Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 36 - Evidence - April 17, 2013
OTTAWA, Wednesday, April 17, 2013
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 4:16 p.m. for a study on prescription pharmaceuticals in Canada.
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
The Chair: I would like to welcome you to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie, a senator from Nova Scotia and chair of the committee. I would like to start by inviting my colleagues to introduce themselves, starting on my left.
Senator Eggleton: Art Eggleton,from Toronto, and deputy chair.
Senator Dyck: Lillian Dyck from Saskatchewan.
Senator Enverga: Tobias Enverga from Ontario.
Senator Black: Doug Black from Alberta.
[Translation]
Senator Maltais: My name is Ghislain Maltais from Quebec.
[English]
Senator Martin: Yonah Martin, British Columbia.
Senator Seidman: Judith Seidman from Montreal, Quebec.
The Chair: Thank you, colleagues.
Before I invite our witnesses to present, I want to remind everyone that this is our final meeting on the third phase of our study on prescription pharmaceuticals, this phase dealing with off-label use. We have changed our approach with regard to government experts in this regard. Normally we invite them to the first meeting to set the stage. However, we have had two previous studies in this sequence, and we felt that it would be much more appropriate to invite them towards the end so our questions could be more informed and perhaps then they can inform us even better than they normally do with regard to the issue. This is a slight diversion from the normal approach to inviting witnesses.
Today we have with us representatives from both the CIHR and Health Canada. By agreement with our witnesses, I will invite CIHR to present first, and I will turn to Dr. Beaudet in the first instance.
Dr. Alain Beaudet, President, Canadian Institutes of Health Research: Thank you, Mr. Chair. I would like to thank your committee for inviting me once again to speak to you about research and specifically today research activities dealing with off-label use of prescription pharmaceuticals in Canada.
I am pleased to be accompanied today by Dr. Robert Peterson, Executive Director of the Drug Safety and Effectiveness Network, or DSEN, sponsored by CIHR and Health Canada.
Dr. Peterson and I have already had the privilege of appearing before your committee to discuss the importance of clinical trials and post-market surveillance of pharmaceutical products.
Honourable senators, we all agree that policy-makers, regulators, health care professionals, researchers, public and private health research funders all have a role to play within their respective mandates in ensuring that our health care system responds to the needs of Canadians. In the context of off-label use of medications, it means ensuring that prescribed drugs are safe and efficient.
As you have heard over the weeks and months, approximately 80 per cent of off-label uses lack strong scientific evidence. In other words, we do not know enough about prescription practices that lead to off-label uses or about the true efficacy and safety of these drugs when they are used off-label.
As you are aware, the Canadian Institutes of Health Research, CIHR, are not involved in drug regulation. Our role, our mandate, is to support the creation of new knowledge based on rigorous scientific evidence, and to ensure the translation of this knowledge into better health and health care.
CIHR has invested $7.9 million over the last five years in different research areas related to the off-label use of drugs. First, we have funded major studies on the occurrence and frequency of off-label prescribing in Canada. For instance, CIHR supported a study conducted by Dr. Eguale and his collaborators from McGill University which revealed that 11 per cent of all medications prescribed were prescribed off-label. As you heard from previous witnesses, the off-label prescription of drugs is particularly pervasive for rare diseases. It is estimated that approximately 80 per cent of prescriptions for rare diseases are off-label. This important issue needs to be addressed.
CIHR is also supporting the development of tools to evaluate the use of drugs, both on-label and off-label. As an example, we are providing ongoing support for research on an electronic health record network aimed at determining whether computer-assisted intervention can reduce the rate of inappropriate prescriptions. Such a tool was found to reduce the rate of inappropriate prescriptions by 18 per cent. It can also be used to assess the various factors that influence off-label prescribing, such as drug, patient and physician factors.
If some of these off-label uses have had detrimental consequences on the health of Canadians, others have proven as effective as, and at times more economical than, currently used drugs. In fact, drug repurposing — that is, finding a new use for an old drug or finding a new target for a drug previously shown to be safe but ineffective — is a new area of research in drug development and a very fascinating one.
[Translation]
For example, CIHR is currently funding a research team that is investigating the effectiveness of a molecule called galantamine as a treatment for glaucoma. As you probably know, glaucoma is a cause of blindness that affects over 50 million people around the world. Galantamine, marketed under the name Reminyl, is already approved in Canada and the United States as a treatment for Alzheimer's Disease.
