Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 16 - Evidence - May 10, 2012
OTTAWA, Thursday, May 10, 2012
The Standing Senate Committee on Social Affairs, Science and Technology met this day, at 10:29 a.m., to study prescription pharmaceuticals in Canada.
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
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The Chair: Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
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I am Kelvin Ogilvie and I am a senator from Nova Scotia. I will ask my colleagues to introduce themselves starting on my right.
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Senator Verner: Josée Verner, from Quebec.
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Senator Seidman: Judith Seidman from Montreal, Quebec.
Senator Wallace: John Wallace from New Brunswick.
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Senator Demers: Jacques Demers, senator from Quebec.
Senator Poirier: Rose-May Poirier, from New-Brunswick.
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Senator Martin: Yonah Martin from British Columbia. Welcome.
Senator Cordy: Jane Cordy, another Atlantic Canadian, from Nova Scotia.
Senator Callbeck: Catherine Callbeck from Prince Edward Island.
Senator Eggleton: Art Eggleton from Toronto, deputy chair of the committee.
The Chair: Thank you, colleagues. Welcome to the witnesses as we continue our study on prescription pharmaceuticals in Canada, specifically with regard to clinical trials. I will introduce each of you as I ask you to present. I will start on my left, which means that Ms. Silversides will go first.
Ann Silversides is an independent journalist dealing with Health Policy.
Ann Silversides, Independent journalist, Health Policy, as an individual: First, I would like to thank the committee for inviting me to present on this important topic. As a journalist, I have researched and written a lot about clinical trials over the years, primarily for the Canadian Medical Association Journal but also for the Health Council of Canada, BMJ and other publications.
I think I have a valuable perspective because, as an observer who is professionally curious, I have read widely and interviewed a diverse range of individuals. As a journalist, I have tried to examine the interests of Canadian citizens and to shine a critical spotlight on government agencies and private companies in an effort to encourage them to better serve the public interest.
Having said that, it has been quite a few years since I wrote extensively about the various aspects of clinical trials for the CMAJ — quite a series of news features there — and as a result my observations will be of a general nature, but I hope useful.
In anticipation of this event, however, I have been doing some catching up, including reading some of the committee's transcripts. It is fair to say that it appears to me that little has changed, at least with respect to the issues I investigated and highlighted in my writing.
A few points for context — obvious, perhaps, but worth pointing out. There continues to be a huge push to bring more clinical trials to Canada or at least to maintain the current complement. The rationale focuses on the benefits to the economy — bringing in funding and supporting a skilled workforce as well as the various commercial organizations, contract research organizations, et cetera, that have emerged to support the clinical trial industry in Canada.
This thrust is in line with the current and, I submit, largely unchallenged and unquestioned push toward the commercialization of research in Canada.
It remains the case that the vast majority of clinical trials are industry-funded — 80 per cent according to a 2008 journal article — and granting agencies, the main one of which is CIHR, still do not fund many researcher-initiated trails. Only a tiny portion of its budget goes to funding clinical trials — something under 4 per cent.
Most trials take place outside of academic centres and are often to gain approval for me-too drugs, thus not adding much to the advancement of science or to the therapeutic arsenal.
Industry-sponsored clinical trials typically compare a drug to a placebo. Head-to-head trials to compare drugs — and hence provide useful information about comparative effectiveness and safety — remain rare, I suspect because pharmaceutical companies are not interested in participating in such trials and public funding of such RCTs is expensive.
Of course there are bright spots in the landscape. I think you have heard about the Canadian Stroke Consortium in which physician researchers evaluate trial protocols submitted by drug companies and decide whether to support the trial as is or with changes or reject it.
However, the lack of disclosure of trial results is still a huge issue, as I trust you are aware, given the patients who have been put at risk and suffered because of suppression of trial results, for example, the widespread prescribing of SSRIs and especially prescribing to teenagers.
Both the FDA and now the European Medicines Agency, as result of a recent ruling, far surpass Health Canada when it comes to making information about drug trials publicly available.
Health Canada has regularly come under fire, including from an all-party parliamentary committee, for placing the commercial interests of drug companies above patient welfare. You probably know that the Canadian Association of Journalists has awarded Health Canada its annual Code of Silence Award on four separate occasions because of its lack of public disclosure.
Pharmaceutical and biotechnology companies "make drugs and devices in order to generate profits. This may be a source of conflict with researchers' obligations of scientific integrity and participant welfare." That is not me; it is a quote from the second draft of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. I am sorry to say that I have not read the final tri-council statement yet.
I suspect that the "general public's" view of clinical trials is still, notwithstanding growing skepticism about the pharmaceutical industry, that trials are about advancing knowledge and improving patient care and that patients who enrol in trials do so out of altruistic reasons.
Those assumptions have been seriously challenged by exposes of the way that clinical trial results have been suppressed. I recall UBC geneticist Dr. Patricia Baird saying to me in an interview that as a result of these exposes and what is going on, she is worried that the social contract that allows research on human subjects is at risk.
People's motives for entering clinical trials are mixed and it depends on the phase of the trial. For example, recruiters for Phase I first-in-human trials pitch to students and poor people, advertising on public transit and in the back of free tabloids. The lure to participate is payment. There is an obvious risk of exploitation here. Patients may enrol in Phase IV, post-market approval trials, primarily to get access to medicine they might not be able to otherwise afford because it is post approval.
What do we know about patients' experiences in trials? Protection of research participants has been a source of concern and controversy in Canada for years and years and years. Back in 2004, Health Canada could tell me that the percentage of trials that were industry sponsored was 86 per cent back then but they could not provide the information on where the trials took place let alone how many patients were involved. I suspect that this paucity of information has persisted.
You will know that UBC Professor Michael McDonald, author of the landmark law commission report on research involving humans, famously said that in Canada we know more about trials involving animals than trials involving humans. I suspect that is still the case.
I was interested when I was told that some potential clinical trial participants now withhold their involvement until they receive written guarantees that trial results will be disclosed publicly within a certain time frame, but I suspect this is rare.
To quote from an article I wrote a few years ago:
The tendency among patients to have an optimistic bias and therapeutic misconception about trials has been extensively documented. Many patients have shown, for example, that they are unaware of the implication of randomization. Others believe researchers will make decisions based on what treatment would provide the best care for patients rather than in the interests of the research project."
I would like to close by saying that I believe the recent federal cuts to health groups such as the Canadian Women's Health Network will have a negative effect on the availability of information about, among other issues, patient safety and clinical trials. The Women's Health Network has been pushing for clear guidelines for inclusion of women in clinical trials and disclosure.
It was because of some modest funding from the Women's Health Network that I was able to research and write a paper on transparency and the drug approval process at Health Canada that became a chapter in the book The Push to Prescribe Women & Canadian Drug Policy. Thank you.
The Chair: I will now go to Trudo Lemmens, Scholl Chair in Health Law and Policy, Faculty of Law, University of Toronto.
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Trudo Lemmens, Scholl Chair in Health Law and Policy, Faculty of Law, University of Toronto, as an individual: It is an honour for me to be invited to speak on this important issue.
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Good health care practice requires reliable data. Safety and efficacy of products are difficult to establish within the controlled confines of clinical trials. Analyzing and interpreting data is complex. Better adverse event reporting and independent analysis after market entry are essential, but access to and analysis of industry-produced and often hidden clinical trials data are crucial to combat the serious public health challenge resulting from over-prescription and over-consumption of pharmaceutical products. In a recent commentary in PLoS Medicine, a leading medical journal, leaders of several European drug regulatory agencies endorse the need for more transparency.
Misrepresentation, subtle manipulation or the simple lack of public availability of important efficacy and safety data are associated with problematic promotional practices. They have affected the health of hundreds of thousands of people, and I am not exaggerating. What is not always emphasized is that unreliability of data also has huge cost implications. The cost of caring for people affected is one; wasteful spending is another. Again, a recent PLoS Medicine article raised serious doubts, for example, about industry-produced synthesis of the data that served as the basis for the public health agency's decisions to stockpile Tamiflu in the wake of the pandemic influenza.
Researchers were unable to obtain access to the full data that the company Roche invoked to support its claim, but they noted that there are reasons to doubt these claims, one being that the FDA disagreed with the company, another that there appeared to be problems with the under-reporting of adverse events in published studies. Billions of dollars were spent on stockpiling the drug. I will simply mention the figures of the U.S., namely, $1.5 billion in the U.S. alone. Doshi and colleagues comment, rather cynically, that "if the FDS is right, the drug's effectiveness may be no better than aspirin."
A key factor is that our drug regulatory system largely relies on industry for the production, analysis and distribution of important safety and efficacy data. One sensible option would be to separate those with an interest in the outcome of the data from those producing the data. Governments could more directly control the design, conduct, analysis and reporting of clinical trials. This would require a reorganization of the system and a shift in the reporting and contractual relations between the pharmaceutical industry and those conducting the trials. This will not happen overnight.
Other useful measures can be implemented immediately. Full transparency of clinical trials data, for example, will promote fruitful exchange and discussion among the scientific community, regulatory agencies, health care funders, patient advocates and industry, and it can reduce the use of data as marketing tools. Further, it will help drug regulators, research subjects and research ethics boards to know what clinical trials have already been undertaken, thus potentially reducing the duplication of unnecessary trials that expose research subjects to potential harm. Finally, it can allow researchers to detect problems with drugs much earlier. There are several historical examples where early access to small clinical trials could have alerted researchers to serious problems and could have helped avoid thousands of injuries and premature deaths. I can share some of these examples with you. I have the publications with me.
