Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 13 - Evidence - March 29, 2012
OTTAWA, Thursday, March 29, 2012
The Standing Senate Committee on Social Affairs, Sciences and Technology met this day at 10:30 to study prescription pharmaceuticals in Canada (topic: Clinical trials).
Senator Kelvin Kenneth Ogilvie (chair) in the chair.
[Translation]
The Chair: Welcome to the Standing Senate Committee on Social Affairs, Sciences and Technology.
[English]
I am Kelvin Ogilvie, a senator from Nova Scotia and chair of the committee. I would now invite my colleagues to identify themselves.
Senator Seidman: Judith Seidman from Montreal, Quebec.
[Translation]
Senator Demers: Jacques Demers from Hudson, Quebec.
[English]
Senator Merchant: Pana Merchant, Saskatchewan.
Senator Callbeck: Catherine Callbeck, Prince Edward Island.
Senator Eggleton: Art Eggleton, Toronto, and I am deputy chair of the committee.
The Chair: Today we are beginning the second meeting on the clinical trial phase of our overall study of pharmaceuticals in Canada, and prescription pharmaceuticals. Today we are very fortunate to have the Canadian Institutes of Health Research and Health Canada with us. With the CIHR we have Dr. Alain Beaudet, who is the President of CIHR, and we have Dr. Robert Peterson, who is the Executive Director of the Drug Safety and Effectiveness Network within the CIHR overall mandate.
From Health Canada we welcome back Barbara Sabourin, Director General of the Therapeutic Products Directorate. We have Dr. John Patrick Stewart, who is Acting Director General of the Clinical Trials Office, and we have Kimby Barton, who is Director of the Bureau of Cardiology, Allergy and Neurological Sciences.
Welcome to you all.
We have agreed that Dr. Beaudet will start the presentations. We have the two normal introductory presentations and then I will open it up to my colleagues on the committee.
[Translation]
Dr. Alain Beaudet, President, Canadian Institutes of Health Research: I would like to thank the Standing Senate Committee on Social Affairs, Sciences and Technology for giving me the opportunity to outline the importance of clinical research in the Canadian health care system and the determining role of the Canadian Institutes of Health Research in this regard.
"Clinical research" means any prospective research to assess the results of diagnostic or therapeutic measures on humans. It's therefore important to remember that clinical trials don't apply solely to drugs. They can also concern cells or other biological products, medical devices or advanced techniques with medical or surgical applications.
[English]
Canada's scientific excellence in clinical research is recognized internationally. For example, Canada's publication impact relative to clinical research investments is the highest in the world. We also have the fourth largest number of clinical research sites in Canada compared to the rest of the world.
Canadians have derived tremendous benefits from public and private investments in clinical research. Health care professionals are provided with state-of-the-art clinical training, thanks to the environment of scientific inquiry that the practice of clinical research provides. The culture of evidence-based practice that our health care system is based upon stems from the development and practice of clinical research. Thanks to clinical research, Canadians have early access to most innovative drugs and treatments. Clinical research is essential for bringing to market innovative products that improve Canada's competitiveness and productivity. Most importantly, clinical research helps identify ineffective tests and treatments thereby helping us provide safe and cost-effective health care to Canadians.
For instance, the work of CHIR-funded researchers Drs. Shamir Mehta and Salim Yusuf of McMaster University has shown that a simple injection of an inexpensive and rarely used drug known as reviparin, an anti-blood-clotting agent, within two hours of the first symptoms of a heart attack prevents the occurrence of stroke in patients who have already had an attack, and reduces death rates by 30 per cent.
I could give many other examples of instances where clinical research has impacted the quality and cost-effectiveness of patient care. Still more needs to be done. Indeed, we know that as many as 50 per cent of clinical interventions have limited or unproven effectiveness and that up to 25 per cent of patients get care that is not needed or potentially harmful. Therefore, it is a question of basic accountability that we step up the clinical evaluation not only of health innovations, but also of current practices to ensure we are doing more good than harm.
Yet Canada's competitive position in clinical research is becoming at risk. Over the last five years clinical research and overall R & D investments by the private sector in Canada — amounting to $3 billion annually — has remained the same despite growing investments globally. Countries such as China, India and Brazil, that have larger populations and market sizes, have become industry's clinical R & D partners of choice. R & D decisions are increasingly made in head offices in New York, London and Zurich, and our competitive position is fast eroding.
[Translation]
Public and private sectors have a defining role in developing clinical research capabilities in Canada. However, both are faced with the same difficulties, notably the rarity of required expertise in biostatistics, clinical trials management and health economics, a lack of clinical research infrastructure and a lack of coordination and efficiency in terms of recruiting patients and performing ethical assessments of multicentre trials.
This is why, in cooperation with the provinces and territories, academic bodies in the area of health care and representatives of the industry, CIHR have developed a research strategy that is patient oriented. Launched by the Minister of Health in August 2011, this strategy should ensure that research will have more impact on treatments and services provided in clinics, hospitals and doctor's offices across Canada.
A better integration of research data into clinical practice will produce better health results and an improved health care system in Canada.
[English]
Since the launch of the strategy in August, we have already made significant progress. In partnership with Rx&D and ACAHO, we have developed a clinical trial agreement with the goal of simplifying and expediting the start-up times for clinical trials, thereby increasing the attractiveness of clinical trial sites for private investments.
In January we launched, in partnership with Genome Canada, a $67.5-million initiative on personalized medicine to help move health care from a reactive one-size-fits-all system towards a system of predictive, preventive and precision care. Such a system should lead to better health outcomes, as well as to a reduction in toxicity due to variable or adverse drug responses.
The week before last, Minister Aglukkaq announced a renewal of CIHR's partnership with Canada's research- based pharmaceutical companies, Rx&D, to strengthen clinical research in Canada. Through this renewed collaborative agreement, CIHR will be doubling its investments to up to $150 million over a five-year period, with a complementary objective from Rx&D members to match this contribution dollar for dollar over the same period. The aim of this investment is to strengthen our capacity to carry out both publicly and privately funded clinical trials, thereby increasing our country's attractiveness for investments in this field and ensuring better health, a more sustainable health care system and a broader economic impact.
In closing, I would like to say a few words about CIHR's Drug Safety and Effectiveness Network. This network was established as part of Government of Canada's Food and Consumer Safety Action Plan. The Drug Safety and Effectiveness Network addresses Canada's gaps in post-approval monitoring of prescription pharmaceuticals by increasing the research evidence on the post-market safety and effectiveness of drugs available to public drug plan managers, policy makers, regulators and others, as well as to increase capacity to undertake high quality research in this field. The network also increases proof-of-value studies on approved drugs. These studies are intended to inform decisions surrounding the utility of a new medicine.
New evidence generated via the Drug Safety and Effectiveness Network would provide decision makers with an important additional source of information contributing to ongoing evaluations of drug safety relative to their therapeutic benefits. This evidence will also support decision making on public reimbursement of drugs and optimal use of drugs in Canada.
Dr. Robert Peterson, Executive Director of CIHR's Drug Safety and Effectiveness Network, as the chair mentioned, is here with me today and will be happy to answer any of your questions on this critical new research initiative.
Barbara Sabourin, Director General, Therapeutic Products Directorate, Health Products and Food Branch (HPFB), Health Canada: Thank you, Mr. Chair and members. It is a pleasure to be here today and to have another opportunity to describe the regulator's role in clinical research. Our mission is to contribute to the health of Canadians and to the effectiveness of the health care system by regulating pharmaceuticals and by providing Canadians with access to information to make informed choices.
Clinical research provides Canadians earlier access to new, potentially helpful treatments. It leads to better medical care for Canadians, as knowledge gained from studies increases the ability to diagnose, treat and prevent disease. This valuable knowledge is gathered during the various stages of drug development, which in turn support the safety, efficacy and quality of a drug product and serve as the basis for the drug marketing application.
Research for new drugs begins when scientists develop various chemical or biological substances through animal and laboratory testing of their effects at various dosages. If these preclinical tests indicate that a substance produces the desired result and is not toxic, the sponsor, meaning the person or the company who takes responsibility for the research, will apply to the Therapeutic Products Directorate or the Biologics and Genetic Therapies Directorate for authorization to conduct a clinical trial.
Clinical trial applications contain preliminary data and information to demonstrate the safety, efficacy and quality of an experimental therapy, such as a pharmaceutical drug. Studies may be conducted to administer an experimental treatment into humans for the first time, to evaluate the efficacy of a drug in patients with medical conditions, or to gather additional information about the risk/benefit profile of the experimental drug or treatment.
Health Canada authorizes the clinical trial only when the protocol is scientifically sound and the drug would not pose unacceptable risks to the trial subjects under the proposed conditions of use. The food and drug regulations require that trials be conducted in accordance with good clinical practices, which are internationally recognized standards that guide sponsors in designing and conducting research in humans. The regulations also require that the protocol receives approval by a research ethics board and that a copy of the risk/benefit statement be given to trial subjects.