But studies with an animal model have shown that this medication was also effective in fighting glaucoma. Randomized therapeutic trials must now be conducted with human beings to demonstrate that it is truly safe and effective as a treatment for glaucoma in people.
As you can thus see, research to evaluate the safety and effectiveness of certain pharmaceuticals that are prescribed off-label is essential for the proper use of these medications.
[English]
In addition to improving health outcomes, additional research on the safety and efficacy of off-label drugs can result in cost savings. For example, clinical trials have shown that Avastin, when used off-label, is as effective as Lucentis, the drug currently approved to treat age-related macular degeneration. Both drugs are made by the same manufacturer and have the same mechanism of action. They act on the same target. However, treatment with Lucentis costs $1,575 a month, whereas Avastin costs $7. It is estimated that systematically replacing Lucentis with Avastin would save over $100 million each year in Canada. However, the U.S. Food and Drug Administration and Health Canada warned against the off-label use of Avastin as the way the drug is currently packaged could give rise to eye infections, leading to blindness.
This example illustrates that a drug proven safe in a trial setting may be found to have deleterious side effects in the real world or in so-called real-world conditions, hence the importance not only of carrying out rigorous clinical trials but also of post-market surveillance.
Whether supported by public or private sectors, this type of stringent evaluative research requires highly qualified personnel and state-of-the-art research infrastructures. This is why CIHR has been collaborating with the Association of Canadian Academic Healthcare Organizations, ACAHO, and Canada's Research-Based Pharmaceutical Companies, Rx&D, in implementing an action plan, developed in 2011, to help increase our clinical trial capacity and create a niche of excellence that will attract more trial investments to Canada. Mr. Chair, I would be pleased to provide your committee with a copy of this action plan if requested.
Increasing clinical trial capacity in Canada is also one of the objectives of the Strategy for Patient-Oriented Research. Through this strategy, also referred to as SPOR, CIHR is working with the provinces and territories, health care associations, private partners and patients in establishing and supporting patient-oriented research networks that will help develop our capacity for clinical trials in areas of benefit for Canadian patients.
Honourable senators, I am pleased to say that CIHR, within its mandate and in collaboration with various partners, will continue to support clinical and evaluative research that will provide decision makers with the scientific evidence they need to make policy decisions that will improve our drug prescription system.
Thank you for your attention. I will now invite Dr. Peterson to speak with you on the activities of the Drug Safety and Effectiveness Network.
The Chair: Before I invite Dr. Peterson, I neglected to inform our viewing audience that Dr. Beaudet is President of the Canadian Institutes of Health Research and that Dr. Peterson is the Executive Director of the Drug Safety and Effectiveness Network.
You presented us with an action plan in the clinical trials. Is that the same action plan you are referring to?
Dr. Beaudet: Yes.
The Chair: We do have that. Thank you very much.
Dr. Peterson, please.
Dr. Robert Peterson, Executive Director, Drug Safety and Effectiveness Network, Canadian Institutes of Health Research: Honourable senators, thank you for the invitation to speak to the issue of research on off-label drug use.
As you heard earlier, DSEN responds to queries from drug plan managers in the public sector, policy-makers, health technology assessors and regulators in order to increase evidence on the post-market safety and effectiveness of drugs in Canada. This initiative, therefore, complements Health Canada's requirements for rigorous pre-market testing of new drugs and supports Health Canada's role in post-market monitoring by focused research on how Canadians respond over time to approved drugs outside of the restrictions imposed by randomized clinical trials, and, as you have heard, in the real world of the Canadian health care system.
CIHR/DSEN has provided grants to stimulate research in drug safety and effectiveness evaluation in special or understudied populations such as children or seniors, populations that are frequently subject to off-label prescribing in Canada. I specify ``in Canada'' since it is often the case that medicines prescribed for children do not suffer from a lack of evidence for appropriate use but, rather, that this evidence has not been brought to the Canadian regulator allowing the Canadian label to be extended to the childhood indication. We know this because evidence exists in databases, in registries of clinical trials, from the medical literature, and from the approval of such agencies as the United States Food and Drug Administration and by drug regulatory authorities in Europe. Action on the part of Canadian lawmakers to mandate the submission of such evidence to Canadian authorities would help align Canadian regulatory requirements with other jurisdictions.
The research methodologies that exist within DSEN lend themselves well to addressing issues of safety and comparative effectiveness of all prescribed medicines, whether on-label or off-label.