The importance of transparency of clinical trials data is internationally recognized. In 2004, the World Health Organization called for the worldwide prospective registration of clinical trials and set up an international clinical trials registry platform facilitating worldwide sharing of data. International bodies now impose trial registration and results reporting as a research ethics requirement, such as the World Medical Association's Declaration of Helsinki, or as a precondition for publication in medical journals. However, clear transparency requirements, control and enforcement mechanisms are essential, since evidence shows that reliance on soft governance does not work. When the U.S. first introduced soft requirements for trial registration for serious and life-threatening diseases, many trials, particularly industry trials, were not registered or were not appropriately registered and reported in results.
At the 2008 Global Ministerial Forum on Research for Health in Bamako, the World Health Organization called upon states to "develop, set, and enforce standards, regulations, and best practices for fair, accountable, and transparent research processes, including . . . the registration and results reporting of clinical trials." Several countries, such as the U.S., Argentina, Brazil and the European Union, are requiring registration and results reporting of clinical trials through strict regulations. In 2007 — this is five years ago — the U.S. Food and Drug Administration Amendments Act introduced severe penalties, including a $10,000 penalty per violation, per day, for non-registration or non-publication of results of Phase II to Phase IV trials of pharmaceutical products and medical devices. This also confirms what many legal commentators, including myself, have argued, that international trade agreements do not prevent Canada from providing better access to clinical trials data.
In Canada, adherence to the Declaration of Helsinki is indirectly requested under the concept of good clinical practice. The new 2011 Tri-Council Policy Statement always requires trial registration and results reporting. However, both are not easily enforceable — they rely significantly on largely unregulated and overburdened research ethics boards — and they remain vague about the registration and results reporting requirements. The TCPS, for example, only binds federally funded institutions. These initiatives will not be enough to enforce compliance of companies that often have a huge financial interest in not publicizing important trials or data.
Recent developments at the Canadian Institutes of Health Research are also a cause for concern. My colleague will elaborate further on the 2011 withdrawal by the CIHR of its Policy on Registration and Results Disclosure of Controlled and Uncontrolled Trials. In the wake of the withdrawal of this policy, CIHR reorganized its Knowledge Translation Unit and terminated the position of one of the scientists who contributed the most to CIHR's internationally lauded transparency initiatives. This all comes at a time when the CIHR is more than ever promoting industry-academia partnerships, for example, in its Strategy for Patient-Oriented Research and its Industry-Partnered Collaborative Research projects. Strong and enforceable rules of engagement on transparency are essential for the credibility and trustworthiness of CIHR industry-partnered research. When CIHR becomes a partner with industry in the organization of clinical trials and drug development, as it is doing with these new initiatives, very clear operating rules and oversight and enforcement are more necessary than ever.
In conclusion, Canada should urgently follow the lead of other countries, such as the U.S. and Brazil, and implement stringent transparency rules that apply to all health-related research. In the meantime, CIHR ought to reassert its lost international leadership role and reaffirm more than ever its unwavering commitment to widely lauded international transparency commitments that have, among others, emanated from scientists who were previously working within the organization itself. I thank you for your attention.
The Chair: Thank you very much.
I will now turn to Françoise Baylis, Professor and Canada Research Chair, Faculty of Medicine, Dalhousie University.
Françoise Baylis, Professor and Canada Research Chair, Faculty of Medicine, Dalhousie University, as an individual: Thank you for the invitation to appear before the committee today.
As you know, medical research is an important social good — I am underlining here that it is a social good — and I am pleased that the committee has taken an interest in this issue. It is presumably with a view to ensuring that researchers in Canada contribute to the production of socially valuable medical knowledge.
In my remarks, I will briefly address two discrete issues. First, I will comment briefly on the issue of transparency and accessibility of trial data with reference to the absence of robust requirements for the registration of clinical trials. Second, I will comment on Canada's failure to effectively promote research involving pregnant women, which is a discrete population that currently is treated constantly off label, without the benefit of evidence-based medicine. I will also comment briefly on policy and practice regarding mandated contraception for women of child-bearing potential.
With respect to clinical trial registration, it is important to do a quick history of what has happened. In December of 2010, we saw the introduction of the Tri-Council Policy Statement, TCPS2. On December 20, a mere few weeks after the TCPS2 was made public, CIHR released its Policy on Registration and Results Disclosure of Controlled and Uncontrolled Trials Funded by CIHR. This policy was developed "to increase the transparency and accessibility of trials by improving their registration and disclosure of their results," an important, laudable goal.
However, then, to the surprise of many, in March of 2011, a mere three months later, this document was rescinded and, I would argue further, erased. It is not able to be found on the CIHR website. It is not there as in "no longer applicable"; it is impossible to find, but for a cached copy held elsewhere.
At the time, the reason given for the decision by CIHR's vice-president of Knowledge Translation and Public Outreach, Ian Graham, was that the overlap between the TCPS, which had been released three months earlier, and this document would cause confusion and inconsistent application of the requirements.
Thereafter, the president of CIHR, Alain Beaudet, also explained this decision in a similar fashion, saying that an effort by CIHR to harmonize all of its ethics policies on research involving humans and to integrate operational requirements in relevant programs, where appropriate and feasible, was the reason for this change.
More recently, March 29 of this year, before this committee, when asked to address this issue, Dr. Beaudet stated:
We decided that our side policies — we had one on trials, one on stem cells, one on Aboriginal people — should all be integrated within the single tri-council policy. It obviously gives these council policies greater gravitas if they are integrated in the real policy rather than being local policy.
I submit to you that these statements are perplexing, at least to me, for at least three discrete reasons. First, there is not a single reference document in Canada for research involving humans. In 2010, when TCPS2 was endorsed by the three federal research granting agencies, CIHR announced at the same time that the CIHR guidelines on research involving Aboriginal people was superseded by TCPS2. It is absolutely true that that document disappeared.
Later, as I have already mentioned, in March of 2011, CIHR rescinded its Policy on Registration and Results Disclosure of Controlled and Uncontrolled Trials. However, CIHR has not done anything with respects to the stem cell guidelines, and they are an independent policy. This is important in the context where we are told that we cannot have more than one policy without engendering confusion.
Second, while the original CIHR policy on clinical trials registration was developed, as I said before, to increase transparency and accessibility, the TCPS2 requirement, as it exists now, does not achieve this goal. Dr. Beaudet has assured this committee, to quote again from his testimony, that "there are only minor elements from the original CIHR policy that are not yet in the tri-council policy statement because we have to consult with other councils and the committees of ethicists across the country who update the policy."
From my perspective, there has been a significant decrease in standard, and I have provided for you a table that I think constitutes evidence in support of this claim. It compares the standards in the CIHR original policy and what is currently in the TCPS2. I think you will see, quite clearly, that there is a huge, huge, difference.
The TCPS2 merely requires that the data be in a "recognized and easily accessible public registry." Further, while the original CIHR policy required that the name of the registry and the identification number be provided to CIHR, in which case the information that would be in multiple registries could be collated into a single national database, so that we would know what clinical trials were taking place, the TCPS2 merely requires that this information be provided to local research ethics boards. This means that you will have little scraps of information spread out across the country, with no ability to pull it together in any kind of national context. More worrisome than these watered down standards, however, are the missing standards. I urge you to pay attention to the huge discrepancies between what the TCPS2 requires and what the original policy statements from CIHR required.
Third, there is no reason why the TCPS2 and the original CIHR policy could not co-exist. The claim about possible confusion seems disingenuous as there has been no similar claim expressed, on the part of CIHR, about confusion between TCPS2 and the stem cell guidelines. Somehow, in that domain, we can have two sets of rules.
Let me move on quickly to the inclusion of pregnant women as this is a topic that is dear to my heart. It is widely recognized that pregnancy is a criterion that nearly automatically excludes one from research participation. This is so regardless of the costs of exclusion or the magnitude or likelihood of the risks of participation. The near complete exclusion of pregnant women from research on drugs and biologics means that there is little clinical trial data on the basis of which health care providers can make treatment provisions for pregnant women. This includes women with underlying health conditions — sick women who become pregnant — but it also speaks of healthy women who are pregnant and who become sick. I would argue that they are entitled to evidence-based medicine. There are good reasons to pursue this research. They are summarized in my written remarks, so I will move on.
I make the claim that justice requires that, if pregnant women are going to use drugs and biologics to manage their health, then we need to study these drugs and biologics in that population. More generally, we need to learn how to make reasoned decisions about risks in pregnancy, and that may mean taking calculated risks in certain contexts.
Moving forward, this goal will require changes by researchers as regards trial design, by REBs as regards research ethics review, by the panel on research ethics as regards the content of research guidelines, by the sponsors, such as CIHR, to make this a priority, by the manufacturers to design and fund such research, and by government to address liability concerns.
I mention all of these obstacles to make it clear that I understand that this is not an easy topic to grapple with but that we cannot ignore the needs of pregnant women.
Last, a few brief remarks about mandatory contraception to say that it is common practice, regardless of what the guidelines say, in Canada and elsewhere, for researchers to demand the use of contraception by women of childbearing potential while enrolled in clinical trials. This practice is deeply problematic for several reasons. Consider, for example, women who are not sexually active at all, women who are not sexually active in a heterosexual relationship, women who are sexually active in a heterosexual relationship but with a male partner who has had a successful vasectomy. Why should these women be required to take oral contraceptives? Consider women who have had a hysterectomy or a successful tubal ligation, women with certain types of infertility or women with male partners with certain types of infertility. Again, requiring these women to use birth control as a condition of research participation is offensive and should not be permitted under any circumstances.
