the hard part.
Dr. Sharma referred to deaths. Yes, it is an absolute event, but what is the cause? Attribution of causality is a really tricky thing. For example, everyone knows the Vioxx story — toxic drug, class action lawsuits. There were at least three drugs that had been evaluated for prevention of bowel cancer if given to people with rectal polyps, and Vioxx just happened to be one. It had not exhibited any kinds of cardiovascular toxicity that were interpreted as being cardiovascular. There were signs already, but the best people missed it.
I think that is inevitable. How we minimize that, I do not know. We are all fallible. That is part of the continuing, ongoing need to capture data and report it to the central agency, each regulatory authority. I hope that answers that question.
Senator Seidman: You have all been extremely candid and informative. Here is my question. Mr. Corman, you said in your presentation that CIHR has not risen to the challenge of doing the job better and that you would elaborate on that if asked. I would like to ask you about that, firstly.
Secondly, Dr. Sharma, you talked a lot about transparency and registering trials. Yesterday, we had an enormous amount of confusion on this subject, it seems to me, when we had the industry here. They, in effect, said that trials are registered. However, are they registered in Canada? Are they registered internationally? There are rules in the U.S. Could you help us with this issue of registering trials, which you pleaded for, and also registering the results of trials? There are many aspects to those results.
There are not only adverse events but also trials that are stopped. There are dropouts in trials. There is a whole series of things. There is also the transparency issue for the health and safety of Canadians and patients who are enrolled in those trials, to say nothing of the information that it gives them if they are looking to particular aspects of treating the diseases.
Mr. Corman: I should add that I have also participated in consultations with Health Canada on the clinical trial registry issue. The information I provided to you at the beginning was based on analysis of the clinical trials registries, so I have a bit of knowledge about the regulatory environment and what gets registered and so on.
Back to the thorny question of CIHR, I think there have been situations where CIHR is focused — not surprisingly — on academic institutions and problems at academic institutions, without looking at the bigger picture. I will give you one example. The Experts Committee for Human Research Participant Protection in Canada, a creation of the Sponsors Table, filed a report. That report recommended a new agency, and it did not have to be a government agency, that would have a number of different functions: One was education, and that is capacity building, for example; and one was accreditation, which is research ethics boards, investigators, and research institutions.
CIHR was probably the most prominent voice that pulled out of support of that approach. I will not suggest to you that it was the only way, but it is an example of "one step forward, one step back." Ten years later we are still trying to solve the problems we knew about, and we are not there yet.
I see the exclusion of the private sector and the focus only on academic centres in the province, for example, of central ethics review, and I am part of that as well with CIHR. I see institutions that I know do not match their regulatory requirements saying they will recognize each other anyway and they do not need to do verification. The standards for the CGSB for the research ethics board have just been passed with at least four areas where it fails to require the research ethics board to meet regulatory responsibilities. I think CIHR needs to step up, for example.
Then there is the SPOR initiative. How will you do good, comparative effectiveness at large enough populations only at, let us say, 42 academic hospitals that might not necessarily even be interested in these areas?
It is unlike the NIH and the example in the United States, where a strong public-private partnership exists and is driven by the needs of society through public funding and brings all the players together. That second study I referenced is good example. It is run and designed out of Harvard.
The Chair: Going to the second question, Dr. Sharma, I will get you to focus your answer on trials in Canada — the data with regard to trials in Canada. Before I ask you to answer, I will ask Mr. Corman if, after leaving here, you would like to think about the question that was asked and specific aspects that occur to you and to provide us further follow-up afterwards.
Dr. Sharma, please respond with regard to the registration, the publication of data of trial information, both positive and negative, as they occur in Canada.
Dr. Sharma: Thank you, senator, and thank you for the clarification. There is no requirement for publication or registration of a trial in this country at the federal level. There are requirements at research institutions; our research institution does require it, and a number do.
The sponsors will very often register trials done in Canada in the U.S. site because they plan on marketing the drug there. I say again I see no reason why we cannot nationally stipulate this requirement.