If the clinical trials show that the drug has potential therapeutic value that outweighs the risks associated with its use, for example, due to adverse effects or toxicity, the sponsor may choose to file a new drug submission with the Therapeutic Products Directorate. The new drug submission contains information and data about the drug's safety, effectiveness and quality. It includes the results of the pre-clinical and clinical studies, details regarding the production of the drug, packaging and labelling details and information regarding therapeutic claims and side effects.
The Therapeutic Products Directorate performs a thorough review of the submitted information to assess the potential benefits and risks of the drug. If, at the completion of the review, the conclusion is that the benefits outweigh the risks and that the risks can be mitigated, the drug is issued a Notice of Compliance, as a well as a drug identification number, which permits the sponsor to market the drug in Canada and indicates the drug's official approval in Canada.
Since 2001, the review of all drug clinical trial applications has been subject to a 30-day default period. This shortened review time provides a positive benefit to all Canadians as it permits faster access to new innovative therapies through the conduct of a clinical trial. It is Health Canada's responsibility to ensure that its decisions are made in a timely fashion, thereby not discouraging the research and development of human drugs in Canada.
In recent years the globalization of disease has prompted the globalization of research. Devices and drugs are now being tested on global scale and have provided global health benefits. However, in the current research environment, Canadian clinical trial sponsors are struggling to stay competitive with other jurisdictions in the world. Therefore Health Canada, as a global leader, continues to support initiatives that seek to facilitate and coordinate scientific collaboration, encourage cooperation among federal and provincial partners and engage with stakeholders to find innovative ways in addressing the challenges that arise from the globalization of research.
The international trend to promoting clinical trial transparency has become an important issue in Canada and abroad. Globally, there is consensus that the registration of study protocols and disclosure of clinical trial results are a key means to improve access to clinical trial information so that patients and health providers can make informed health decisions.
Since 2007, Health Canada has been encouraging clinical trial registration and disclosure of information in publically accessible registries recognized by the World Health Organization. New regulations for clinical trials came into force in 2001, with a commitment to assess their impact within three to five years. A comprehensive review was conducted in 2006, with the involvement of stakeholders, to identify areas for improvement within the regulatory framework.
In 2008, following this review, Health Canada published a document outlining a series of targeted measures that focused on revising industry guidance, enhancing the current application processes and increasing accessibility to clinical trial information. As such, several initiatives are currently under way to increase efficiencies, streamline reporting, encourage submission of electronic data and clarify guidance to sponsors.
Drugs approved in Canada are based on high quality clinical research. The results of clinical trials are a key part of the drug approval process and provide important information about the safety and effectiveness of a drug product. For these reasons, Health Canada supports clinical researchers in their research efforts by continually removing unnecessary regulatory hurdles of clinical research and supports greater openness about the evidence base for drug products to assist patients and health care providers in making important choices.
Facilitating research in Canada and supporting the Canadian research environment benefits Canadians. However, efficiency should not have a negative effect on the safety of participants in clinical trials. As the regulator, we recognize that safety can only be achieved through the involvement of government, industry, research ethics boards, health care providers and patients. We are committed to achieving world-class excellence and safety and quality standards, and continue to value stakeholder input as it informs our research, our programs, as well as improving the efficiency of drug development.
Thank you for your attention. We would be happy to answer any questions.
Senator Eggleton: Good morning and thank you for being here. Let me start with CIHR and thank Dr. Beaudet for the contributions they have made to our health accord examination. Your organization gets a fair bit of mention in the report and I hope you have had a chance to look at it.
I want to ask you about personalized medicine, on which some of your comments were based. It is a fascinating area, but I have been hearing both yesterday and today about this regime for clinical trials and for the entire processing system, which is very complicated at least for a layperson I think.
How adaptable do you think we are? How quick could we bring personalized medicine into existence given the system that exists in Health Canada?
Dr. Beaudet: It is a very good question. It is a challenge, but it is already there. Already, as you know, we are practising personalized medicine in certain areas, cancer, for instance, where we will only prescribe certain drugs after determining that the drug has indeed the proper receptors for the drug expressed by the tumour cells and will therefore be sensitive to the treatment. That means that we would no longer subject patients to treatments that they would not respond to anyway and would have all the side effects of the drug.
That is already an advantage that is being exploited in certain areas. Of course, we are talking about the future. The enormous advantage, of course, is that personalized medicine will offer, we hope, very different ways of doing clinical trials and the possibility of doing trials on the smaller number of patients who have been extremely well identified. Because they will be genetically more homogeneous, we believe that the significance of the effect will be obvious with a smaller sample, on the one hand. On the other hand, we will be able to target and market the drugs, once they have been approved, to very specific patient populations, thereby decreasing the useless exposure of non-responders to drugs that they are currently taking. There is a dual advantage here. You will be able to target the drug and test it on a smaller sample of patients and not submit patients who do not have the biological characteristics to respond to the drug to be part of the trial.
Second, once the drug has been proven effective and approved, you will be able to truly target these patients, rather than submitting the entire population to drugs that, sometimes, there is no way they would respond to. Obviously, the regulatory mechanism — and you certainly would be more able than I am to respond to that — will have to adapt to these changes, but that is where we are going. I think it is important for us — and we are doing it — to support research not only in the detection and discovery of new biological markers and new genetic markers but also in new ways of integrating, in a seamless fashion, personalized medicine into clinical practice.
Senator Eggleton: How are we compared to other jurisdictions, either the United States or Europe, which are quite frequently brought up in the context here, in terms of the development of personalized medicine? Are we also working with them, to a fair degree, on this issue?
Dr. Beaudet: We certainly compare favorably in terms of research. We are there with the most advanced countries in terms of research. In terms of implementation, I would say that certain European countries are further ahead. We need to step up our investment in that area of research. That is why we decided, with Genome Canada, to invest massively to ensure that we keep up with the game that is certainly being upheld in the U.K., the U.S., Australia, and the European Union.
Senator Eggleton: Ms. Sabourin, are we able to keep up in terms of the regulatory framework and trying to implement the research that CIHR is doing?
Ms. Sabourin: In terms of personalized medicine, from my perspective, we are looking at a continuum of changes and evolution in how clinical trials are designed and also how drugs are developed. Certainly, for situations where there is a genetic reason why a certain person or group of people might respond or not respond to a particular drug, there are ways to adapt to the situation within our regulatory world. We have examples of drugs that have been approved with corresponding diagnostic tests so that only those people who actually have the particular and correct genome type to be able to respond to the drug would be given that drug.
Dr. John Patrick Stewart, A/Director General, Clinical Trials Office, Therapeutic Products Directorate (TPD), Health Canada: It is important to point out that the present regulatory framework for clinical trials mandates that it is up to the sponsor — the academic centres, the pharmaceutical companies — to come up with hypotheses and develop protocols to design trials to explore a question. If a pharmaceutical company has a promising therapy that they think would fit the mandate of personalized medicine, they can design a protocol and bring it to the regulator to evaluate whether it is appropriate to come to the market in Canada. The regulator's objective is to look at that protocol and to see if it is in the best interests of the clinical trial participants to participate in that trial, that it does not put them at undue risks, and that the objectives of the trial are achievable. Those are the overarching lenses through which we look at clinical trials. If the protocol comes forward with scientific evidence to support the hypothesis that supports the level of exposure to the subjects proposed, then Health Canada would not object to that trial happening.
It would be our mandate to keep up with the science to be able to evaluate these protocols and to see if the hypothesis and studies done to support the protocols are appropriate and safe.
Senator Eggleton: I am reading about having research ethics boards at each clinical trial site. The research ethics board cannot be affiliated with the sponsor, and there are a number of other conditions I see here in terms of how it is appointed and who is appointed to it. Who appoints it? Do you appoint it? Does Health Canada appoint it? Who does?
Ms. Sabourin: I will let my colleague, Dr. Stewart, speak to this. We have a different role; we have the regulatory role.
Dr. Stewart: The regulations stipulate that, prior to a clinical trial commencing, they must get the research ethics board's approval for the protocol and for every site. It is up to the sponsor to identify a research ethics board that meets the criteria. The regulations stipulate the characteristics of the board — who needs to be on it — so as long as that research ethics board is compliant with the characteristics described in the regulations, then the sponsor can use that ethics board. Many academic centres and teaching hospitals have research ethics boards. There are larger research ethics boards that are for profit that will also do this kind of work.
Senator Eggleton: The organization of it is then done by the sponsor, although it says that it cannot be affiliated with the sponsor. However, the sponsor has the responsibility for putting it together.
Dr. Beaudet: The legal responsibility is with the sponsor, and the sponsor could be the hospital, a university or an academic science centre.
Senator Eggleton: It could be the manufacturer.