Beyond this, why not just trust women not to be sexually active if you have informed them of the risks, if they understand them and if they would prefer abstinence to the use of oral contraceptives? This would actually be a better way of avoiding pregnancy. Current practice, however, with respect to mandatory contraception is discriminatory in that it is typically exclusively applied to women and in that there is really no ethical justification for this blanket requirement. If the worry is the risk of fetal harm, then it is also important, I would argue, to recognize the potential male contribution to this harm.
Thank you very much for your attention.
Senator Eggleton: Thank you, all three of you, for your presentations. You paint quite a different picture from what we heard from past witnesses. I even read a bit more about Professor Lemmen's contributions, through the American Journal of Law and Medicine, about the human rights case for clinical trials transparency, which deals with an international context I guess. There is a lot of commentary on the United States but some of that, obviously, would be applicable to Canada. This is a very biting report to say the least.
As to this whole question of transparency, when we had the Health Canada and the CIHR officials before us, we were led to believe that things were moving along as they should and that, while we did not have quite the same registration requirements as the Europeans or the Americans do, really, it was all — or most of it or the important stuff — was happening anyway, regardless of whether it was mandatory through legislation.
The CIHR comments, at the time, by Dr. Beaudet, were that they have all of their clinical trials open and transparent, so I am kind of confused about this withdrawal of policy matter that you have referred to.
Tell me where the holes are here. We are hearing two sides of the story here. Are there parts of it that do work in terms of transparency but other parts that do not work? Maybe you can help us understand which do and which do not. Are you supporting mandatory legislation — I guess you are from what I have heard so far — to increase the transparency of all of this? Where are the main problems in terms of the transparency issue?
Mr. Lemmens: You are asking whether I am recommending legal regulation, and I would say yes. I can actually provide concrete examples of studies that looked at what happens when soft governance, such as guidelines and recommendations, is used. It does not work. You actually, with guidelines and soft governance, catch people who may be inclined anyway to play fair and to be more transparent. You also create a difficulty where industry may feel in a bind because they are not sure that competitors will play according to the same rules. There are studies showing that registration and results reporting do not happen even when regulatory agencies, such as the FDA, with its significant power, strongly urge companies and others to register clinical trials. There are studies that have looked at this and have shown that when you do not attach a penalty to it and do not control it sufficiently, it actually will not happen. Strict regulatory requirements are absolutely essential.
This is the way the FDA has gone. I emphasized in my presentation that they actually impose potential financial penalties of $10,000 per violation per day. If a company in the U.S. forgets to or ignores to register a clinical trial or does not report within a given time frame the results of its clinical trial, for every day it does not report, it can be penalized $10,000 per trial it does not report or the results of which are not reported. Yes, I think strict regulation is possible and is actually required.
If you also look at the histories and the instances where trials have been hidden, where results have not been widely disclosed, they are actually very troubling, and they implicate the health and well-being of — I am not exaggerating, these numbers are cited in reports that looked at some of these controversies — tens, hundreds, thousands of people who have been affected by the prescription of drugs. If we had more information, if the scientific community had had more information, it would have been able to connect various sets of clinical trials, not only in Canada, but also perhaps internationally. It would enabled them to urge for further research or it would have enabled them to alert the regulatory agencies as well to intervene.
Therefore, I would say, yes, I am in favour of strict regulation, strict imposition of clinical trials, registration and results reporting. I think the problem is serious simply because we know that there is an interest in sometimes not disclosing very relevant safety and efficacy information. Why? Because it often actually allows off-label promotion of pharmaceutical products that are already on the market. I think it is a serious issue.
Senator Eggleton: That is an industry reluctance?
Mr. Lemmens: Yes, the industry is reluctant, but actually, to be honest, I think if the rules were clear and there was no doubt about it, I think they would have to go along.
The FDA actually does make an exception for Phase I trials as I mention in the article. Commentators have argued that we should go further, that we should also include Phase I trials in mandatory registration results reporting.
Some of the cases I mentioned are cases where researchers actually have looked at some historical promotions of particular drugs. I can cite you the example of anti-arrhythmic drugs which were widely prescribed in the 1980s, and an important clinical trial that was conducted in 1980 was not available until 1993. In hindsight, the researchers actually now conclude that if we had information about that clinical trial in 1980, we would have immediately seen that there was a significant problem with the prescription of those particular drugs. The prescription of those particular drugs, and I quote the article, is associated with 20,000 to 75,000 lives lost per year in the United States in the 1980s. In the 1990s, the prescription of the drugs was stopped because the evidence was clear that this was actually a very dangerous practice.
Senator Eggleton: In passing over to Ms. Silversides, you also mentioned that Health Canada and others want to increase our involvement in clinical trials, that we have been losing ground there, as one person said yesterday. Is this part of the reason why there is a reluctance to go to full transparency and making it mandatory, some feeling that we have to try to open up to get more clinical trials in Canada? What do you think is the reason for the reluctance?
Ms. Silversides: I am a journalist; I am not supposed to speculate on that kind of a question.
Senator Eggleton: I always thought you always did; journalists always do, do they not?
Ms. Silversides: I will stick to quoting people on the facts.
It is an interesting hypothesis. I actually wrote the BMJ article that first revealed the withdrawal of the CIHR clinical trial policy.
Why was I saying that? I was surprised to see Dr. Beaudet questioning that. What I pointed out in that article was that withdrawal also happened at the same time they were negotiating their next agreement with pharma, their five-year agreement, when that withdrawal took place. There is good reason to suspect that.
I wanted to follow up briefly on what Mr. Lemmens said. It is about guidelines and how ineffective guidelines can be. Last year I had a CIHR health journalism grant to look at prescription painkillers. As you know, we have an epidemic of serious addiction and so on because of particularly OxyContin. Opioid prescribing guidelines came out. This is not about clinical trials particularly, but guidelines came out, and it did not make a change. Doctors did not use them. With time, some algorithms have been developed to help doctors, but guidelines do not work. Things that are not in legislation, things that do not force or require disclosure or, in this case, changes in prescribing do not work. It is just another example of the weakness of the guideline approach and the recommendation approach to issues involving health care, involving prescription drugs in particular.
Senator Eggleton: As Ms. Baylis answers, could she also talk about whether we should make it mandatory in terms of obliging drug makers, investigators, through regulation to deal with trials involving pregnant women?
Ms. Baylis: I think that the issue with respect to trials involving pregnant women is very complicated, as I tried to illustrate at the end, in terms of the number of people that have to come on board. There are two different kinds of approaches. We can have a carrot or we can have a big stick.
Some of it may require a big stick in terms of the fact that there is no real incentive to do research in this population. It is a very small population. Most women, if they are lucky, only stay pregnant for exactly nine months which means they are not a really strong advocacy group once they are un-pregnant again; and it is a context where, quite frankly, pharmaceutical companies can afford to not have that share of the market. There is actually an incentive to just say "not for use in pregnant women," recognizing that pregnant women do get sick. They get hypertension, they get diabetes, or they have it beforehand, they have depression. They have all of these health needs, but then companies are in a position to say, "But we told you not to use it." However, if you are a family physician or an obstetrician/ gynecologist and you have a patient in front of you with Crohn's disease, what do you say? "Sorry, nothing we can do for you while you are pregnant; come back in nine months"?
We cannot; we do not. We care for these women, but we do that in a context where we do not have good information or we have information that is anecdotal or case reports or acquired over time. There are ways we can incentivize the pharmaceutical industry to do this, but there are ways we could also choose to legislate.
If I can, though, I would like to draw people's attention, in support of comments that have just been made by both of my colleagues, to the schemata that I put at the back of my submission with respect to clinical trials, showing you the relationship of the three funding councils to the Panel on Research Ethics, and I think you want to think about that in terms of an issue of structural conflict of interest.
They are reporting to themselves. They are setting the guidelines for themselves. It is all a very sort of internal kind of mechanism, and the Panel on Research Ethics reports to the three presidents of SSHRC, CIHR and NSERC. In that context, we need to pay attention to what the primary goals and objectives are and what happens when there is a conflict between what is in the interests of the research community, what is in the interest of Canadians, what is in the interest of particular constituencies. There are some huge issues here worth looking into generally with respect to guidelines set internally, as if they are sort of professional guidelines as contrasted with rules and regulations that apply across the country and not only to that which is funded by those organizations.
Senator Eggleton: Thank you.
Senator Callbeck: My thanks to the three of you for appearing today.
Ms. Silversides, I want to ask you about an article that was published in the Canadian Medical Association Journal 2011 called "Clinical trial participation poses ethical, practical issues."
Now, you stated here that the University of Toronto's Faculty of Medicine prohibits the offer or acceptance of finders' and completion fees.
First of all, the acceptance of finders' fees, is that physicians or is it other health care professionals? Who exactly are finders?
Ms. Silversides: Finder fees?
Senator Callbeck: Finders' and completion fees.
Ms. Silversides: Senator, you are making me pull back in memory. It is actually not 2011 because I have not worked at the CMAJ for quite a while now, a couple of years.