The one difference between us registering a trial at the U.S. site, for instance, and an American trial, is that all we have to do is register the initial parts, which are the trial design and what happened during trial flow. We are not required to put in the results. Results are a requirement, federally, in the U.S. Once again I would suggest it is a reasonable thing for us to do.
Senator Seidman: Could I follow up on that? Yesterday the industry people asked us if we wanted them to duplicate this; it was like, "Why would we register trials in Canada? We would only be duplicating what we are doing around the rest of the world in the U.S. and Europe, where they have these requirements." Could you respond to that, please?
Dr. Sharma: I would suggest not duplicating it. I do not think we need to waste the resources on it. I would invite you to go to ClinicalTrials.gov. It is very detailed in what it requires. It has 12 years of history behind its use. Check out what it requires in registration, patient flow, drop-ins, drop-outs, accounting for patients and what it requires in terms of results. However, we could stipulate the use of that site, for instance, or another one that Health Canada prefers.
The Chair: To be clear on your answer, certainly you have indicated there is no need for duplication, but the idea of registering all of the data and the results of clinical trials in Canada in is essential, in your view.
Dr. Sharma: Yes.
The Chair: If all of that is published on a universally recognized website, that is adequate, but it must contain all of these elements. Part of it is not sufficient; is that correct?
Dr. Sharma: Absolutely.
The Chair: We have understood you. Thank you.
Mr. Corman: It is extraordinarily dangerous if we talk about registering or providing raw data. I know that is an initiative at one time that CIHR was headed in. You are talking about the possibility of misunderstanding or misuse of data by people who do not understand how to analyze it properly. They also need the entire data for the clinical trial globally, at large, and you are also talking about the possibility of intellectual property issues.
Registration and what that means needs to be defined, and I do not know it should include the raw data. I do not think that is what Dr. Sharma was meaning, either, but I know that is something CIHR wanted.
There is one last thing and that is the phase. If you require registration of Phase I clinical trials of normal, healthy volunteers, there is no point to that. I can tell you that no agency around the world requires that. With that exception, my personal view is to support Dr. Sharma 100 per cent.
The Chair: Right; however, we understand there could easily be a clearly recognized standard of transparency with regard to this issue. I think you made your point very well in that regard, Mr. Corman, and indeed that is part of the background issue.
Senator Seidman: Thank you; that is helpful.
Senator Callbeck: Ms. Stevenson, you are the president and chief Executive officer of the Reformulary Group. My understanding of your group is that you help employers and insurers to lower the drug cost by providing a formulary. You get that information from analyzing clinical trials. Is that right?
Ms. Stevenson: Yes. Similar to some of the provincial processes, we have an expert committee we have convened that is reviewing the data — I will say a little bit less the trials and rather the aggregate data. For instance, it would be reviewing reports that are published through the Common Drug Review; reports from NICE, the National Institute of Clinical Excellence in the U.K.; the Cochrane Reviews — Canadian international bodies that do reviews on the clinical trials.
Senator Callbeck: You say "similar to the provincial processes"; does every province have its own process?
Ms. Stevenson: Not every province, but certainly some do.
Senator Callbeck: Do provinces use your information? Is it available to them?
Ms. Stevenson: Do you mean the information coming out of our private group or the information that comes out of the individual provinces?
Senator Callbeck: Out of your group.
Ms. Stevenson: I will say "not yet." We have just completed the creation of our formulary and the whole review of the data. The provinces do not yet, although we are hopeful we can be beneficial that way.
Senator Callbeck: If the provinces do, will they be paying for this information? How are you funded?
Ms. Stevenson: Do you mean how we are funded as a private company?
Senator Callbeck: Yes.
Ms. Stevenson: We have an organization that is a strategic partner and that has provided some funding for us to get up and running. Then we have our clients that are insurance companies on behalf of their employers.
Senator Callbeck: If the provinces want to use your information, will they have to pay for that or will it be available to them?
Ms. Stevenson: They cannot use our information, per se. However, our formulary, so to speak, which is a list of drugs — just like provinces have formularies — is something that we are offering as a subscription, right now through the private sector. However, it is possible for some of the provincial bodies as well.