Dr. Beaudet: It is the board of, let us say, the hospital that will appoint the members on the local ethics board for review. That also is one of the reasons why the ethical review of a multi-site trial can be cumbersome. You may undergo up to 140 reviews for one trial, if you have 140 sites. More and more, we are trying to simplify the process without, obviously, compromising the ethical protection and the protection of the patient.
What is happening now is that, at the provincial level, some more global ethics review boards — for instance, there is one pan-Ontario ethics review board for cancer studies — are being set up. I think that, eventually, we have to bring these recognized bodies to use the same standards so that we can nationally, rapidly get ethical approval for these multi-site studies and not lose competitiveness because you can imagine the time it takes to get approval for all the boards.
The Chair: I will come back to this later when I get a turn at the end. However, Senator Eggleton mentioned that the company could choose the ethics board. Could you just make the clarification with regard to the sites at which the clinical trial is held versus the company who is the owner the patent, if there is in fact any distinction?
Dr. Beaudet: There is. Obviously there will be a contract signed between the company — if it is a privately funded trial — and the various sites that are involved in the clinical trial.
The Chair: That is the point I wanted to get at. It is the site that has its own ethics board approved?
Dr. Beaudet: It is the site. That is also true for publicly funded research. Before we send the money out, we ensure that there is a proper board at each site.
The Chair: That was an important issue in his question. I wanted to make sure he got the full answer there.
Senator Seidman: I would like to go back to some of the questions I asked yesterday to try to get more explanation. They refer specifically to the transparency issues that we began the discussion on. My question is for both Health Canada and CIHR, but slightly different for each of you.
As far as CIHR is concerned, I do believe that in 2004 CIHR adopted registration of all clinical trials. In 2011, the policy was withdrawn and replaced with a tri-council policy statement. Those are not yet adopted or enforced, so I was just wondering what the current situation is, at CIHR, with regard to registration of clinical trials.
Dr. Beaudet: That is a very good question. We did not withdraw anything. We crystallized things. As you know, we updated the tri-council policy on ethics for the protection of human subjects.
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 want to reassure you that, concerning clinical trials — and we have integrated that in the policy — all clinical trials must be registered in a public registry before the first participants are recruited.
There are only minor elements from the original policy that are not yet in the tri-council policy because we have to consult with the other councils and the committees of ethicists across the country who update the policy. I know this will eventually be integrated. I want to dispel the misunderstanding that we are withdrawing or decreasing our standards. We just want to give them more formality and gravitas, and we want them to apply to all research that is under the umbrella of the tri-council not only under CIHR.
Senator Seidman: I appreciate that. That is an extremely valuable clarification here. There is a lot of publicity to the contrary as far as that is concerned.
Dr. Beaudet: I know.
Senator Seidman: If I could then go to Health Canada on that issue, there was an article published in the Canadian Medical Association Journal calling on Health Canada to make clinical trial registration mandatory and to make the results public. The article suggests that there is no legal hurdle to making such disclosures but rather that the barriers are institutional. I would like to know if you could please comment on those barriers to clinical trial registration and access to clinical trial results.
Ms. Sabourin: I will start by talking about what we do already make public. We make public, on a quarterly basis, statistics about the number of clinical trial applications we have received and the numbers we have approved. Those are always available and have been for some time.
We have just published an aggregate inspection report on the results of the clinical trial inspections over the last, I think, five or six years. It went up on Health Canada's website. All of our guidance documents that describe the expectations of Health Canada in terms of how clinical trials should be conducted are public on our website. In addition, you would find risk communications there. If we needed to inform Canadians about a particular aspect of either a marketed drug or a drug that might be in clinical trials and if that information needed to go out quickly, you could find that on our website.
For marketed drugs, the results of clinical trials would be found, on a summary basis, in some of our summary- basis-of-decision documents. Also, the product monographs, which are on our searchable drug product database, provide, basically, the results, in terms of the benefits and the risks, of those particular products. There is summary information already there.
In terms of the actual trials being run in Canada at this time, we have been encouraging clinical trial registration and disclosure of information in two publicly accessible registries recognized by the World Health Organization since 2007. There is a steady increase in the number of trials from Canada that are being registered. The Office of Clinical Trials has also added new text, into the letters that go to sponsors indicating that they can start their trials, encouraging them to register their trials within 21 days of the trial's onset. We continue to assess options, including regulatory options, to mandate clinical trial registration through our modernization initiative. We did go forward with Bill C-51, which then died. That included some powers to try to compel registration and other kinds of disclosure of information. We are now considering what other options we might have to move that forward.
Senator Seidman: I just want to be clear, in all that information, whether the registry requires researchers to update any changes in a research protocol, end of trial, patient withdrawal from trials, or even adverse events. Is any of that part of any registry process?
Dr. Stewart: Our regulations have specific requirements around reporting adverse events to the regulator when there is a change in the safety of the trial or they discontinue the trial. They do not require sponsors to report when a trial is finished or if they never actually start a trial, for whatever reason.
With the international registries that we are recommending they voluntary register on, it is up to the sponsor. There is advice around what should be registered. There are, obviously, documents around the advantages of providing not only the fact that the trial has started, what the objectives are and, what the clinical trial sites are but the results of the trial. I am not aware of any compelling authorities of any of these registries to dictate what they register.
Senator Merchant: I have one further question on transparency because you have answered many of my questions.
Our notes indicate that in some cases clinical trials are carried out in public in Europe and the U.S. What does that mean? That is what it says here. I did not understand that.
Ms. Sabourin: Mr. Chair, perhaps I could try to provide some information that might clarify this situation.
I believe that the senator is referring to expert advisory committees. In the United States, there is a system where those committee hearings are generally open to members of the public, and, in addition, there is a process where they put forward the agenda, on their website, a certain period in advance.
In Canada we have, in a similar fashion, several standing science advisory committees made up of external experts with various types of expertise. We also publish on our website, in advance, the agendas for those meetings, and we also publish the records of decisions from those meetings.
In general, however, we are not, at this point, holding many of those meetings in a public fashion. From time to time, we do have those kinds of meetings in public, and members of the public can ask to attend.
For any of those science advisory committees, any member could ask to attend as an observer, and the chair would decide whether or not to allow that. I think that is the information that you are referring to.
Senator Merchant: Thank you for the clarification.
I have a few questions on post-market surveillance. Is that something we can deal with today?
The Chair: No, I will rule those in abeyance until we get to that particular part.
Senator Merchant: I will leave it at that because all my questions were about the transparency beyond that.
The Chair: Thank you very much, senator.
Senator Campbell: Since I am not a regular member of this committee, if my questions are outside the limit, let me know.
I am interested in clinical trials and studies into rare diseases, specifically childhood diseases. In that vein, I am interested in how in Canada we go about setting up for what are called orphan drugs where they are for people who suffer from rare disease which means you are less than 1 in 2,000, but it still affects about 3 million Canadians. I know in Europe they have a way of setting it up. It is the European Medicines Agency. Do we have the same type of thing in Canada?
Ms. Sabourin: In Canada at this point in time we do not have a separate framework for orphan drugs. It has been under consideration, and we have consulted widely through our modernization initiative on what we might do differently for orphan drugs. We are still determining what that might be.
I would ask if my colleagues have anything to add in terms of clinical trials for rare conditions and how those get set up.
Dr. Stewart: We would evaluate a clinical trial application for a rare disease the same as we would any other application. We would look at the evidence in the document to support the hypothesis, the research proposed, the design. We are aware that rare diseases, orphan drugs, present a number of major challenges, not the least of which there is usually a small number of patients distributed across the world. There may be 20, 30 patients in Canada with the condition, and they may be in 12 different locations, and you have to have clinical trial sites, and so it is a real logistical challenge to run an orphan disease-type clinical trial. We can help facilitate, but the administrative and logistical challenges are quite enormous.
However, from the point of view of evaluating a protocol, we would approach it in the same way we would any other protocol. Is it in the best interests of the clinical trial participants? Does it put them at undue risk and are the objectives achievable? We are certainly aware of the efforts that the EMA and the FDA do. They provide advice around protocols and so forth, and that is helpful to us. If a protocol comes in and they have already received advice from other regulators, that is usually useful. It gives us some comfort in the design of the protocol, that the objectives are achievable.
Senator Campbell: In that vein, these other agencies provide incentives to companies to look at developing medicines for rare diseases. I would hope that we would look at that also.
The second question I have, and one that I had no idea about until I got involved with this group, is that many times we have drugs that are developed for a specific purpose. We are going towards finding a treatment here and at the end of the trial we realize that it does not make a difference there, and this drug then goes up on a shelf and sits on the shelf. What we have found, in British Columbia at least, is many of the drugs sitting on that shelf with no use actually have a use in the rare disease process. Is there anything, any way that we can bring about change so that this happens more often? There has to be a central gathering place for all of these drugs that really are not useful for the specific cause. Is there any way of going about that or is this outrageous?