Can you speak to that, finder fees? It is recruitment; it is contract research organizations, I believe, that does that.
Mr. Lemmens: Yes. A couple of years ago I wrote two articles on the finders' fees, one in PLoS Medicine and another one in The Journal of Law, Medicine & Ethics. The reason I came to write on this issue was that I was contacted by a clinician, an academic professor, who was a specialist in geriatric care, and he invited me, and I worked with a colleague, then a student, Paul Miller, on the topic. We investigated what the practice is to a limited degree. We did not do social sciences research, but we looked actually at what the legal issues are.
What is interesting is that the geriatric specialist asked me to write particularly about this because he felt that in the context of geriatric care, for example, he was — and this was his statement — confronted with the fact that it was increasingly difficult to find people focusing sufficiently on clinical care. He said many of his colleagues are actually running clinical trials. There is already a problem with access to geriatric care in the community, but the clinical trials conducted on elderly patients are so widespread and are paying so well that we have a problem in terms of making sure that people focus sufficiently on clinical care. That was his statement.
We looked into it, and there have been reports certainly in the United States as well, from committees like this one, that looked into the phenomenon of finders' fees. There have been a lot of media reports of the use of financial incentives to recruit patients, sometimes with additional payment if you recruit faster than others.
Does this create a tension with respect to the duty that physicians have towards their patients? It is an important issue that you bring up.
Senator Callbeck: However, these financial incentives, who are the finders? Is that just the physicians, or is it other health care professionals?
Mr. Lemmens: It is also health care professionals. Again, this is anecdotal evidence, but when we were looking into writing something, we would hear, for example, of nurses being offered certain incentives to make sure that a patient who was in the hospital would be recruited to the physician with whom the nurse was working. It is not only physicians; it is also other health care professionals, but I think primarily physicians because physicians are the ones leading the clinical trials in our hospitals, and so they are the primary contact people, the primary recruiters, and actually the people who then are also involved in some of these clinical trials.
Senator Callbeck: It says "finders' and completion fees." Are there two fees involved here? The physician gets a fee for finding the patient and then what?
Ms. Silversides: For completing the trial, yes.
Senator Callbeck: There are actually two different fees.
Ms. Silversides: I believe so, because if they do not complete the trial, they do not get the money at the end.
Senator Callbeck: Now in this same article it stated that one doctor claimed he earned $2,000 for each patient he recruited to a trial. Is that the generally accepted figure?
Ms. Silversides: As I say, you are drawing on my memory here, but I do not think we actually know very much about that. In fact, I do not know if that is an attributed comment, but there is not a lot of evidence about the amount of money that is paid to physicians.
It is interesting that you should raise that article as an example, because the top part of that article was rewritten, which I do not agree with, by my news editor at the time, which is maybe part of the reason I do not work there anymore. It put a more sensational top on that article than I would agree to.
Senator Callbeck: So because of these payments that are made, is there potential for accurate clinical trial results? What is your opinion on these payments?
Ms. Silversides: I think the risk of the payments is bringing patients who might not be really truly eligible for trials into trials. That has been raised by other people I know, but it should not necessarily call into question the results of all clinical trials.
Mr. Lemmens: I will quickly add something to that also. It is difficult to actually find out what exactly is happening. Physicians are appropriately compensated for, say, extra time that they would spend on filling out forms, and so it is very easy to hide. If you give a payment, you can hide it simply as compensation for extra work, but if it becomes actually an incentive to recruit additional patients, there is certainly a risk that there can be skewing of the inclusion criteria. Therefore, people who actually should not be in the trial are in the trial, or we all know that informed consent is an imperfect means to ensure that people really freely decide what they want to do.
There is actually a risk that people will be softly pushed. People like to trust their physicians, so there are two concerns: Inclusion criteria can be skewed, and people who may not be inclined and may prefer a standard medication that has been on the market for several years, that has proven a certain or has a certain known efficacy and safety record, are now pushed to participate in a clinical trial where they may end up taking a drug that is not effective.
Ms. Baylis: One of the things to perhaps be aware of is that research ethics boards, which look at research proposals before they go out to the community, will often look at financial transactions, but they typically tend to look at the transactions between the researcher and the research subject. For example, there can be completion fees that are offered to participants in order to try to keep them in the trial, but very often — and this is something that some research ethics boards do better than others — the members do not actually look at the contracts and the contractual arrangements between the company that is sponsoring the trial and the researcher, so they may not have the same kind of full information about what those financial incentives are, and some of the concerns also could be addressed in what is the role of the research ethics board in getting access, requiring access, to those contractual terms.
Senator Callbeck: So is it difficult, generally, to find participants for clinical trials?
Ms. Baylis: It depends on the trial, but I think it is important for you to know that there are some trials that open, that go through all the work of being passed by a research ethics board, and they do not recruit a single person and end up closing the trial. That is why you are seeing global initiatives, you are seeing multi-centre trials, et cetera. It is also why a number of people have complained about the situation in Canada where you have all these individual local research ethics boards. You go to one and they say yes, and you go to the other and they say no, and you go to the next one and they say change it three ways from Sunday.
It is a very long and tortuous process, and people who are interested in quality research are asking how it can vary that much from one institution to another. There are some broader issues about the governance of research ethics in Canada that need to be addressed.
Senator Seidman: I think "perplexing" is the word you used, Dr. Baylis, and I think all of us are feeling a little perplexed because we have had a host of contradictions on so many issues as we sit here listening to the different witnesses, or just different perspectives. Maybe "contradictions" is not the right word but "different perspectives." I totally appreciate what all of you are saying to us, and I would like to just ask some questions now, very specifically. If you do not have the answer to give immediately, if you would be able to send us materials, I would appreciate it.
On the issue of transparency, as recently as yesterday we heard there were no issues in terms of registering trials because all the large trials are registered internationally. I think you are telling us there are issues here in Canada, but what I would like to know very specifically is this: Is there anywhere a delineation of the type of data, the exact data that should be collected for purposes of patient safety, and even just for basic information for patients, families and doctors in this country? If there is a delineation of the kind of data that should be collected in the system we are talking about for a clinical trial registration and ongoing information of that trial, I would really appreciate it if you could send such a list to us later.
I do not know if we want to get into any delineation of that kind of information.
The Chair: I will go to Professor Baylis.
Ms. Baylis: There is disagreement at this point in time about how much or how little should be in there and how much or how little can be in there. There are concerns about proprietary information, et cetera; so there is a disagreement out there.
There is one thing that I think is important for you to pay attention to. If I can, I would just like to speak a minute to the table that I tried to put in front of you there as support for the kind of concerns that I would encourage you to look at. If you look at what is now required, it says it should be any easily Web-accessible public registry. To me, that is not even an attempt to have certain kinds of standards. Whereas if you look at what was in the original CIHR policy statement, it said any WHO or ICMJE — which is the International Committee of Medical Journal Editors — endorsed registry.
One at least has the good housekeeping stamp of approval of WHO and ICMJE and the other one has the stamp of approval of being easily accessible on the Web. I would submit to you that is already an issue in terms of standards.
There is an attempt to say that if they have been endorsed, then presumably they think it has met some minimum standards of disclosure.
Another important thing to draw your attention to is the first element, the Prospective Registration of Trials. That information, once you have done your registration, is to be given to CIHR. That means that there would be the possibility of a committee like yourselves saying to CIHR, "Could you please give us the data on all the clinical trials registered in Canada?" and they could at least say, "We have funded these many hundreds of trials. They are registered in these six different registries but they are all approved by WHO/ICMJE, et cetera, so we can give you this data."
With what has happened now, you could go to my institution, you could go to Mr. Lemmens' institution — you could try, but it would be difficult to do that.
As a researcher in this area, when I want to know what is going on in a clinical trial, I go to ClinicalTrials.gov. I go there, and I can see. That becomes really important for specific trials. I have done a lot of research and writing about the Geron trial, which was about stem cells. One of the things you may have followed in the news is that they stopped their trial midway. It is a Phase I trial, and I argued that they abandoned patients. I was partly able to make my argument because I could go and see that they were originally planning to enroll 10 patients in this clinical trial. They did not. They stopped at the halfway mark. There were four patients enrolled at the time, and they made comments to the effect that "Do not worry; we will be able to provide you with the very same data as if we had finished the trial." I said, "Wait a second. Either you needed 10 patients or you did not. Which is it?" You cannot after the fact say you were just going to put in 10 because you just picked 10 out of a hat. Presumably you had good reasons for picking those numbers. Now, if you are stopping partway through, you are actually undermining the effort of knowledge production.
Again, if you go back and you look at the original CIHR policy, it says you have to get in touch with them about your early stopping. You have to do a whole bunch of things. There is nothing now.
When you are told, "Yes, it is not quite all there but it will be," what is not there is actually pretty important. The only part that is there, the only part where there is any overlap, is a general statement that it must be in a registry. Beyond that, there are no standards. There is no possibility of national data, and all of the other elements are missing.
The Chair: I will interject here because I think we need to be fair to the witnesses we have heard before. There was a distinction made with regard to the evidence being available by those trials that are international in nature and those for which there is a Canadian component.
The argument was made that, in those trials, all the evidence does get published, according to the international trial standard, particularly those that have a United States component. The website that you referred to was one of the examples given. Regardless of CIHR policy, those trials are required to place that evidence in the international forum in order to have them recognized, published and so on.
What I think we have been hearing is the distinction between international trials of which there is a Canadian component and those trials that are mandated within the Canadian system that have issues that you are referring to.