Senator Callbeck: You say "offering" but that is for a price, is it not?
Ms. Stevenson: In the private sector for private companies, yes. Those companies are subscribing to us for a price; that is right.
Senator Callbeck: Do you analyze these drugs after the clinic trials?
Ms. Stevenson: Yes. We have two processes. One is with respect to drugs that are already on the market. The private sector is typically much more open with their coverage. Typically, as soon as a drug gets approved by Health Canada, they go onto the private formularies, compared to the provinces, which would do a more in-depth review and make decisions specific to the province. We are doing the review of existing drugs but also have a process with respect to all new drugs that have been approved by Health Canada.
Senator Callbeck: You do the review of the old and the new, and if the new drug costs more than the old one, and if the old drug is doing the job, you would continue to recommend it, would you not?
Ms. Stevenson: We would. We are a new concept in Canada, though it would be a very common concept in the U.S. That concept is of managed care, where people pay very little for drugs that are considered very effective and cost- effective. We introduce that element of cost-effectiveness, which really is not a theme of clinical trials. Then, for drugs that are similarly clinically effective and yet cost five times more, individuals would have to pay a larger portion for them out of their pocket. Therefore, that speaks more to the notion of co-pays. It tries to encourage decisions that consider cost-effectiveness as well.
The Chair: I will pull this one back, too, because you are moving on to decisions following clinical trials. That said, we have some good information there.
I will ask senators who were on the list I announced if I could insert a colleague who has another special event on the Hill so she can ask a question before she has to leave. Senator Martin, would you ask a question quickly?
Senator Martin: I thank my colleagues for changing this.
All of you mentioned today the need for collaboration and the concern about Canada losing its edge, trying to attract more clinical trials and being able to conduct that in Canada. My question is in regard to collaboration. I see the expertise you bring in your specific stakeholder groups and the importance of this kind of conversation. Is there a mechanism where there is ongoing dialogue or a sense of collaboration that we are working together within Canada to really achieve this goal?
I see the absolute need for it and you all have used that word, and we have heard it from other witnesses, as well. Therefore, are we collaborating effectively enough? What are some of the barriers? I know the silo effect is something that all industries or sectors face. Would you speak to the need for collaboration, and what some of those barriers might be that we should be addressing?
The Chair: You have all made comments on the importance of the distinction, so I do not want to repeat issues.
Dr. Sharma: I think that is at the nub of whether we will succeed in the future. To answer your question directly, right now there is no overarching structure or group or indeed even venue where different parts of the spectrum can get together and discuss these things. Things like the Canadian Stroke Consortium were created by researchers because we saw the need, and there are other groups similar to us: Cancer, Alzheimer's and Parkinson's disease, to name a few. However, there is no venue or capacity to do this in a comprehensive way.
If you think of it from the point of view of sponsors, one thing that would make it easier for them is if there were one stop in terms of approaching a group to know if the capacity and interest were there to participate in a trial.
The Chair: I want to ask you two specific follow-ups on this, Dr. Sharma. Within your consortium that works together, do you use a common ethical board approach and a common contract approach?
Dr. Sharma: The answer is no. The way the regulations are currently written, each research institution is responsible for the ethics board. I think there is a great deal of benefit to be had from moving to a common approach, but what it requires is leadership at the level of CIHR, I think, to bring about a harmonization, first, of standards across the institutions and provinces and jurisdictions, as well as laws and issues of indemnification. All of these things would need to be worked out.
The Chair: You answered the second question I would have asked: Who should take the lead in doing that? Clearly you are saying CIHR would be a logical choice.
Dr. Sharma: Yes, sir.
Mr. Corman: I would say that there is one organization that has newly been created that has the promise of being able to bring all parties together, at least on a provincial level, and that is Clinical Trials Ontario. They have, in effect, an executive director position that is being well fulfilled and, although initially solely focused on academic centres, they have now broadened the perspective to include all stakeholders. I think that needs to be done.
I do not believe CIHR is the best vehicle because of its focus on academic centres, which is natural. Unless the focus is broadened, I think we will continue to work in silos.