Dr. Beaudet: Actually, it is not outrageous at all. It is a very good idea, and it is called repositioning drugs. Some major initiatives that have just started in the U.K., sponsored by the Medical Research Council and the National Institutes of Health, are also looking at that and we are also looking at the possibility of doing that. The idea here is not necessarily for rare diseases. It could include rare diseases, but it is to take drugs that have gone very often through the phase I, which is the safety in patients, and so we know they are safe in patients, and yet, as you say, they were shown in phase II not to be effective for the indication for which it was tested.
Well, the idea is then to give researchers in the lab access to these drugs that would look through, very often, high throughput screening systems for other possible uses for these drugs or perhaps a combination of drugs. Perhaps the addition of those drugs could change, let us say, the resistance of a bacteria to antibiotics, for instance, that sort of thing.
There is a lot of future there, and we are certainly looking very seriously at the possibility of facilitating that. Obviously we do not have the ownership and there are huge issues of protection. The companies have the intellectual property of these drugs, so it is dealing with this intellectual property to get access to this drug, but several companies are very interested not in doing it in-house because they no longer have an interest of doing that but seeing if the research community is interested in repositioning them and doing it.
Would you like to add something?
Dr. Robert Peterson, Executive Director, Drug Safety and Effectiveness Network: I can be brief. It is an excellent question. The pre-market clinical trials, as you pointed out, focus on the development of a product for a specific claim. As we move beyond the time when the product has been decided for market or against, we change our focus to health outcomes.
In that sense, not only are we sorting through a number of products that may not have developed their particular objective in their first clinical trials to bring them back into subsequent clinical trials, but we also look at combinations of products since the concept that one particular product will cure a disease may be fine in certain infections but becomes very problematic today where we are looking at the application of a treatment protocol that involves many products.
This complicates the work in the pre-market phase because many companies then have to come together. When we look at sponsoring research that is more specifically focused on patient outcomes, we can step across those commercial barriers and choose the best treatments.
A very good example I would direct your attention to is the Children's Oncology Group of researchers that have done incredibly successful work in childhood cancer for which they are not driven by commercial sponsors. Rather they are driven by experts in the treatment of childhood cancer who will select the products based on prior experience and clinical trials for those they believe will work best.
Senator Campbell: I hope to see some changes coming down the road. We have been paying attention to this issue, but we just have not been able to break the logjam, so thank you very much.
Senator Callbeck: This morning I want to ask on the clinical trial funding and the costs. It is generally thought that the pharmaceutical industry pay the costs. Is that correct? Do they pay it 100 per cent or is it just a certain percentage?
Dr. Beaudet: You have clinical trials that are sponsored by the pharmaceutical industry, and there are clinical trials that are publicly funded. CIHR is funding clinical trials, and some of these trials are very expensive. They could be testing drugs; they could be testing or comparing drugs that are currently available in the market and comparing their efficiency, comparing the side effects, comparing outcomes. We are sponsoring a number of clinical trials that are looking at different types of treatments, new practices; so it is not only the pharmaceutical industry that supports clinical trials, and some charities also support clinical trials in their area.
Senator Callbeck: However, are all clinical trials for new drugs paid for by the pharmaceutical industry?
Dr. Beaudet: Yes. It is their new drug. It is not for the public sector to subsidize company "X" to test a new drug.
Senator Callbeck: The people that are involved in the test, do they get the drug free during these trials?
Dr. Peterson: Under most circumstances, that would be part of the sponsorship of the clinical trial. Again, we are focusing on trials that are designed to bring the product to Health Canada for market access. There are many trials that take place subsequent to that where the product may be paid for within the health care system. It may be paid for by sources other than the sponsor.
Senator Callbeck: Sources other than the sponsor, so the money from the federal government, but any other sources?
Dr. Peterson: As Dr. Beaudet had pointed out, there are many foundations for research that have specific focus, cardiovascular, neurosciences; there are hospital foundations; there are other interest groups that are philanthropic. The Vancouver Foundation, for example, provides good funding for individuals to look at, in particular, special populations.
Senator Callbeck: Do you have any idea what per cent of the funding that is spent would come from these other organizations?
Dr. Peterson: I do not, but we would be pleased to look at that and provide you with some additional information. The answer will be stratified based on whether it is the commercial sponsor bringing the drug to market or whether the drug has already achieved market status. Things change greatly at that juncture.
Senator Callbeck: Has there been a lot of changes in recent years? Have organizations become more involved in this type of research, or is it about the same?
Dr. Peterson: I am not sure that they have become more involved. As I say, the Canadian Cancer Society, the Heart and Stroke Foundation of Canada have had very focused interest on improving health outcomes in their respective areas of interest for a very long period of time.
What we are seeing is a good deal of additional research being focused after the product has been brought to market, and the reason for that is the following.
To bring a brand new product molecule to market requires focused and specific clinical trials. You can only ask and answer one or two focused questions within a clinical trial, and yet when the product is now introduced to the Canadian health care system, we have a multitude of questions that go beyond those that were addressed and answered by the sponsor to fulfill their regulatory obligations. Therefore, it is not only the organizations that are interested in funding research who step up to the plate but organizations such as CIHR that work hand in hand with many decision makers within the health care system to address that multitude of additional questions that need to be addressed.
Senator Callbeck: All right, I have a question about a couple things that have come up.
The clinical trial application, I read in the notes here somewhere that it does not need to receive approval by the Research Ethics Board at the time of application. Is that right?
Ms. Sabourin: Yes, that is correct.
Senator Callbeck: However, there is only a default target of 30 days?
Ms. Sabourin: Yes, we have 30 days in which we can review the application and object to it going forward. In general, when we object, we provide questions to the sponsor. However, we can issue what is called a No Objection Letter to say we do not object to that.
Senator Callbeck: It does not go forward unless you have the approval of what?
The Chair: I think it might help here by clarifying the stages. Ms. Sabourin, you are referring to giving authority for a trial to go forward, but you do not conduct the trial. It then goes to that next stage where the ethics board comes in to play.
Ms. Sabourin: Yes, and I will ask Dr. Stewart to go through how we see that moving.
Dr. Stewart: Division 5 of the Food and Drug Regulations mandates that prior to a trial starting, prior to the sponsor or the qualified investigator starting to dose patients, they not only have to get authorization from Health Canada but they have to get Research Ethics Board approval for the protocol as well as every site. The regulations do not stipulate the timing, the sequencing of that, but generally the practice is that it comes to Health Canada first; Health Canada, if they have no objections to the design of the protocol, will issue the letter; and then they will seek Research Ethics Board approval. There is often quite a delay from the time an NOL is received to the time the trial actually starts because of a number of logistical challenges, one of which is getting all the Research Ethics Board approval.
The regulations — one other point — do stipulate that the sponsor has to tell the regulator at the time they submit the application if in the past for this protocol they have received a negative review by an ethics review board, and we have seen that on occasion.
Ms. Sabourin: Perhaps I could just add that in terms of research ethics boards, there has been a bit of a collaboration around the country, as I understand it, to try to develop some standards for research ethics boards that could be applied across Canada to ensure that there is consistent application of the framework for research ethics boards.
Senator Callbeck: Thank you.
Senator Seth: I think it is a very interesting topic we have been discussing. Maybe after being a physician for some time these questions come to your mind.
When the pharmaceutical company is doing the clinical trial, at what stage do they approach physicians to do a research trial for a particular drug? Do we know that? What stage is it at?
Ms. Sabourin: Perhaps I could start and then ask Dr. Stewart to add on. There are three main phases of clinical trials, and physicians would be approached, in my view, more around phase II and III in terms of conducting and signing on for sites, but I would ask my colleagues to add to that.
Dr. Stewart: There is a well-described international approach to development of new drugs, and prior to it ever entering into a human, there is an extensive amount of research that has to be done to prove a concept, that it acts on a target, that in animal studies it is not toxic and that it shows potentially some efficacy if the animal model is correct.
At the time a pharmaceutical company developing a new drug wants to enter humans, it then comes to the regulator, in this case in Canada Health Canada, to seek approval to start research in humans. As part of the requirement of that regulation, there has to be a qualified investigator at every site where that clinical trial is taking place; and by definition, the qualified investigator has to be a practitioner, which is a physician or a dentist under the definitions in the regulations.
However, physicians get more and more involved I think as it gets into broader use. Phase I is more looking at how that drug is behaving in humans, pharmacological type studies, learning something about the toxicities as the dose escalates. In phase II you are getting into actual patients with the condition, with the disease and looking if it works. There you will see more physician involvement. You will see more sites, more patient exposure, and then when you get to phase III, there has already been evidence this drug is efficacious against the condition and you are looking for broader proof of that and a better understanding of the less common adverse events, and so there is a lot of physician involvement because there is usually a lot of sites and it is usually multinational.