Ms. Baylis: I think that is correct. However, the point I am making is that I think it is important as a nation that we be able to marshal our own data, whether it is in one context or another. I think that is a key thing.
The Chair: I was not arguing your point on that. I just felt it was important to clarify what we have heard in terms of other witnesses and the two categories. It is not to argue with your point whatsoever.
Mr. Lemmens: Just to make a point about that; that is only partly true. I have mentioned some countries that have imposed strict registration results reporting requirements, but not all countries have.
The Chair: Again, I want to be clear: Witnesses have told us about those that have a clear requirement. If there was a Canadian component, then the Canadian component information has to be published the same. They were not saying every other country has that kind of standard.
Mr. Lemmens: But it depends on what kind of international trial it is.
The Chair: Absolutely. We understand that, but I wanted to make that clear for the record.
Ms. Silversides: I wanted to respond to the senator. I might have misunderstood, but I think you were asking also about what becomes available to the patients and to the public about things.
Senator Seidman: Yes.
Ms. Silversides: Accurate information cannot be available to them without the information being available so that researchers can mine the data for things. Again, we have example after example of clinical trial data that has been suppressed. Therefore, patients, let alone physicians, do not know they are at risk. Physicians do not know they are placing patients at risk and patients do not know they are at risk because the data has not been there to examine it to find things out.
That raises the issue of post-market surveillance, as well, because clinical trials only cover a very limited number of people. Unforeseen things can happen afterwards when a drug goes to market, which is a really important issue. I know you are looking at that subsequently.
Senator Seidman: Do I have to go on second round?
The Chair: No. I interrupted you.
Senator Seidman: Thank you.
Actually, I had another question, and it has already been referred to. It has to do with the infrastructure fragmentation that Dr. Baylis referred to in terms of ethics boards, for example.
Yesterday we did have quite a discussion about moving towards a national standardization and a reduction of the multiple forms or multiple boards and all the things that inhibit or maybe confuse and take a lot more time to even get clinical trials on the road as a result of there being so many levels and so many differences across the country.
We talked about who would be responsible for developing this kind of national standardization. Some of the suggestions were that the federal government could have some kind of role in this in terms of leadership. Someone suggested maybe the professional associations might. We did talk about CMA, for example.
However, one of the things that came up in discussion after that we did not discuss was the Royal College. We know that the Royal College of Physicians and Surgeons does govern education for physicians and a lot of standards in the country for the profession, especially specialists who are in academic institutions, for example, and are very involved in clinical trials.
When you think about the infrastructure fragmentation, specifically as it applies to clinical trial contracts and ethics boards, how do you see this in terms of developing some kind of national system? Who should take the lead, and does the Royal College have a role to play?
The Chair: I will go to Professor Baylis first and then follow up with other interventions.
Ms. Baylis: My own intersection in terms of work with the Royal College has really been around education, especially at the residency level, so I am not sure that I would put that responsibility there.
In other contexts, there are two main driving forces in research. One of them is knowledge production and what we want is good, reliable, quality, robust knowledge. The other thing that we really want is to protect human subjects who make this contribution to knowledge production.
I have argued elsewhere that I think it is important to leave the responsibility for determining what constitutes solid research, from a science point of view, with the funding councils in terms of their responsibility to identify that research and to fund it. However, when it comes to the ethics issues and the oversight, where one can anticipate that there may be strategies in terms of science that may not be as protective of subjects — and that society as a whole is trying to balance those two very legitimate interests — it is better to have the second set of interests with respect to protecting research subjects outside the responsibility of the funding councils. Let the funding councils do what they do really well, hopefully, which is to identify excellent research and fund it, and look at the protection of research subjects as being the responsibility of a separate organization.
Mr. Lemmens can speak to this, but that has happened in a number of other jurisdictions most notably to the South. The United States has two different bodies responsible for that. I have argued that it should be the bailiwick of Health Canada, but Health Canada has heard that argument many times and has not demonstrated — at least over the five or 10 years that I have argued it — any interest in taking up that responsibility. I sometimes wonder how much of that has to do with concerns about liability and being responsible for the outcomes of trials. I say that because it overlaps with my concern with pregnant women. One of the reasons we do not do that research is because of concerns about liability. However, if society thinks as a society that it is important to do that research, or other research with the population, then we need to think about no-fault insurance and about a whole new way of understanding our commitment to protect research subjects while trying to get knowledge that will benefit the community as a whole. If we could find some way to do that, we would actually be able to improve a lot of research in this country.
Mr. Lemmens: It is clear that this is one of the areas in Canada where we are dealing with the jurisdictional issue. I think there are immediate steps that can be taken with certain areas of research. In the area of clinical trials, the Food and Drugs Act and the Food and Drug Regulations already cover some of the clinical practices and allow Health Canada to supervise or have some control over what is happening in the context of clinical trials. When it comes to clinical drug trials undertaken for the purpose of drug approval, I think Health Canada and the federal government could solidly regulate research ethics boards to the extent that they deal with clinical trials in the context of drug or medical device approval.
There are other models out there. Obviously with the assisted human reproduction reference, it becomes unclear what kind of clothes hanger the federal government can use to exercise jurisdiction over research in general. It will probably be reasonably difficult. The privacy system is an interesting model as well, where the federal government has enacted the Privacy Act, which has allowed the provinces some leeway in developing coherent regulatory systems surrounding privacy that are in line with the federal system.
I think federal-provincial collaboration is essential and will be needed not only to cover clinical drug trials but also other areas of research. I think there are interesting models out there that we can think of and there are interesting examples of provinces that have enacted legislation. For example, Newfoundland has taken the lead in enacting a statute — but I do not know exactly to what extent they have implemented the whole structure — where they created a mandatory research ethics board review structure with one research ethics board for the whole province. That is certainly much easier to do in Newfoundland than in Ontario, but Ontario, for example, could do much more. I would say that some provinces have not shown leadership as well. Federal-provincial collaboration can be essential, but in the area of clinical drug trials where we know there are significant problems, the federal Parliament could enact stricter rules.
Senator Cordy: Thank you to the three of you for giving us a lot to think about.
Ms. Silversides, I was interested in your comment that head-to-head trials are rare in Canada. We have trials of a drug with a placebo but not head to head. We hear a lot of stories about Canadians who are doing well on a drug but, coincidentally, the patent is almost up and the drug that then becomes available is much more expensive and the drug that they had previously is not available anymore. When we talk about head to head, is that the kind of thing that you are talking about?
Ms. Silversides: No, I mean drugs may be from two different manufacturers that address the same condition, that are designed to help the same condition. A head-to-head trial would compare the safety and efficacy of those two. That is a different matter from the thing that you are raising.
I am interested in what you mentioned because if the drug has gone off patent, you mean where there is no generic drug that has come on patent?
Senator Cordy: Yes.
Ms. Silversides: I am not so familiar with that issue. Is either of you?
Ms. Baylis: I was going to take the opportunity to say that we have here in Canada a couple of people in research ethics who have made significant contributions to the international literature on the issue of placebo-controlled trials, me-too drugs and the issue of ensuring that if you are looking at researching a new compound, you want to compare it to the best available intervention and not compare it to a placebo, nothing. That work builds on the work of another Canadian, Benjy Freedman, on the notion of clinical equipoise, which has been taken up internationally.
If you have not already, I would encourage you to extend an invitation to Dr. Jonathan Kimmelman at McGill University, who has written extensively not only on this topic but also on a number of issues concerning Phase I and Phase II trials, the quality of data. He had an article come out last week in Science on Phase IV trials, which I think will be of interest to this committee.
The point you are raising is important in a government-funded health care system, where what we are interested in is socially valuable medical knowledge. It is not socially valuable to have another me-too drug that just costs 50 per cent more. It might be useful if it is 50 per cent less, but it does not always work in that direction. You are raising an important point that needs to be addressed at trial design.
Senator Cordy: Ms. Silversides you also said and we have heard that the number of clinical trials occurring in Canada is dropping. We saw charts that indicated that. You said that there seems to be a push for commercialization of clinical trials. Is that a good or a bad thing?
Ms. Silversides: I was talking about commercialization of research particularly and biomedical research in general, not commercialization of trials.
Senator Cordy: What do you mean by that?
Ms. Silversides: I had an Atkinson Fellowship in Public Policy and looked specifically at this issue of biomedical research in the public interest and wrote a piece in The Walrus a few years ago on the thrust towards the commercialization of research in Canada in general. I was saying that this is where everyone believes we should be going.
Yes, we need to be able to capitalize on the terrific research that Canadian scientists do, but let us also question what kind of commercialization, for whom and in whose interest and that kind of thing.
Senator Cordy: I am concerned about the comments of Professor Lemmens and Professor Baylis about the CIHR and the rescinding of the policy and registration results disclosure in that it sort of disappeared into no man's land and we cannot find the document. That concerns me because a lot of clinical trials are done through CIHR. How challenging will it be for people to get information? I think you said, Ms. Baylis, that scraps will be spread out all over and it will be difficult to get the information.
Ms. Baylis: I think the problem is a bit more complex. I think, as Ms. Silversides said, in fact CIHR is not funding the bulk of clinical trials; that is happening really in the private sector. One of the complicated things about the Canadian situation — now building on a comment made by Mr. Lemmens — is that because we are relying on guidelines rather than legislation, we need to remember that the scope of those guidelines applies narrowly where those agencies have authority. The CIHR guidelines, were they still in place, strictly speaking would only apply to CIHR-funded clinical trials. When I say that, it is always important to remember that means trials where CIHR is funding the trial or the investigator or the trial is in institutions that receive CIHR funding, which is not always appreciated.