The Chair: At least it would move those multiple silos into something. You already indicated that, in the private centre side, you are able to get some general harmonization. We have been hearing that the major lack of harmonization is largely in the academic centres.
Mr. Corman: On that very point, it is a matter of will. There is a publication that you may know about called CenterWatch. It is the world's most comprehensive reporting newsletter, if you will, on clinical trials. It is out of United States.
There was a report in there about the Canadian Clinical Trials Summit held in 2011, which is a landmark event limited to academics. I and one other private-sector person were there, and that was it. Specifically, that article mentioned a key person at CIHR saying no private ethics and, by extension, no private researchers. How do we collaborate unless the will is there?
Ms. Stevenson: To add your question about collaboration, I would advocate that there needs to be much stronger collaboration in the post-marketing phase of a product.
The Chair: We will deal with that as a full study on its own and we will hear about that aspect there.
Senator Cordy: I think my questions have mainly been asked. You were just talking about the National Ethics Committee by another name, but that is what you were referring to. I think you are saying that we have to first set national standards guidelines; is that correct?
Mr. Corman: Yes. For 12 years now, I have seen dysfunction, most recently with an attempt to set a national standard for research ethics boards. It is almost a psychologist's issue: How do we get ourselves into a position such that we have trust and can work together? The Experts Committee reviewed the idea of a national ethics board and countries that have that. It is not the answer. The U.K. has had that for eight or ten years and what happened? It resulted in a decline in clinical trials. It sounds great, but when you implement it, it does not work — at least not if it is solely a monopolistic, government-run agency.
Senator Cordy: How do we make it better? We have 30 or 80 different contracts and 30 or 80 different requests —
Mr. Corman: I think there was a great start with the ACAHO principles for common contracts. It was also announced. I can tell you there are problems on the ground at implementation.
This is a national body, and we need to bring the provinces on board in a really effective "how to get it done" dialogue; you have to get all parties together.
The Chair: We are clearly hearing, Mr. Corman, the idea of having standardized contracts and standards requirements across ethics boards. You can have individual ethics boards that still have to be clear that the data meet the requirements, even though it is a standardized format. The idea of the difficulties of implementation is another issue. Let us stick to what is really essential in terms of requirements that we can recommend.
Mr. Corman: I do think that there needs to be uniformity in how the inspectorate does its work.
The Chair: Yes, that is the pursuit.
Mr. Corman: In addition to these mechanistic things about contracts, there has to be a way to build trust between ethics boards. I do not think national or regional boards are necessarily the answer.
The Chair: Mr. Corman, I think we have the idea of the various recommendations. We want to hear the various possibilities. One of them is a national ethics board. We are not hearing that consistently. Another approach to that is agreement on what ethics boards are looking for and then have the individual ethics boards, which are charged with ensuring that the procedures in their institutions are ethical, meet ethical standards. If that is the case, then a sponsor of a clinical trial could put together a single package that goes to each of the boards. Right now each board can require a different package.
Mr. Corman: Yes, I think —
The Chair: We will not argue the value overall. We want to get the possibilities on the table.
Mr. Corman: I would like to refer back to the Experts Committee recommendation: a coordinating body responsible for education, accreditation and policy. That is taken out of the funders' bailiwick because of the conflict of interest. It has to be an independent agency. For not a lot of money, you could have it and it would accomplish exactly what you are saying.
The Chair: That suggestion of yours is one we have noted and it is a very important point. Thank you.
Senator Cordy: We want to be able to make recommendations that will work.
I would like to go back to the idea that it all sort of ties in with the private and academic agencies working together. I think, Mr. Corman, you suggested that there are different regulations for private versus academic clinical trials, did you not?
Mr. Corman: The regulations are the same with a difference in the degree to which there is scrutiny in each of the different areas. The clinical trial regulations apply across the board. However, the intense scrutiny that the private sector gets is not present in academic circles. I know from people who have been involved in assessing them that the academic centres typically do not meet the same standards.