Senator Seth: How much are we supposed to be transparent to the patient? Yes, we know we take the signature and all that, authorizations. What happens if there is a serious adverse effect on the patient? There is a bit of a legal problem. Who is responsible? Is the physician supposed to be or is it supposed to be the pharmaceutical companies? It can happen, and then of course we have to stop the research at that point. Where do we go from there?
The Chair: Remember we are focusing on the clinical trial stage.
Dr. Peterson, would you like to comment?
Dr. Peterson: I can share experience having sat on a large research ethics board as to how that is addressed within the consideration by the board.
Typically the consent form, as you have indicated, that needs to be disclosed in an understandable manner to a study participant will, in fact, specify exactly what would be the responsibility on the part of the sponsor, on the part of the investigators with respect to any harm that might have occurred as a consequence of that study. If this is a commercial sponsor that is developing a drug for the marketplace, then they have the responsibility for the harms that may occur within a clinical trial, and they have equal responsibilities in law to report any adverse event.
By the way, that is not only if the adverse event occurred within the arm of the trial that took place at a Canadian centre but, if this is an international study, adverse events that occurred anywhere when that drug was under evaluation.
The information that would transpire regarding the adverse event that occurred to the patient would take place with the clinician who is responsible for providing the care and the patient.
We do require, and oftentimes those academic organizations that are responsible for hosting clinical trials will also, that there is indemnification in the form of insurance that has been taken by the institution.
Senator Seth: Thank you.
The Chair: I would like to come to three specific questions, and they really have been touched on by my colleagues initially but I would like to get your further expert clarification.
Dr. Beaudet, I would like to come back to something you put very well at the outset and I would like to broaden it a bit. You mentioned the importance of having an effective clinical trial process and organization structure, otherwise the advances in research never make it to the public because they have to meet a standard and requirement before they are approved in that area.
We also know that, in terms of market opportunity, Canada is a relatively small market relative to other industrialized nations. Therefore, in order for us to be attractive in having drugs come to market that can benefit Canadians we have to be effective in making a case that this is a good place to hold those trials.
I want to come back to the issues, and you all have made comments that are helpful. The specific aspect I am going to ask here, we know that over recent time we have understood that our medical research centres, those that would carry out clinical trials, have been quite disorganized in terms of bringing them together for a large trial that has been characterized, and you have touched on it today, by having processes to set up their ethics boards that differ, and these take different times. Even though there are basic requirements each organization develops on its own, and ultimately it has to meet its own requirements in this particular area, these things can often lead to delays.
If a country is known for delays that are due to disorganization, it may well be that the trials will not be carried out here, and yet we have, as you have pointed out, outstanding researchers in this country and we have a highly developed population that needs to benefit quickly from new medications that are in fact effective.
I wonder if you could just clarify a little bit more the progress we are making with regard to the standardization of the research protocols and the ethics board requirements.
Perhaps Dr. Beaudet may start.
Dr. Beaudet: You have certainly explained it very well. This is the reason we are launching with partners, including representatives from the provinces, because they are responsible for health care, and with the charities, because they also support clinical trials in their various domains, with the pharmaceutical industry.
We have set up a national task force to establish what we call a strategy for patient-oriented research, with which you are familiar. One of the elements is to improve the quality of the research infrastructure for clinical trials. By research infrastructure we are talking about largely human infrastructures. That means supporting the health professionals who do the clinical research, ensuring that we keep on training health professionals — and not only doctors, but nurses, physiotherapists, dentists, et cetera — to the high standards of clinical research we have in this country, and ensuring that we collaborate more across the land.
As you know, one of the problems in this country is that the population is not very large and, in many cases, for certain diseases we do not have a population that is large enough to be recruiting very effectively and rapidly. There is a huge advantage to collaborating and putting on enticements for researchers to collaborate together, developing biostatistics, which has always been important but is becoming even more important as key players in the analysis of clinical trials and the computerization and collection of data.
We are working really close in hand with both the private and public sector with the provinces to set up that infrastructure, both locally through clinical research support units and also nationally through pan-Canadian thematic research networks and clinical research networks, that we believe will not only allow us to increase collaborations in certain domains, such as in mental health or even more specifically depression, but also will be certainly attractive at the same time for the private sector. They will have a one-stop shop. They can go to the head of the network and negotiate the capacity to carry out a trial across the country rapidly and recruit more rapidly.
I have already mentioned that we are working on improving the speed and effectiveness of the ethics review process, and the contracting as well, which is slow, and we are making progress in that area.
Dr. Stewart: I would point out to this very point there was a submission in September 2011, cosponsored by CIHR, by Rx&D and the Association of the Canadian Academic Healthcare Organizations to look at the present logistical and other challenges related to carrying out clinical trials in Canada. There was an acknowledgement at that point that there were a number of different initiatives that could be undertaken to move this forward.
The other point I was going to mention is there is presently work being led by the Canadian General Standards Board, Health Canada, and I believe CIHR is involved, to develop voluntary standards for research ethics boards. This is a document that will describe the composition and behaviour of the Research Ethics Board. At this point it is envisioned to be a voluntary process, but if there was ever a move toward an accreditation process for REBs in Canada, this document could be the starting point for a framework.
The Chair: This is a very encouraging. Rumour has it some of those institutions have not been mutually cooperative in the past, so this is very good news.
Dr. Peterson, I would like to come back to the clear comments you made with regard to monitoring adverse events during trials and the issue of truncated trials. You gave a very good answer. I would like to drill down a little bit and get your opinion on how the doctor practitioner is overseeing the localized patient group and the nurses who actually are most likely to be the ones dispensing the pharmaceuticals and so on and who may well be the first ones to observe some unusual behaviour in one of the recipients.
To what degree are we becoming increasingly effective in having that combination actually recognize that it may well be an adverse event that has just occurred and therefore it needs to come through in the reporting stage that you have already articulated? I do not need you to go back to that part, but how good are we at getting them recognized as adverse events?
Dr. Peterson: This is not an easy question. You have addressed the most difficult aspect of this. The regulations require that serious and unexpected adverse events be reported within a clinical trial. That is an attempt to help distinguish what might be an adverse event in a patient as a consequence of the disease or the condition they have versus something new that would be introduced by virtue of this experimental therapy at the time.
There is an extensive investigator brochure developed and reviewed by Health Canada and also by the research ethics boards when they do their job in looking at exactly how capable the local investigator and local institution are in conducting this trial with specifically that objective in mind, identifying safety concerns for the patients.
In addition, we work in this environment where clinical trials are often blinded in order to get this very high quality. The investigator does not know what the treatment is, whether it is a placebo, the new experimental treatment or whether it might involve an arm that is an established, effective therapy. The patient does not know what they are receiving. As a consequence, when adverse events are reported by the patient or by the investigator, they cannot themselves draw the conclusions that you might be seeking, and that is as early as the event occurred that we can identify if there is a problem. Those events are then reported to Health Canada.
The solution to that dilemma has often, for those clinical trials that do have the potential to create substantive harm — and they are only approved, by the way, for those products that have the promise of providing substantive benefit in the outcome, that we recruit and require data safety monitoring boards. These are boards independent of the company, independent of the investigators, independent of the organization for whom, at pre-specified times in the trial, after a certain number of patients are recruited or after a period of time has transpired, will be given access to the data and they will look at the information that has been garnered at that point in time. They have in the past, and they will continue into the future, take decisions that will recommend that the trial be stopped at this point for safety concerns.
In addition to that, they may make recommendations that say, "We will stop this trial at this point because the benefit has clearly been established and there is no longer the necessity to blind patients or have patients in a placebo arm."
The answer to your question is a complicated one. We undoubtedly will continue to address how quickly we can identify that a harm has occurred and that there is something that needs to be introduced at that point in time. At this point, as I pointed out, it is serious and unexpected events that occur within the trial that the focus is placed upon.
The Chair: Thank you for the clear overview of the situation. I have a request for you to follow up, Dr. Beaudet and Dr. Peterson. I think you indicated you would do this, but I would like to get the actual number on the percentage of trials that are sponsored by CIHR, the percentage by the tri-councils and then any other.
Dr. Beaudet: Public versus private, basically.
The Chair: Exactly. Thank you very much.
Senator Eggleton: We started discussing yesterday clinical trials in terms of what is done here within Canada, but also what is done in a cooperative way internationally.
I think I asked this yesterday but I am not sure if I got an answer. Of clinical trials we hold in Canada, how many are totally domestic operations, all three phases, versus ones that are done in an international, cooperative way with other countries or whatever? How much of this is done internationally now?
Dr. Beaudet: For the drug trials, most of them are large international trials, particularly when you come to phase III certainly.
On certain practices, for instance, you could have smaller, domestic trials. For the large drug trials, when it comes to phase III, I think most of them are international. Is that correct?