If I come in as a private company and I build my building and I set up my researchers and it is a completely discrete, private enterprise, there is nothing — there is not even the little standard that applies with the panel on research ethics. One of the things that some of us in ethics are concerned about is that this is fine when it seems all networked, but if you can work outside the system, and you have a context where there is an interest in attracting research dollars to the country, will you end up with a race to the bottom? You do not have to do it in a CIHR-funded institution and you do not have to use CIHR-funded researchers. You can be a wholly private enterprise, and there is then no framework that would be binding on you because these are guidelines, which already have the problem of enforcement as guidelines, for research funded by these agencies or done in institutions funded by these agencies. I think there is a more complicated problem when you actually look at where the research is happening, who is doing it and the fact that, in Canada, we do not have legislation that other countries have.
Senator Cordy: We should have legislation is what you are saying?
Ms. Baylis: I think we could benefit from legislating certain aspects of clinical trials. I think we want to do that in a way in which we keep our eye on the ball, which, for me, means looking at strengthening protection for research participants rather than looking at improving the economy. We need to pay attention to that. This is a health issue; it is not about economics. I think this gets blurred a lot in a contemporary context, particularly, as Ms. Silversides said, with this drive to attract those dollars. It is also important to pay attention to the phase of trials. If you think about it in terms of investment, you are using Canadians' intellectual capacity and power with the earlier trials — Phases I, II and III. That is where we are really making important contributions to knowledge production. Phase IV, the post-marketing trials, are often just about money moving through the system, publicity and a number of other goals. I am not saying that they are not worthy goals, but they are very different in terms of what our contribution is.
Senator Dyck: In your answer to Senator Cordy, Ms. Baylis, you were talking about different categories of researchers. You said that scientists funded through CIHR are most likely located on a university campus. Those who are not CIHR-funded might still be on a university campus, let us say in a research triangle or research park. They do not have to follow the same guidelines. Do we know how many there are in each of those two major camps?
Ms. Baylis: We do not, but, in the example that you gave, it is quite possible that they would be captured. That is the line that keeps getting missed in the Tri-Council Policy Statement. The Tri-Council Policy Statement arguably applies to a CIHR-funded individual researcher or to an institution that receives CIHR funding. How you understand that becomes a function of the MOU that is signed with the institution. They could say, "Yes, it is a research park, but it is on the University of Toronto campus; we fund the University of Toronto. Researchers, therefore, you are captured by that, which is why you will have to follow the rules." It is not always understood that way, and we certainly get push back, in certain contexts, where people say that they believe that they are or are not governed by those guidelines. That example would not necessarily be the cleanest. The cleanest would be if I go out to the hinterland, build my building and hire all kinds of people independently to do that research. Then, you would say that there is nothing that requires you to follow anything. That is not 100 per cent true; the lawyer will tell you that there are little pieces of legislation that would apply, but it is not an overarching bill that has to do with research involving humans.
Ms. Silversides: I want to add to that that in response to requests from community doctors who are being asked to engage in clinical trials and have questions about the ethics or the remuneration and so on, the CMA had to develop a set of guidelines for community doctors because there are so many of them. At least, when I wrote, there were so many of them being asked to participate in these trials outside of the academic setting.
Mr. Lemmens: One of the challenges for clinical researchers has been that so many clinical trials have moved outside of academia. There is certainly an interest there, from the academic researchers, to keep a connection with clinical research, which also brings in research dollars to the institution. With the new emphasis of CIHR, which also relates to the previous question, there is a worry that we will again see a blurring of the line between what is more academically focused and interested research and what is industry-controlled and -designed research. The new program, for example, the Strategy for Patient-Oriented Research, and some of the funding initiatives by CIHR emphasize the need for collaboration with industry. There is nothing wrong with collaborating with industry. The problem is that this core program itself will emphasize, for example, that there will be collaboration on higher-quality clinical trials, better guideline development, improved knowledge translation and improved patient-oriented care. If you look at the controversies that have arisen with respect to the hiding of the data, many of the problems were with respect to low-quality trials or the hiding of the results of the trials, lack of clear guidelines and clinical trials that were not sufficiently focusing on patients. I would say that there will be a problem in implementing guidelines if we do not have strong support from the legislators.
Senator Martin: I think I agree with my colleague, Senator Seidman, about how your testimony today is providing us with a different perspective or lens through which we are looking at this very important topic.
We have heard, over the last little while, about the importance of keeping clinical trials in Canada at a certain rate to be competitive with the rest of the world. It is a global market. However, I am also hearing today about the very important need to ensure the quality of these clinical trials and to establish the standards to capture all of the research that is happening in Canada.
Ms. Silversides, you said that, in 2004, 87 per cent of trials were industry-sponsored?
Ms. Silversides: That was information from Health Canada in, I think, 2004. They gave me the information for 2002. I think it was 86 per cent actually.
Senator Martin: Would you say it is currently similar?
Ms. Silversides: This is the problem; I have not been writing about it a great deal. The latest figure I have is 80 per cent. Maybe that shows a slight improvement, but, yes, it is similar for sure.
Senator Martin: I think other colleagues have asked this question or something similar. As we are looking at wanting to keep Canada competitive and keep the trials in Canada — that is so important for the Canadian population — we must look at how to maintain the quality of these clinical trials.
Ms. Silversides: And protect the health of Canadians.
Senator Martin: Exactly.
I want to ask you a question regarding the inclusion of pregnant women. Although they seem like a subgroup or a smaller group, this is how we all came into the world, so this is a really important group that needs to be addressed. What can we do to improve the rate at which these women are included in the trials? What can we do in Canada, specifically, to ensure that they are not excluded and are included?
Ms. Baylis: We need to change the starting assumption. Right now, the presumption with clinical trials is that we exclude pregnant women. I would like the starting assumption to be that everyone is entitled to health care and that everyone has an opportunity to participate in clinical trials. If you are to exclude a population, the onus is on you to make the argument as to why they should be excluded. There are cases in which it would be perfectly legitimate to exclude pregnant women. If you are doing research with what is known as a category X drug — Accutane would be an example — you would not want to include pregnant women in that trial. If you were doing a research project with Thalidomide, you would not want to include pregnant women in that trial. There are grounds on which you would want to exclude specific populations, but I can tell you that there are many trials that I have reviewed where I sit there and it just comes across as a boilerplate, and it says "Of course, we will exclude all pregnant women." If a pharmaceutical company is sponsoring that trial, you can understand why they want that in, but it is then the job of the research ethics board to ask, "Why? You have to give us a justification, and then we would determine whether that justification is acceptable or appropriate. It is a pragmatic problem. I have just published an article, in Clinical Investigation, with Scott Halperin, who is a trialist. In it, we have actually tried to answer the pragmatic question of trial design. We actually try to ask and answer the question: If you believed us, from an ethics point of view, and thought it was the right thing to do, how would you go about doing it?
One of the things we are suggesting is that when you get to a Phase III trial, which means you have done Phases I and II and have good data about safety and efficacy in the general population, as you more into Phase III, you would then approach this new population, the population of pregnant women, and bring them along too.
As you move forward with your knowledge production, you are also starting to get knowledge about pregnant women such that eventually you know when you get to market with your drug that you will have the possibility of being able to offer that to pregnant women. That is where, going back to an earlier comment to Senator Eggleton, I was saying that it is a situation where at that point you can have a carrot or a stick. You could say the company will not get their drug on the market until they make it available for all the population, or they will only get it for a certain time, or they will get preferential treatment with respect to patent rules if they do this for that population, which would be more of a carrot. There would be different ways pragmatically of thinking about it. First, you need the will — if you believe my argument that sick women get pregnant, pregnant women get sick, and they deserve access to evidence-based medicine.
Senator Martin: Can this only happen through regulatory changes or legislation?
Ms. Baylis: There have to be changes at all levels. There have to be changes in terms of the guidelines that are put out for research ethics boards to follow; there must be new education of research ethics boards members; and CIHR must make this a priority. CIHR has the ability to take a portion of its budget and say this is a priority for the population and therefore we will invest in it.
As I said, the big issue will be what will be done with respect to manufacturers who, at some point, will argue that they have responsibilities to their shareholders, and their lawyers will certainly tell them this is not something that is particularly interesting to the company. That is why I think it is such a complicated problem. However, you need to start the conversation to find out ways of going forward.
Senator Martin: If it is so complicated, has any attempt been made in the past? Are we moving toward that? It seems like it will require the will and quite a process to come up with an actual solution.
Ms. Baylis: This is absolutely true, but there are areas in which some people are starting to do some trials. For example, trials have been done around depression and the use of certain pharmaceuticals there, et cetera.
Let me step back and give everyone a recent example that I think you can relate to. Think about the H1N1 pandemic that we went through. I do not know if you recall, but pregnant women were actually given conflicting advice. First they were told not to worry, take the adjuvanted vaccine; and then part way through were told "No, no, do not do that. You better take the unadjuvanted vaccine."