There is another critical issue here that is often forgotten: Canada is the largest recipient of U.S. federal funding for clinical trials in the world, after the United States. Those institutions that accept that U.S. federal funding are obligated to follow U.S. regulations.
Once again, we need to review how we go about harmonizing what we do to achieve uniformity. I think we can do something on a national level that ensures that all institutions that receive this kind of funding work from a common set of approaches, have a common set of procedures, common quality standards and so on. Maybe CIHR would be a good place for that.
Senator Seth: My question is very short because I have to go, as well.
I am very impressed with Dr. Sharma, who has been telling us about the trials on stroke. I know stroke is the leading cause of death and disability. What is the latest trial we have happening for stroke? What are the challenges we are facing at this point?
Dr. Sharma: There are three types of trials in stroke in different phases. The largest ones, and I would suggest the most cost-effective ones, are in the area of prevention. Those, as I said, are dropping off in number from 24 in the 1990s to 6 since the year 2000. Those are the ones where I think, as a society, as pairs, we have the most to gain from those prevention studies.
The second phase is the acute treatment studies. We know that for the most common type of stroke — when a blood vessel is blocked — everything supplied by that blood vessel is deprived of blood and will die in a certain frame of time. It turns out that time frame is realistically between four and six hours. We have developed treatments that can open the blood vessel if adopted in that time frame. I should point out that Canada is the leading jurisdiction for applying that treatment to the population in the world. Our rate here in Ottawa of treatment for ischemic stroke is 34 per cent versus a U.S. national rate of 2 per cent, so not comparative at all.
We know time is one factor that decides death, but more complicated issues are to know how much of the brain is still salvageable and how much is not. The current cutting edge of research for that is imaging to decide what is salvageable. Intravenous medicines have hit the limit and we are currently testing devices to open up the blood vessel.
Senator Seth: I do understand. I was there. Is any special drug under trial?
Dr. Sharma: There are a number of them under development. Did you have an area in mind?
Senator Seth: I was thinking of stroke. Is any drug on trial to clear up the vessels?
Dr. Sharma: The last small trial that was published acutely was for TNK, which is a thrombolytic, and a larger trial is pending.
Senator Seth: Is pending, okay. Thank you.
The Chair: I would like to come back to an issue that has come up here today a number of times. It has been part of the issues we are looking at in the previous meetings: the way in which the clinical trial is set up. We know the historic gold standard is new entity versus a placebo — the double-blind study.
Increasingly there is evidence — and Dr. Sharma gave a very good account of efforts being taken to prevent this from occurring — but there is increasing evidence that in clinical trials as many as 50 per cent of the participants might have figured out whether they are on a placebo or on the new entity. Parenthetically, the major reason for that appears to be some reaction in the body from a new entity. People have a tendency of thinking that new drugs will cause some effect, other than just the colour of the material.
There is evidence that an increasing percentage of patients on clinical trials may have figured out that they are on the trial, which can have an impact because we know there is also a clear and real placebo effect. One report I was reading indicated that as many as 80 per cent of the overall physician managers of a trial may have figured out which patients are on the placebo and which are not — or at least speculated that they knew.
The second issue, which has also come up today, is the ethical issue where you have people dealing with a serious disease for which there are existing drugs and the ethics of taking such a patient and actually providing them with a placebo if there is in fact a drug already on the market that deals with that. This happens by virtue of the way the trial is set up.
I think Mr. Corman stated the FDA explicit requirement with regard to the placebo trial and so on were rules that emerged initially in an effort to give a clear and unequivocal result to some benefit from a new entity. If in fact, over time, the population becomes much more aware, informed and understanding of things in general — such that it puts the traditional placebo trial at risk in the manner that I have indicated, and especially in those cases where there is an already existing drug on the market — what are your views about the value of going to a trial? We know a number of them have occurred already where you have the new entity, some are on the new entity, some are on the placebo and others are on one or more existing entities. Would you care to comment? Mr. Corman, I have referred to you. Perhaps you can start.