Dr. Peterson: I will confirm that. In fact, when we talk about large trials, even though you had mentioned the discussion around genomics earlier, where the trials may be able to get smaller, for many new products today the incremental benefit over established therapies may be very small, and as a consequence the clinical trials are very large: 15,000, 18,000 patients recruited as compared to 2,000 that you might have looked at in a traditional large clinical trial. In order to recruit that number of patients they are undoubtedly international.
When we speak international, we are talking 50, 60 countries for some of those drugs and hundreds of trials sites where they would take place, such that 18,000 patients recruited into a clinical trial may have had only 1,000 or 2,000 from Canada that had been introduced into that trial.
Senator Eggleton: Are the protocols therefore fairly common in the world? How do we ensure that we meet our standards here when part of the input is coming from somewhere else?
Dr. Peterson: The protocol is identical. It must be identical in that fashion. While there might be variances at the local level, based on research ethics considerations, the protocol itself is largely identical.
Dr. Beaudet: It is important to be aware that some of these very large international trials are actually led by Canadians. We have an excellent reputation and really the know-how in this country to lead these large trials.
Senator Eggleton: I have a couple of other questions.
The Chair: On this, where you described it as a huge trial dealing with a certain outcome and, as we heard yesterday, companies may go after a slightly different indication in different countries, there the clinical trial basis would not necessarily be identical; is that correct? We want to make sure we understand we are dealing with a situation in which, across the jurisdiction, the planning is consistent.
Dr. Beaudet: Absolutely.
Senator Eggleton: Colleagues raised this question of the clinical trial registration and the transparency issue. We talked about the Tri-Council Policy Statement. I gather, from what I have been hearing in the answers, that in our case we encourage things to be done, whereas in the case of the Europeans or the Americans it must be done; it is a requirement.
Do you not feel we should be on the same level as they are, or do you think the system works fairly well the way it is?
Dr. Beaudet: We are not a regulatory body at CIHR, so I will speak for CIHR right now. I can tell you that CIHR would not fund a trial that does not abide by these principles.
Senator Eggleton: How does that work for the ones that are not CIHR?
Ms. Sabourin: We did look at this issue a couple of years ago. First, there are multiple websites where clinical trials can be registered. One of the concerns, when we consulted, was not adding to the confusion by adding yet another website where Canadians might have to go.
We are continuing to look at the options and determine how we might make this more transparent, and at the same time try not to add any regulatory burdens to the group.
I have also responded earlier about the fact that we do, as you mentioned, encourage the sponsors to register their trials on this website. Having checked those, I can tell you that a large number of them do register their trials.
Dr. Beaudet: You have to understand also that all the academic health science centres that receive money from CIHR abide by the TCPS, hence the importance of it.
You have to realize that the privately funded trials are carried out in the same sites that already abide by these ethical rules.
Senator Eggleton: I hope this meets your requirement here. I was just reading about the 2010 annual report from the Patented Medicine Prices Review Board, which says that the pharmaceutical companies, this would be Rx&D, their applications with respect to applied research, including all phases of preclinical and clinical trials, is down some 10 per cent from 2009. Is there an explanation for this? Maybe CIHR is picking up some of the things they are not doing.
Dr. Beaudet: As I mentioned in my introductory remarks, one of the reasons is they are moving to countries where there are more patients, recruitment is more rapid and the cost is lower than in Canada. I think that what we have to provide for is more efficiency and attract them in niche areas where they will be attracted by the quality. I do not think that we will ever compete with India for the costs.
Dr. Peterson: I can contribute the fact that the trials that are going off shore that have been referred to are the phase II trials and some phase III trials that require rapid recruitment of patients, and oftentimes treatment-naive patients, that can take place in those countries.
The market access, getting the drug to the market and having a licence by Health Canada, in the past was the specific limiting factor for access to medicines by patients and health care providers. Today the cost of new medicines is such that an individual rarely can afford to assume that responsibility on their own.
Therefore, beyond the approval of the drug for market there are many decisions that have to be taken, and these are the questions that I alluded to earlier.
For example, does this drug perform as well or better than one currently on the market that may be less expensive? Canada has been addressing questions that come into play after the market authorization has taken place that will ensure that decisions within our entire health care system are the right decisions. That is what Dr. Beaudet referred to in research that contributes to the proof of value determination. How does this drug perform relative to another? Should a province pay for this publicly? Is there a sub-population that apparently would benefit in a more cost- effective fashion? These are among the multitude of questions we are addressing, and this is where, given the large number of academic and private sites for research to take place in Canada, we can very nicely transition that gap that we may have begun to see eroded to offshore sites coming back here, because the results that take place within the Canadian health care system are respected around the world as being representative of what would take place in other health care systems.
Ms. Sabourin: To speak to the statistics around the clinical trial applications that we have received over the last five years, we have seen a bit of a decrease on the pharmaceutical side. In 2011 we received 537 applications and in 2007 we received 656, so there has been a bit of a downturn. However, as I mentioned yesterday, on the biologic side there has been an increase. So when you look at the pharmaceutical industry overall, both the chemical as well as biologics, in Health Canada we are not seeing a decrease in the number of applications.
As Mr. Glover mentioned, though, it depends on which report you look at, what the stats mean and the amount of dollars going to research in Canada. Just on the cost side though, we have seen in the past a bit of a correlation. I do not know if I would say anything about statistics around that, but we have seen a trend of the trials somewhat following the situation in the country in terms of economic situation. We are seeing a bit of a downturn in the economic situation and we would traditionally see a bit of a downturn in clinical trials as well.
Senator Seidman: I would like to ask about informed consent. We know that regulations specify that the sponsor has an obligation to receive written informed consent from all trial participants. This issue would fall within provincial jurisdiction. Is there some kind of standardization among provinces? Do provinces all manage this in the same way or are there challenges that may create issues in terms of authorizing clinical trials?
Dr. Beaudet: This is exactly what was referred to earlier when we talked about the standardization and the establishment of standards. We hope indeed that the establishment of these standards country wide will allow us to eventually accredit the various ethics review boards so that we may no longer need to use so many ethical boards. Since each of the boards will be using exactly the same standards, you could accept the evaluation of another board. That would be difficult at present because of the lack of accepted standards by all ethics committees and all provinces.
Dr. Stewart: With regard to the informed consent form document, the ethics review boards have the final say on what is appropriate, but as part of the requirement in Division 5 the risk statement that is part of that informed consent is submitted to the regulator and we evaluate that. We look at whether the risks associated with participating in the study are accurately reflected given the information in the protocol investigator's brochure. If we feel that the statement does not accurately, in language appropriate for participants, reflect what we believe are the risks associated, we will comment to the sponsor.
The final approval goes to the ethics review board as to whether it is an ethical document and accurately reflects the risks and the responsibilities of both the sponsor and the participant.
Finally, good clinical practice has a large section on informed consent and defines that. If we were to go into a clinical trial site as an inspection, we would evaluate good clinical practice, which includes informed consent.
Ms. Sabourin: The report, which is an aggregate of the inspections done against good clinical practices, does have a small section on informed consent and some of the findings that were made across Canada when those inspections were done.
Senator Seidman: I will carry on with the inspection aspect, which we talked about yesterday. Could you tell me a bit about what the inspection actually entails? I think you said yesterday that the standard is about 1 per cent of trials. I believe you said that that is an international standard. Could you tell me what an inspection entails?
Ms. Sabourin: I will ask Dr. Stewart to go through the information on that. To clarify, my understanding is that the range internationally is around 2 per cent of the trial sites that are inspected annually, and that is about what we try to accomplish.
Dr. Stewart: It is in the responsibility of the inspector, which is part of the Health Products and Food Branch. They have a GCP compliance unit, the mandate of which is to evaluate clinical trial sites and determine whether they are complaint with the requirements of good clinical practice. They have a number of regional inspectors who go into sites and evaluate various aspects of the clinical research, including documentation, whether there has been appropriate consent, whether the procedures as defined in the protocol are being followed properly, whether the labelling and the control of the investigational agent is being done probably, whether there are concerns about documentation around the trial, and whether there were any adverse events and, if so, whether the adverse event reporting requirements are being followed.
They look at the whole picture to determine whether that site is following the design and the description of the protocol, whether they are following the mandated requirements of good clinical practice, and whether there are minor inconsistencies or major concerns. They will often visit more than once, depending on their concerns, and will discuss findings centrally and then decide how to proceed.
Senator Seidman: Are the results of inspections made public?
Ms. Sabourin: Health Canada has recently published an aggregate summary of the results of those inspections indicating the kinds of observations that were made and the kinds of outcomes that were observed. However, the results of individual inspections are not currently made public.
Senator Seidman: What are the possible outcomes of those inspections?
Ms. Sabourin: Compliance with good clinical practice or noncompliance with good clinical practice requirements.