If I were to take you through that decision-making, I would show you that none of that decision-making was based on good, robust evidence. It was based on circumstances at the time. If you actually go back and look at what we knew in terms of clinical trials, animal models, anecdotal evidence, et cetera, we should have made different policy decisions, and that is the important thing. How we do research and produce knowledge is important for the health of Canadians, and it is important directly because it influences the policy content in terms of what we do or do not provide for Canadians. I sometimes think when we get excited about the economic parts of this complex issue that we forget that we need to keep our eye on the ball and the question is how can we improve the health of Canadians.
Senator Martin: One last question regarding this. If you do not have the answer, perhaps you can submit it afterwards. What has been done in other jurisdictions to be more inclusive of this population?
Ms. Baylis: Specifically pregnant women?
Senator Martin: Yes.
Ms. Baylis: Around the world, we are all advocating for that. I can point you to a group of researchers in the United States called the Second Wave, women who are advocating with their government to pay attention to this population. I would say that is true around the world. The one major difference is, if you look at international guidelines, they have made the move that I suggested. The presumption is they are included and you have to argue to exclude them, so at least you have a public international statement that is consistent with what I am advocating. The problem I am identifying is not unique to Canada; it is a worldwide problem. However, it is an area in which we could show leadership. If you are interested in trying to find a way to stand out and be attractive to a certain cadre of researchers, there are ways to design a system that would be interesting.
Senator Poirier: I am not a regular member of the committee; I am filling in for someone. Therefore, I may be following a line of questioning that may not relate to the study. If so, I am sure someone will correct me.
I find over the last few years and going forward we are hearing more and more of people going into the line of natural medication instead of drugs in order to deal with their health. I am curious to know if in vitamins and the natural medicine line there is as much research done for safety. Are clinical trials being done? What is the difference? Are the guidelines the same or is there a difference?
The Chair: I will rule the question not in line with our clinical trials study here. That is an entirely separate area. Legislation is being developed to deal with natural products, and that is a whole different aspect. The issues of any material that would come from any source that goes into a clinical trial would be dealt with in the same manner that they have been answered on those questions.
Senator Poirier: Thank you, chair. I was new on the committee, just replacing someone and I was not aware.
The Chair: I suspect this committee will be dealing with that in another area down the road.
Senator Wallace: I guess it seems pretty obvious from what each of you have said that you favour a strong regulatory regime in Canada rather than one of solely self-governance and, in particular, simply having guidelines. Because of the seriousness of the issues at stake here, that certainly seems to make sense.
A lot of this is new to me as well. You drew out some issues that I did not fully appreciate. There is this distinction between CIHR-funded research and that of private companies that would have no relationship to that and what the requirements would be for those companies that research and would fall under CIHR.
Mr. Lemmens, in your comments you said that to develop these standards, to develop requirements relating to the trial registration and results reporting, some initiatives are taking place but they would not apply to privately owned companies. You further said that some of the initiatives that have taken place would not be enough to enforce compliance of companies that often have huge financial interests to avoid registering clinical trials or publicizing their data.
What does that huge financial interest centre around? Is it a matter of the companies protecting their proprietary interest, the patent or pending patents they would have for those products? Is that the major concern they would have in not making their information available? I have a couple of questions, but I will start with that one.
Mr. Lemmens: What I meant with my comment about the trial registration requirements of the TCPS, they do not apply to private companies. There was indirect urging of clinical trial registration results reporting because Health Canada requests, in the context of good clinical practice, that companies, industry partners, follow the Declaration of Helsinki. If you look at the requirements of the Declaration of Helsinki, they are very general. You have to register a clinical trial and report your results of data. They are general requirements that state the ethics or make some general statement about the ethics of clinical research. It is hard to see how that could be enforced in Canada if someone violates the rules.
The ICH-GCP, the International Conference on Harmonisation — Good Clinical Practice guidelines, for example, is a guidance document in the Canadian context. It is not part of strict regulations. There are some problems of enforcing the internationally recognized but not nationally translatable standards.
At the international level, the World Health Organization has made important initiatives and has identified in much detail what essential elements should be registered in the context of clinical trials, but again, that is not immediately enforceable in the Canadian context.
Could you remind me what your second question was?
Senator Wallace: The wholly private companies, you have said there is a huge financial disadvantage. I am wondering what that disadvantage would be. In particular, I am coming to your later statement where you say the United States and Brazil have rules that apply to all health-related research, which I would take applies to these wholly private companies. How do they get around the concerns that these companies seem to have in Canada, but there they are operating in the U.S. and Brazil?
Mr. Lemmens: Sometimes we simply accept certain statements that are made. I participated in a hearing, for example, of the World Health Organization where there was a discussion about trial registration and results reporting. One member of industry made the claim that this could actually undermine patent protection, as well as financial interests and investments in the clinical trials data, but other members of industry disagreed. If you also see that industry went along in general internationally with trial registration, and if you look at the arguments that we developed in the paper that was distributed, I do not think it makes sense to think that patents would be affected, because patents are taken far before the clinical trials are undertaken.
There is an element about the investment in clinical trials, so we have to be fair to industry in the sense that the innovative industry invests in the conduct of clinical trials. It is an expensive business. It is an expense that the regulator imposes on companies.
Again, if you look at the arguments that we develop in the paper, there is already protection of data. Generic drug companies, for example, cannot just take the clinical trials data and get their drugs approved. We have in the U.S., Canadian and European contexts data-protection regimes that actually exceed the patent life of particular drug products.
There is already sufficient protection of the investment in data out there, so I would say the patent concern is not the reason companies are reluctant. I think it is more because of the fact that you can use data. You can actually use data or clinical trial results as marketing tools. However, if the results are negative, you do not have any incentive to publicize them, to put them out there in the scientific literature, and to start saying to the world, "Our drug may not be as effective." You see there is kind of a financial disincentive to publicize information.
Senator Wallace: Yes, and in Canada we want to encourage clinical trial research in our country. If we were creating a regulatory regime that was going to drive them out of this country and they could go to the United States or elsewhere to conduct the same research, we would obviously take that into account. However, I get the sense — in particular with the U.S. and perhaps Brazil as well — that what you are looking for, the type of regulatory regime you are thinking would be appropriate, hardly seems to be out of line with what other major countries are already doing; therefore, there would hardly seem to be a risk that we would drive that business and that excellent work out of Canada.
Mr. Lemmens: Canada used to be — again, more at the soft guidance level — a leader. People working at the CIHR promoted trial registration and results reporting, having intense debates at the international level about what should be registered, what should be transparent, and what we should have access to within the scientific community. For example, the Ottawa Statements, which were spearheaded by people within CIHR, and the Cochrane Collaborations were very influential in informing the World Health Organization to establish its trial registration system.
However, if you look at the same researchers who have been active in arguing about this, many specialists argue that we should go further than the United States. Canada used to be a leader; we should actually, at the legislative level, be interested in looking at what we can do to make it even better. There is an important component that even in the U.S. context is not necessarily publicly accessible, which is the Phase I early trials. There are strong arguments in the literature to say that these trials should also be publicly accessible.
Ms. Silversides: As a journalist, in the wake of the withdrawal of the CIHR policy, I was at Dartmouth University. There is an international group of people there, and I have to say that withdrawal really did send shock waves. There was a lot of attention paid to that internationally because Canada had been seen as a real leader in this area. There was a lot of attention paid to that, not just in this country.
Senator Demers: Dr. Baylis, can you please explain to the committee why Health Canada should oblige drug makers and investigators, through regulation, to design and conduct smaller, specifically designed clinical trials for pregnant women?
Ms. Baylis: Are you asking me to explain what I mean by that?
Senator Demers: Yes, please. Thank you.
Ms. Baylis: Basically, what I am suggesting is that there needs to be some kind of a push or incentive provided to say that it is important to recognize that that population is a part of Canada and requires access to good medicines. My concern right now is that there is absolutely no incentive in the system for that to happen. I am looking to say: Are there ways that organizations, persons, and places of authority could say this is a priority?
Ms. Silversides: To add to that: In the absence of that, as Professor Baylis said, it is essentially off-label prescribing of a lot of things to women, so there are unanticipated consequences because it has never been studied. That is really underscoring her point.
The Chair: I want to ask some questions to follow up on a number of the questions that have already been asked.
With regard to Senator Demers' question, which follows on other comments that senators and you have made, and with regard to the specifically clearly identifiable subgroups, such as children and pregnant women in particular, you, Professor Baylis, mentioned both the carrot and the stick approach. One of the carrots that we have had evidence of in the study to this point is the extension of the patent life by approximately six months, I think the example was, in the case of children, when they are included in a trial.
You have given us, Professor Baylis, a sense of the complexity of bringing pregnant women and women into clinical trials. However, in addition, there are the physiological issues in children and in certain subgroups that are considered to be different from that of the general adult population. The evidence has been that additional effort needs to occur in order to ensure the protection of those individuals in a clinical trial, more observation and so on, and therefore a slightly longer time to reach potential approval.
Is a slightly extended patent life a reasonable example of a carrot in these areas?
Ms. Baylis: I think so. The example you are giving with respect to children was one of the ways they tried to incentivize that. In an earlier life, I used to work full time at the Hospital for Sick Children, in the early 1990s. At that point I was actively involved in arguments for research involving children, saying that children are not just little people; that their bodies are, in fact, different and we need to pay attention to that. About 10 years later I was fighting the fight with respect to research involving women, saying women are not just men with hormones. My argument now is that pregnant women are not just women with big bellies.