Mr. Corman: I would agree with you that it is not as cut and dried as it used to be. As more treatments are available and more complicated illnesses are being examined, the way a placebo trial is designed and where it is designed is becoming a really critical thing. For example, a short-term, two week, four week, six week trial in diabetes with placebo — as long as you have adequate safety measures — could be defensible.
An asthma study in a child with severe asthma that is either randomized to placebo only or new treatment: not acceptable. Maybe it used to be okay in the past. It is a real challenge for sponsors, regulators to get it right.
I have lost my train of thought. There was a corollary to your question, I think.
The Chair: I set a number of basics for the question as to whether moving towards trials —
Mr. Corman: I recall. I was going to give you an example. Back to Vioxx. There was a study with rofecoxib/Vioxx against naproxen sodium/Naprosyn in osteoarthritis of the knee. No placebo. There was a higher incidence of cardiovascular events in the Vioxx arm. It was written off because the drug does not have cardio-protective effects, which were noted with naproxen, so there was a logical explanation for the higher degree of cardiovascular toxicity in that arm. I have seen publications that said had a placebo been included in that study the toxicity would have been shown. Again, where you use placebo and how you use it is a critical question.
The Chair: That is an excellent point. Dr. Sharma, would you like to comment?
Dr. Sharma: I will be as concise as I can be. I think in general it is difficult to justify a placebo when an effective treatment is available. There are scientific justifications, certainly, as have been pointed out. This occurs frequently where people complain afterwards, "If only we had done this." The position I would take is that I would not run a trial I would not participate in myself or could not recommend to my mother or daughter. I think primarily we do not wish to harm participants for volunteering for the trial. If there is an effective treatment available it should be done.
Your other question, in terms of how to eliminate unblinding or how to minimize unblinding: First off, recognize that people are ingenious in terms of how they go about sorting this out. There have been anecdotes of patients participating in clinical trial in the waiting room comparing and switching tablets and things like that. Unless you stumble upon it you have no knowledge of this happening.
There are three ways that we do it. First is to minimize the difference between the treatments. Let us say it is a placebo. I can give you one example of niacin which is used to treat elevated blood cholesterol. It causes flushing and it is quite a noticeable sensation. In the placebo that was designed there was a benign agent that causes flushing so you could not tell what you were taking.
The second thing is to go back to how you evaluate the end point. Let us say it is difficult to blind it completely. The evaluation should then be done by an individual who has no knowledge of the trial and does not have access to that information. It is a blinded evaluation.
The third way around it is to measure if there is unblinding. There are trials we have participated in where, upon conclusion, I was asked to guess who was on what. Perhaps I am worse at this than the figures you quoted, but I have never gotten anywhere near 80 per cent. Patients are asked to guess as well. That is a piece of information that feeds back into the process and I ask the question, "If you, as a patient, guessed you were on active treatment, how did you know? What was it about it?"
The Chair: I want to get to another question, but I want to take Mr. Corman's answer, which was very good and a very good example to something Dr. Sharma said earlier about built-in bias in the way we interpret data. In fact, I think the example Mr. Corman gave is a very good example of how one tended to look at data under that circumstance. As we move forward, perhaps this colossal example may help inform the clinical community with regard to how to look at the outcomes and the symptoms that they are seeing. It is an evolutionary process along this line.
Dr. Sharma, I want to come to another issue that I understand is becoming increasingly challenging to companies that come up with new entities in complex disease areas. Stroke is certainly a difficult disease area.
I have heard anecdotally that companies, after finding an entity that they think may have some benefit to a complex situation, are almost paranoid about coming up with a final clinical trial protocol because it may well be the minute they attempt to test the new entity in Phase I and Phase II that something becomes immediately evident because of the complex biological systems we humans are. The problem is, as I understand it, that they then say the trial is not designed correctly; there is an issue here we need to deal with. However, if they now stop that trial to reconstruct a better, more informative clinical trial — or one that will lead to the real evaluation of the drug against the clinical symptom — they stand a chance of having the drug rejected for further approval in these areas.
Could you comment on this evolving concern with regard to adapting clinical trials on the basis of evidence as the trial moves forward?