Senator Seidman: Are there only the two?
Ms. Sabourin: In addition, it is normal practice for observations to be provided to the head of the site so that they can make any corrections needed, even when the site overall is rated as compliant.
Senator Seidman: We also talked yesterday about the difficulties in achieving the kind of results we would like to achieve in clinical trials for women and children. They are not often included in trials, and this is an ongoing issue and concern in terms of indications for drug use and adverse reactions. Could you talk about this, please, and tell me if there is progress being made in this area?
Dr. Peterson: I am happy to report that there is a good deal of work within CIHR. As you know, we have institutes that are oriented toward children and the developing child. We have worked in the drug area very extensively with them and have let a number of grants within the last two to three years, particularly subsequent to the initiation of DSEN, to focus on special populations. We have incorporated those populations, in addition to those that you have spoken about, seniors and Aboriginal people, that you do not often have the opportunity to find in a substantive number within the clinical trial environment. We remain challenged, of course, when a brand new product is brought to market and you are evaluating the benefit to harm, to attempt to restrict the exposure to children such that we will garner the information first in older populations.
Dr. Stewart: Health Canada is aware that this is an important issue that should be addressed. It is certainly discussed internationally. In 2007, the Strategy Policy Branch hosted a conference entitled Context Matters: Gender, Diversity and Clinical Trials. There were a number of stakeholders from both the public and private sectors exploring the challenges around encouraging and facilitating research in subpopulations like women.
Following through with the input from that, Health Canada has revised their guidance document on the inclusion of women in clinical trials. On January 9 it was posted on the Health Canada website in draft format. It is looking for comments on the document from external stakeholders. It is much more comprehensive and has a much broader scope than the one that is presently active, which is from 1997.
We are trying to move this forward as an important issue and to encourage sponsors. If the plan is that the drug will be used in a subpopulation, let us say women, then the research should have appropriate representation of that population in the clinical trials.
Ms. Sabourin: To add briefly, this has been describing the initiatives in terms of including children and other populations in clinical trials. At the drug approval stage it is also important to ensure that the information is available on the use of the product in that population. Ms. Barton may be able to add to my comments here, but certainly when the approvals come through for use in, for example, the pediatric population, we are very concerned that the trial data supports, for example, the age range that is proposed by the sponsor, and often we will change that to ensure it is more in line.
Kimby Barton, Director, Bureau of Cardiology, Allergy and Neurological Sciences, Therapeutic Products Directorate (TPD), Health Canada: Within the product monograph at the time of the approval we are very clear on which populations have been studied in the clinical trials and which have not.
Often right underneath the indication you will see a section entitled "geriatrics" and a section entitled "pediatrics" that will be quite specific about what information we have on those particular subpopulations.
In the post-market phase, we now get risk management plans that are submitted at the time of approval, and often targeted in those risk management plans is garnering further safety information on those specific subpopulations so that the sponsors will actually report back to the regulatory authorities on an ongoing basis on any particular safety issues that might have been identified.
Senator Callbeck: Am I correct that there are three phases in clinical trials?
Dr. Beaudet: There are four.
Senator Callbeck: In any given year, roughly how many drugs would enter the first phase and how many would end up passing the fourth phase?
Dr. Stewart: I can give you general statistics on that. We receive around 2,000 clinical trial applications per year for review. Some of those are for bio-equivalence studies, some are for phase I, II and III studies where they are developing the drug for a specific indication, and some of them are amendments to protocols that have already been approved. Presently, of those numbers, if you are looking at the clinical trials that are for a drug development, 20 per cent are phase I studies, 37 per cent are phase II and 43 per cent are phase III, and most of the phase II and phase IIIs are multinational trials. Probably 80 per cent of those are being carried out not only in Canada but in many international jurisdictions.
Senator Callbeck: I am just trying to get at how many new drugs are coming on the market every year.
The Chair: I think the essence of Senator Callbeck's question was, of the new entities that are coming into the trial system how many emerge at the end with an approval?
Dr. Stewart: I would say it is probably better for RX&D to speak to that. I think there is quite a high crash and burn rate. The personalized medicine initiative is an initiative to try to decrease that, to identify strong potentials early on and to eliminate ones that are not.
Ms. Sabourin: Perhaps I could add a bit on this statistics issue. In 2011 we approved 65 New Drug Submissions. Our average over the last five years was in the order of 40 submissions per year. That number does not include biologics. They are tracked separately. We can certainly provide the committee with statistics around the number of new drug approvals and some breakdown as to new active substances, so first-time use, et cetera.
Dr. Peterson: One out of 11 products that enter into clinical studies successfully meets the market according to a number of international publications, and we can refer you to those. However, there is a very high failure rate at phase II studies. This is when you go into the patient with the disease and ask the question: What is the benefit? What is the potential harm? There is a very high failure rate in phase II studies that limits those going forward.
Senator Callbeck: If they are going from phase II to III, is that determined by the sponsor and by Health Canada? Who determines whether they can go from one phase to the next?
Ms. Sabourin: The sponsor generally makes a decision about pursuing the development of that particular molecule or drug and then would provide us with an application for a clinical trial at the phase with a protocol that they believe is appropriate. We would then have the opportunity to determine whether we agreed with the sponsor or we thought some other information needed to be developed first.
The Chair: I would like to follow up in an area on which we received some very good information from you, and that is the area of specialized focus. We got into personalized medicine and the new efforts to use genetics. The cancer example was an excellent one and I want to come back to that at the end.
I would like to get the comments of CIHR in particular on this. There have been reports stating that in evaluating what occurs during a clinical trial up to 50 per cent of the patients involved and in the vicinity of 80 per cent of the physicians monitoring the trial have figured out very early in the trial which patients are on the placebo and which are not. The principal reason for that, as I indicated yesterday, appears to be that nearly every drug gives some sort of reaction, even just a mild feeling of warmth if not something more serious. Patients have come to think that unless they get some reaction to a drug, they are not on the drug, they are on the placebo.
If there is credibility to these observations, it comes all the way back to the clinical trial stage in terms of the effectiveness of the clinical trial in determining whether a new entity is really successful. It might also impact the decisions on whether there has been an adverse reaction, particularly if the individual is incorrect in their assumption.
I want to have a discussion around using the trial of a new entity versus an existing drug. Of course there is a serious ethical question around this with regard to removing patients from their existing therapy to take the new entity. Would you address that issue?
Dr. Peterson: You are addressing an issue of placebo control trials. The strength in a placebo controlled trial is that it is a superiority trial. It is intended to be blinded. No one knows what the therapy is. The statistical analysis of that trial is such that it is successful if it shows that the experimental therapy is superior, by predetermined measures, to the alternative therapy.
It is the case that the easiest superiority trials to design are those against placebo, but I hasten to add that a placebo today, based on a number of ethical and other considerations, rarely involves no treatment. Therefore, we are looking at new treatment either as being added on to standard treatment or we are looking at new treatment being substituted for one element of standard treatment.
Whenever that occurs, by the way, and a standard treatment is withdrawn, typically the trials are very limited in duration and they frequently are evaluated as the trial evolves to determine whether sufficient information has already been derived so that you do not have to continue to enrol patients under those circumstances. The issue with regard to how one would design the trial in order to have the highest quality and the best integrity of that trial involves all of those factors. The cleanest bottom line to show that a drug does what the manufacturer claims that it does, based upon the fact that no one has ever experienced that drug before, is in this placebo superiority trial design that I have referred to.
For all the other health care decision makers, by the way, how well this performs against nothing is not very informative. Therefore, you really want exactly what you are alluding to, and that is an active comparator. How well does this drug perform against an existing drug on the market?
However, this is the dilemma that we face: A company is not required to prove that their drug is better than another drug. Ford does not have to prove that it is better than Toyota to introduce a new automobile into the market. They have to fall within the standards for safety and efficacy. Oftentimes, these comparator trials fail to show that it is better. They can show that it is the same as, or statistically the measure is "almost as good as," and that "almost" is determined as a factor that we do not believe is clinically important. For all apparent purposes, it is the same. That trial design is much more problematic because the greatest integrity you get is when you show that your drug is better than another. When you do a study that shows that your drug is almost as good as another, there are many more concerns about the trial design that you have identified.
There are a number of scales — one is called the Jadad scale, and I will provide you references on that — that actually evaluate the criteria that were followed in the design and the conduct of the clinical trial that rank it from 0 to 5 on how excellent this trial was or not.
The Chair: I will go to Dr. Stewart in a moment, but just on that comment, obviously this would be of great interest to those who are developing formularies and who are approving things in the public health system. We are not going there today. That is not part of our issue.
Dr. Stewart: I was just going to repeat what Dr. Peterson said. In fact, practically, we see very few placebo- controlled trials. The vast majority are active comparators, or what we call add-on placebos. For example, you have a new cancer therapy and you have a standard of care. Both arms of the trial may get the standard of care. One arm gets the new drug or the investigational product and the other arm gets a placebo. They do not know whether they are getting the extra drug or a placebo. That is called an add-on placebo. Those are sometimes used.