You are exactly right. That is what we have seen, that different populations have been excluded from the benefits of research. In the last 20 years, we have shifted as a society, such that we understand that research is something that is potentially beneficial, not only for us, as Canadians, who might benefit from the knowledge, but that there are also benefits to the actual research participants. It is important to pay attention to the whole community. Yes, I think that is exactly right.
The Chair: Thank you.
Professor Lemmens, you have given us a number of examples of the issues around regulations, guidelines and things of that nature, and you referred to a number of jurisdictions around the world. Specifically, you have referred to the U.S. and Brazil in your comments. Obviously, Europe is another major area of significant regulation with regard to clinical trials. I would like to ask you and your colleagues and the witness group today to identify what you consider to be examples of best practice in the regulation of clinical trials and to send those to us. I am not asking you to find one country that has them all. I am simply asking which pieces of this country's approach to clinical trials you consider to be very good models with regard to specific aspects, not the total picture, in addition to all the general and specific comments we have heard today. If you could think about that, all three of you, we would welcome that specifically.
The issue of a common approach to ethics board requirements is very interesting. We have heard significant arguments for the development of a common ethics board in order to ensure that clinical trials will continue in Canada. We have heard that from the competitive point of view, that is, the time it takes to do a clinical trial is important to those companies attempting to bring a new chemical entity to the market.
However, in your comments, you have introduced another potentially interesting side of that today when you indicated the importance of protecting the patient in the clinical trial. I wonder if this is not another aspect of a reason for having a clearly published, highly recognizable, standard ethics requirement for the treatment of patients in a clinical trial from the point of view of actually ensuring protection of the patients in a clinical trial. We have been hearing that in some cases you can have dozens of different ethics boards involved in writing approaches to requirements in the area. One could imagine in very small trials, which may be academically driven, that there might not be a lot of external observation with regard to the ethic approval for a particular trial.
Is there an aspect of protection of the patient that could benefit from a standardized, highly publicized ethics board approval requirement for clinical trials?
Mr. Lemmens: There is movement all around the world and different models exist around the world. I would say it is clear that the tendency, for example in much of the European Union, is to move towards a more government controlled research ethics board structure where governments will issue clear regulations around how research ethics boards have to be organized, who can be a member of research ethics board, and what the territorial jurisdiction is of research ethics boards. I teach a course on pharmaceutical governance, and I explain to students who have never really thought about the issue of research ethics board that in this country in several provinces you actually submit your clinical trials to one commercial research review committee or an institutional review committee. You can be rejected, but you can just turn around and go to the next one. People are stunned by that.
I am not saying that commercial research ethics boards are necessarily worse and others are necessarily better or that there are not good research ethics boards in this country functioning appropriately, but as a system, it is quite surprising. If the protection of research subjects and their right and well-being is the purpose, in the language of research ethics boards, of these research ethics boards, it is very strange that we can have commercial competition between these research ethics boards for their clients, which may indirectly impact on the health of Canadians. As a consumer, I am not assured by that system.
Ms. Baylis: I would like to recommend to the committee the report called, I believe, Moving Ahead, authored by the Sponsors' Table, which is another document that has been erased. I have a copy that I can get for you if you are interested.
The Chair: Under the table.
Ms. Baylis: A colleague of mine at the University of Dalhousie, Jocelyn Downie, was involved with that project. I mention her by name because she was also involved in the report of the Canadian Association of University Teachers on the Nancy Oliveri debacle. She may have some interesting perspectives there.
My summary of the report Moving Ahead is a statement to the effect that the system is broken and really needs to be fixed. Part of that is looking at issues like regional boards for some areas of research, perhaps, and national boards for other areas of research. For example, national boards pay attention to things like what the experience is with a drug, but they also pay attention to what expertise they need around the table to properly review it. That expertise might be quite limited in a new area of research.
A classic example would be stem cell research. When we start doing embryonic stem cell research in the context of clinical trials, not in the context of derivation but wanting to put that into patients, how many people in this country are going to be both sufficiently distant from the research — do not have a conflict of interest — but also have the experience and skill set to do that. I would argue that you cannot leave that to every individual idiosyncratic local research ethics board. That may be an example of an area where you want to have national oversight. After 10 to 15 years of experience, it might go down to regional levels, and when it becomes more routine it might go to the local level, if you want to keep a tiered system. That is an easy example to hold onto to show that the system cannot continue the way it is if the goal is protecting research subjects and paying attention to their interests. Especially with respect to stem cells, I would point out that that is the one piece that is outside the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans and is solely under the purview of the CIHR. You could say that is good because there will be one committee — oversight committee — looking at it, but then I would raise the question of conflict of interest because it is internal to the CIHR.
The Chair: We have the document you referred to.
Ms. Baylis: Great.
The Chair: You have both provided information that I am pleased to hear on the record.
In one of your responses, Professor Lemmens, and I am not attempting to put words in your mouth, I heard something that is generally reflected in the competitive world of commerce. I believe that you said everybody has to play by clearly defined rules and that industry generally respects that because they are all playing by the same clearly defined rules.
However, in the case of clinical trials, where one has guidelines versus regulations, it may well be in the minds of competitive industry, as I think the implication was, that not everybody will necessarily play by the highest standards within those rules and, therefore, there is a competitive disadvantage perhaps to some companies.
Is it your anticipation that if there were very clearly defined regulations that very clearly applied to all industries attempting to enter clinical trials, the industry would not be opposed fundamentally? What is your opinion of industry's reaction to that kind of approach?
Mr. Lemmens: I cannot speak for industry. It also depends on which industry you are talking about.
The Chair: Speak generally with regard to pharmaceuticals. I do not want you to break it down.
Mr. Lemmens: It is important to know that there is an important other constituent: the clinical trials industry. It is a billion-dollar industry.
The Chair: I am sticking to the companies that bring the chemical entity forward.
Mr. Lemmens: There may be a variety of opinions, but I have certainly heard already the opinion that some people within the pharmaceutical industry realize that there is a lot of waste and a lot of investment in clinical trials of a competitive nature and doing more trials than actually needed just to obtain interesting data for regulatory approval. Maybe if the trials were more streamlined and organized, we would have fewer clinical trials, more focused trials and, perhaps, less need to invest in these.
The Chair: Thank you. I want to come to the broader issue of the types of clinical trials. We have gotten a little more into that today, though it has come up as separate examples throughout our hearings. We have clearly defined today that in the vicinity of 80 per cent of the clinical trials done in Canada are company-sponsored, for obvious reasons. I want to come to the remaining 20 per cent, which may largely fall within CIHR jurisdiction.
Yesterday, we were given examples of very small clinical trials that are almost physician-driven. These often arise because of post-market information on an existing approved drug that physicians may see, that there are reactions that are positive with regard to other indications. An individual physician or a group of physicians within a given hospital may apply for permission to carry out a very limited study on a very select group of patients to determine whether or not the drug has benefit.
As well, we know that, in Canada, in the research centres, there is a very significant amount of world-leading effort on rare diseases, particularly genetic-based diseases where there may only be two or three, four or five, under ten cases in Canada at any one given time. The need to try the research into bringing benefit to some of these cases obviously can only apply in the initial cases to very limited numbers of people.
Is there a role in this situation for CIHR having some flexibility with regard to some of the aspects of clinical trial, or would you argue that a good, ethical approach across the board should apply equally in these narrow cases?
Mr. Lemmens: It is interesting that you mention the area of genetics and pharmacogenomics. The whole move towards personalized medicine will create more difficulties with respect to the organization of large clinical trials. You will have more focused trials. There is an expectation that you will have more narrow trials, smaller patient groups.
I would say there may be practical problems when organizing larger trials there, and the drug regulator may have to look into what kind of evidence would be sufficient to make certain decisions in that area. That is a scientific and a practical question about the reliability of evidence and how to organize these clinical trials, but I do not immediately see that that would be a reason to make an exception with respect to the transparency of clinical trials. To the contrary, I would say it makes it that much more important to be able to see at an international level what is happening.
I want to emphasize here that this international move towards registration of clinical trials also allows researchers to really make connections that previously were hard to make. Computer technology offers us fabulous tools to look at what has been happening in different countries with small patient groups and make connections that previously would not have been possible, or not with the same ease.
I would say that in this particular area, actually, international collaboration and transparency would be even more important.
The Chair: Thank you. I thank you on behalf of my colleagues for your presentations and the directness of your answers. Obviously there are broad issues and questions for which time will perhaps be required to give us absolute answers, but there are obviously many areas for which things are very clear, and you have helped us a great deal with that today.
I asked you one specific question to think about after leaving here but, on behalf of the committee, I would also like to request that if you think about anything that has come up during our meeting today and as you leave you say, "Oh, this example or this particular aspect is one I wish I had thought to put on the table right then," or that you think we should be aware of, we would urge you to send it to us.
Ms. Baylis: I would encourage you to have a look at a proposal. It is an international proposal that is referred to as the Health Impact Fund, as a new way, thinking completely outside of the box, to incentivize big pharma to look at rare diseases and to look at what should be funded in a global context when your driving priority is socially valuable medical knowledge. It is an amazing initiative, if it ever comes to pass. I know they are in conversation internationally with WHO and a Canadian is one of the co-sponsors of that initiative. I think that would be something really interesting to look at and how that might play out in a Canadian context.
The Chair: That is the kind of example I am asking for. I will draw the meeting to close, but I ask you to follow up with those examples. On behalf of the committee, thank you very much.
(The committee adjourned.)