Dr. Sharma: Absolutely. There is a huge financial risk that pharmaceutical companies take when they embark on these things. The trials that we participate in cost hundreds of millions of dollars each. In terms of adjusting designs, there are several principles that I think are helpful. In the vast majority of these trials, the sponsor should not, and does not, have control over the protocol design once it has been set. Who does have control is a steering committee of the investigators and the data safety monitoring board.
There are very nice examples in our field. One was for an acute stroke treatment which was funded by NIH, where the treatment resulted in heart failure in a number of participants. The trial was correctly stopped. One approach would be just to give up on that. However, the sponsoring agency, NIH, invited a response from the team of investigators. They identified a profile, a subgroup of individuals, where the treatment was unsafe, altered the protocol so that subgroup was eliminated — they were at risk and would not benefit — and proceeded with the trial.
I think that the sponsor should not have control over the design because the sponsor has their own biases, appropriately. They are a company and have a lot of money at risk. It should be in the control of the investigators and the data safety monitoring board with oversight from NIH or Health Canada in terms of changes in trial design.
There are other innovative designs that are coming up called "adaptive randomization" where you can test three different arms. Rather than doing it sequentially you do it simultaneously and arms are dropped off if, by a statistical rule, they are proving not to be beneficial. I think that will enhance our ability to do these in an efficient manner.
The Chair: You are optimistic that in complex disease areas, under the appropriate controls, trials will be able to be modified appropriately to lead to a thorough analysis of the possible efficacy?
Dr. Sharma: Yes.
Mr. Corman: I think it has been shown that adaptive designs can be really helpful in identifying promising candidates or knocking out those who look like they are problematic early on. That is the best use of adaptive design. You have to be able to analyze data and adjust as you go and I will not use the word adapt, no matter what the phase is.
When a compound is identified to move forward into clinical testing I think there is real room for Health Canada to collaborate with other regulatory agencies, the FDA and European Medicines Agency on what kinds of studies will be required to provide sufficient evidence of safety and efficacy. Moving forward, I think that can solve a lot of problems where we have been idiosyncratic in approach. That is perhaps the single biggest thing that we can do.
Senator Eggleton: Mr. Corman, in passing you mentioned off-label drugs but I was not quite sure what your issue or concern was with that.
Mr. Corman: I think certainly the climate around scientific discovery, scientific investigation and testing ideas that come from the researchers themselves runs up against the regulatory and legal environment. Where a physician may have the right to try different treatments and then maybe design a study, it is outside of the legal framework. For example, you can have the best possible clinical trial that, in the case with the JUPITER study, shows effect but you do not have regulatory approval. How do you get the message out? A publication alone is great — the New England Journal of Medicine, it does not matter. There are shackles on drug companies to share the information. It is dangerous to promote off-label use. I do not condone that, but when Pfizer gets fined $2.3 billion for off-label marketing, it produces a freeze.
Again, this is an area for comparative effectiveness testing, for example, publicly funded research to promote investigations of off-label use. However, it needs to be done in a relatively risk-free, threat-free environment for the clinician, rather than an environment that chills that kind of innovation.
The Chair: We are going to go into off-label as a full study in its own right so we will come back to that issue.
Senator Eggleton: Can I clarify one thing here? I found it interesting that you have offices in Toronto, Montreal, and Boca Raton, Florida. You follow the snowbirds, do you?
Mr. Corman: It is a fortuitous coincidence. We were asked to establish a research ethics board, or IRB, in the United States by a Canadian who had established a clinic in Canada and was expanding into the United States, and I was happy to do that. Also, because the regulatory environment here is in so many ways driven by the American scene, you really need to know what is going on down there.
Senator Seidman: I would like to ask you about another design challenge that has to do with certain populations, subgroups that are typically not included in clinical trials such as children, pregnant women and the elderly. Could you give us some insights from your perspective about that?
Mr. Corman: There actually is a regulatory imperative in the United States to ensure that subject selection is equitable, so that means you include vulnerable groups like that a priori, unless there is a reason to exclude them. There is a role for the ethics board to try to move that agenda forward, and Health Canada has recently published guidance on including women and children in earlier phases of research where the risk is higher. The question is, how do you protect them? I think there is a role for government to provide better incentives than have existed in the past, and to increase capacity. We need more researchers that are capable of undertaking that kind of work.