However, the fact is that many diseases have a standard-of-care treatment, which has been proven in properly designed trials to have a positive impact and a reasonable risk/benefit profile. If you are going to bring a new drug into that sort of domain, it is not normally ethical to have a placebo-controlled trial where, say, a diabetic gets no treatment and your drug. You have to compare it to an active comparator or add on to an active comparator. Those are the kinds of designs we see most often with drugs in development.
The Chair: Is it fair to conclude that this trend is increasing in this direction?
Dr. Stewart: I think it is fairly consistent. Internationally, there is a lot of discussion around placebo-controlled trials. We have seen certain unique situations where active treatment may or may not have an outcome, such as a minor ear infection, and where certain regulators may require placebo-controlled trials, but in general, yes, this is an international thing.
The Chair: Thank you. I want to move into the area of personalized medicine from a particular point of view.
In the recent past, over the past decade or just slightly longer, we have seen an example of a potentially very beneficial painkiller that led to a significant adverse reaction in a subset of a population; however, not just a subset of a population, but a subset of that population. This happened to be in the area where it affected heart patients with serious clinical outcomes. Even though in this case the adverse effect is on a subset of a subset of the population, the numbers in that subset are quite large because of the nature of that particular condition.
One could imagine that had we had the ability to screen for certain indicators in that subset of the population, and that were applied prior to the prescription of the approved drug — the drug was approved and was widely marketed. In fact, there was more than one in that category. Do you see us moving to a point where one might be able to get at those identifiers earlier in the experience with an approved drug, such that a drug — and the appearance is that this particular class of drugs can be enormously beneficial in mitigating pain in a significant percentage of the normal population, but of course the results that have occurred have adversely impacted that use substantially.
This would be a very obvious example of where, if we get to the point of being able to detect this early — and perhaps that might have been done in the clinical trial stage, if perhaps certain observations had been more clearly identified — but are we moving, in your opinion, to a point where such an entity, a chemical entity, might well be better identified in terms of the significant adverse effects such that we could use that benefit to the much larger percentage of the population that could truly benefit from it?
Dr. Beaudet, would you like to comment?
Dr. Beaudet: The question is had we been able to identify the patients that reacted unfavourably to Vioxx, could we have used and could we keep on using Vioxx because we know that on certain individuals it is the only anti- inflammatory that actually works? That is your question, right?
The Chair: Yes.
Dr. Beaudet: It is clearly the hope that the personalized medicine will be able to allow us to segregate and stratify patients in such a way that we could indeed identify these potential side effects ahead of time and exclude this population.
Dr. Peterson: Only to add that you have pointed out the very important distinction within pharmacogenomics; we can identify patients who will respond to and benefit from a product based upon their genetic constitution. We also have the ability to identify individuals who may be harmed by virtue of that.
Moving this into the early clinical trial development phase, however, is problematic, and for the following reason: If a product does not benefit the majority of the patients in the clinical trial, it will fail; it will not move forward. If a product harms a substantive number of patients within the clinical trial, it will not move forward; it stops there.
We treat patients with drugs that have a number needed to treat in order to get a good outcome in the realm of one in five — one patient will derive the benefit for five patients being treated — and make no hesitation in a payment listing decision around that, for example. If it is that you need to treat 100 patients in order to get one health outcome, questions are asked around that. However, these are largely benefits that are accruing to substantive numbers of the patient population. It is safety issues that are 1 in 10,000 that may actually kill a drug from its ability to be used judiciously across the health care system. Provided we have the opportunity for a diagnostic test to identify that 1 in 10,000, then exactly what you are seeking is what we would hope to accomplish.
Ms. Barton: Dr. Peterson has just touched on one of the things that I was going to raise. Certainly there are benefits to having that approach, but there can be limitations in terms of that there is often a need to have a validated diagnostic kit so that you can be sure you are targeting the correct patient population.
There is also often a question of what happens when the product then goes out into the market. Certainly, with many of the drug safety issues we have seen, often it is actually associated with off-label use, and sometimes we have in fact indicated that there is a safety issue with that particular use, and that can sometimes relate to practise of medicine. What you see with the final outcome, when a product ends up being removed from the market, is that really it was the determination that the risk could not be mitigated, which, in some instances, even though we know that it should not be used in a specific patient population, we cannot control how the product is being used. That would still be true, I think, in the case of personalized medicines. There would still be that potential for the off-label use.
The Chair: As Dr. Beaudet indicated, hopefully we can reach a point where these things can be determined, because we do have in this case many people who would benefit enormously from such a drug. We have seen, for example, in the past where drugs such as thalidomide, which had terrible outcomes in one area, are the only treatment for other issues, and it is now used in a very significant area.
I want to drill that down even a little bit further and come back to your example with the cancer treatment, which I think is a remarkable example of moving forward, and hopefully that development will progress quickly where we see enormously expensive drugs with enormous negative impacts on patients who have to take them even though the cure is hopefully worse than the treatment itself in the end, but to be able to target much more specifically those patients who can actually benefit from this. It is my understanding that this largely is emerging — and of course in the case of cancer — in the well post-approval areas, post-initial clinical trial areas, in any event.
Again, Dr. Beaudet, I wonder if there is anything in my question that you can bring back to a clinical trial aspect in this area, or will this continue to be something that emerges in the post-approval kind of stage?
Dr. Beaudet: The only point I will make is that in fact what you are touching upon is an important point about personalized medicine. Personalized medicine is not necessarily only about genetics, and certainly not only pharmacogenomics; it is also about proteomics and about developing biomarkers. It is about, as you mentioned, having in tandem, at the time of approval, a diagnostic test that will tell you whether your target exists or not, in other words, whether the patient has a chance of responding or not, because if the target is not expressed, forget it; the drug will not have an effect.
Dr. Peterson, you may want to add something a little more specific.
Dr. Peterson: No, except that we are clearly on the threshold of the ability to perform the types of evaluations that you are referring to. For a long period of time, clinical trials have involved an enrichment phase before the trial actually begins. You may take a thousand patients, give them for a brief period of time the new product, and ask the question: Can they respond to this product? You will select from that population only those who will respond; and those are the ones, the enriched population, that you will take into the clinical trial to determine what its full benefit to harm is.
That has been very effective in helping us to answer some of these questions early on. What it leaves unspoken, however, is how can you identify which of the patients in the general population, after the clinical trial, will respond and which will not? That is where we are directing our attention to differentiating why, in that enrichment study, would this number of patients respond and this number of patients not respond? The ultimate goal of that would be the diagnostic test that Health Canada has referred to that would allow for you to distinguish that early on; and again, tests to assess safety considerations and tests to assess benefit.
Ms. Barton: I wanted to raise the fact that we have had information from Canada's research-based pharmaceutical companies that in fact this is a major area of development for them, that a number of them are currently working on medications that in fact are being developed at the same time as companion diagnostic kits to identify those genes. In fact, just recently we did approve an oncology therapy that had a companion diagnostic at that time and was for a specific population, a genetic subpopulation. It is not just in the post-market phase that those are being approved at this point; it is also occurring pre-approval.
The Chair: Senator Seth, did you have a question?
Senator Seth: Thank you, chair. It is a very small question that keeps coming to my mind.
Since we never do clinical trials with pregnant women, and yet we do prescribe some medications when they are pregnant, of course, how do we draw the line? How do we decide this medication would be safe? We are arguing, yet we have not done any trial on them.
The Chair: Without getting into the post-approval process.
Dr. Stewart: There is a lot of dialogue around encouraging research in this subpopulation. There are obviously a lot of concerns around safety, ethics and so forth. One thing we see a lot of value in is that we do get in the clinical trial area adverse drug reactions in patients who were not thought to be pregnant, and when they ended the trial, they ended up being pregnant. We value that information, because now we have exposure to an individual who is pregnant and we can follow the effect on the fetus. We often will ask them to follow that for years to see how this child develops, whether this drug had an impact.
I think there need to be efforts at a number of levels to find a way to do the research with pregnant women. There are a lot of concerns in terms of safety, ethics and legally, but it is very valuable. For example, many antidepressants are used with women who are pregnant and the evidence around their safety is not fulsome.
The Chair: I want to thank my colleagues for their questions and I certainly, on their behalf, want to thank all of you for the clarity and the breadth of the information you have given in your opening statements and in your responses. It will be tremendously helpful to us as we move forward.
I want to also remind you that should something occur to you after you leave that relates to questions we have asked today that you think would benefit us, particularly if there are specific examples or documents that relate to some aspect, I invite you, on behalf of the committee, to follow up with that.
On that note, I declare the meeting adjourned.
(The committee adjourned.)