The Chair: Would you include the elderly in a category that should be looked at?
Mr. Corman: Absolutely. Back to the purity of the scientific method and the scientific model, you try to minimize the numbers of confounders. When you do that, you lose the ability to extrapolate the results of a clinical trial for registration purposes to general use in the population. You have sometimes very nasty surprises that will inevitably happen.
Senator Seidman: When you say incentives, could you please elaborate?
Mr. Corman: Patent protection. It has already been done. In Europe there is a requirement for a pediatric research plan to do a certain amount of pediatric research to get your drug approved. You get an extra six months of patent protection. Those kinds of things can be useful.
The kind of research you need to do to demonstrate that your drug will work in the general population is back to the post-marketing thing. I am glad to hear that you will have a separate session on that because I think it is a really important subject to explore.
Ms. Stevenson: I have a brief comment to highlight that it would be right at a provincial level where you are making decisions around what to pay for. It would be hugely beneficial to incorporate that to the degree possible in the trials. You are mandated with a decision of making decisions around drugs. For instance, in the absence of any studies on the elderly — which in Ontario and many other provinces is the vast majority of the people that are covered — it makes it more challenging to make those decisions. Not to go into the access point, but it also then makes us targets for criticism around not providing access. In fact, it really goes back to the fact it has not been studied in that group.
Mr. Corman: It just occurred to me that we make an assumption that there are all kinds of people who will want to take part in these studies. If you are 78 years old you have this disease and that disease, or maybe you are not sure. I think there is a role for the federal government to promote the importance of participating in a clinical trial. That is something that Health Canada ought to be charged with doing better.
The Chair: The issue of people being willing to participate in these categories is a separate issue from whether there should be testing, and we understand those two aspects.
Dr. Sharma: If I can address the issue of the elderly, the average age of stroke in this country is 70. Senator, I must confess to you that my definition of elderly changes every year with my own age. It is officially my age plus 17.
They are included, just by nature of the disease we study. I would make two points. First, we have to be careful about assuming that things that are demonstrated in 70-year-olds do not apply to 80-year-olds. There is a tendency to say if a trial only included individuals up to the age of 80, then if they are 82 we have no idea. Epidemiologists currently would take the stance that if there is a good reason in that population to suspect it will not work — and there may be — that it should be applicable.
Where this mistake has been made is in antihypertensive drugs to treat high blood pressure. In our way of thinking about the biology, these drugs take some years to have an effect. In every population studied they reduce stroke. We feel they reduce dementia and mortality as well. It had not been studied in older individuals, and physicians were reticent about translating that data to older individuals. A study was done in individuals over the age of 85 and guess what? They benefited at least as much as younger individuals.
Mr. Corman: I want to bring back the regulatory environment and off-label thing. If a drug is approved for use, say up to the age of 70, and doctors use it outside of the approved indication and there is a disaster, you can understand the liability issues. I would suggest that at some point those issues get looked at as well, if possible.
The Chair: This is why we have designed this study to be in sections where we will look at those things. Your points are well made.
Ms. Stevenson and Dr. Sharma if after you leave here you think of anything you would like to further clarify or inform us on — with regard to the publication, required public dissemination of negative results in trials — we would welcome that. You were very clear in some of your answers. I am not suggesting we did not understand, but it is an important aspect. Mr. Corman if you would like to think on that —
I mentioned you two because you specifically mentioned that aspect. We would welcome that further input from all the witnesses.
Furthermore, as you leave here if you get that insight into that specific example or aspect of an issue that just clicks, please follow up with us. We will welcome input from you up until the time we have completed our actual report on this. If you think of issues you would like to add to our information, please get those to us as soon as you can.
I think you will have noted we greatly appreciated, as was specifically stated, your frankness and clarity with regard to important issues. On behalf of the committee I thank you, and declare the meeting adjourned.
(The committee adjourned.)