At present, DSEN does not fund clinical trials. However, those clinical trials that are funded through other programs or institutes at CIHR are required to comply with Health Canada's regulations governing clinical trials. Hence, while a practitioner may prescribe off-label, when a formal research program to examine its use is funded, it no longer constitutes off-label prescribing but becomes an authorized use of the product within the context of the clinical trial.
The monitoring of adverse drug reactions is a responsibility that falls under Health Canada. The passive system of reporting of adverse drug reactions has many limitations that you have heard about from others. DSEN uses methodologies that do not constitute ongoing monitoring of general drug use but which happen to be extremely powerful tools to contribute to a risk assessment of the benefits and the harms of a drug or a class of drugs.
While regulatory focus is often just on the ``harms'' aspect of a drug, the risk of not achieving a benefit from a prescribed drug is often of greater importance in the mind of a prescriber or a patient. DSEN balances this risk assessment by examining both benefits and harms wherever possible.
Honourable senators, the CIHR/DSEN program provides evidence for a balanced assessment of the comparative value of a marketed drug not only in terms of the risks associated with its use in the real world, but also in producing evidence used in determining the economic value of the product, a factor that is so essential to a sustainable Canadian health care system.
The Chair: I will now turn to Health Canada. We have two people from Health Canada with us today. Dr. Sharma is the Senior Medical Advisor of the Health Products and Food Branch, and Dr. Marc Berthiaume is Director of the Marketed Pharmaceuticals and Medical Devices Bureau, Health Products and Food Branch.
Dr. Supriya Sharma, Senior Medical Advisor, Health Products and Food Branch, Health Canada: Honourable senators, thank you very much for the opportunity to present before you today. I will introduce myself and then I will turn it over to my colleague in terms of the opening remarks.
I have returned to the department and we recently developed this new position of Senior Medical Advisor with the Health Products and Food Branch, which oversees the regulation of drugs and medical devices and a variety of health products. My colleague is from the Marketed Health Products Directorate, which is responsible for the post-market surveillance of the products. With that, I will turn it over to Dr. Berthiaume.
[Translation]
Dr. Marc Berthiaume, Director, Marketed Pharmaceuticals and Medical Devices Bureau, HPFB, Health Canada: Thank you, Mr. Chair. I am the Director of the Marketed Health Products Directorate of the Health Products and Food Branch, Health Canada.
While I am here today, I want to talk about the department's role in authorizing drugs for sale in Canada, our responsibility for monitoring the safety of those drugs, and some initiatives we are taking to strengthen these programs as they relate to off-label use.
Health Canada reviews the evidence submitted by manufacturers to support the quality, safety and efficacy of drugs, and, when deemed satisfactory, authorizes their sale in Canada. Submitting a drug for approval involves costs. So drug companies, for business reasons, may choose not to seek authorization for these new uses. For these reasons, some uses or patient subgroups may not be thoroughly studied and would not appear in the manufacturer's submission to Health Canada.
Health Canada authorizes the use of drugs for specific treatments, but does not have the authority to recommend which drugs individual Canadians should use. Those decisions are taken by patients, typically in consultation with health care professionals.
The practice of medicine and pharmacy are not regulated by Health Canada. Health care professionals like physicians and pharmacists are regulated by colleges and registries under provincial and territorial laws, and are subject to professional codes of ethics and standards of practice.
[English]
The prescribing of off-label drugs for new emerging uses is not a Canadian-specific phenomenon. It is an accepted practice of medicine and one that in some circumstances might be beneficial to patients, for example, when no other alternative treatment exists. Use in children or pregnant and nursing women is frequently off-label, since these groups are not commonly studied in the clinical trials that are completed at the time of market authorization.
Off-label use, however, is broader than use in children or in pregnant or nursing women. A physician might find it necessary to use a drug at a higher or lower dose than approved in product labelling or at the same time as other drugs, despite warnings against simultaneous use or in patients with conditions like kidney or heart failure, for which there may be warnings or contraindications on the label.
Health Canada has undertaken several initiatives to strengthen knowledge about the benefits and risks of health products used to treat children. The department has implemented a six-month data protection extension to encourage manufacturers to conduct studies on the use of health products in children. Health Canada has also established a Pediatric Expert Advisory Committee to strengthen the availability, use and sharing of information on the benefits and risks of health products, and on food safety and nutrition for children and for nursing women. Health Canada has established a partnership with the Canadian Paediatric Society to promote the collection of safety information on drugs used in treating children.
As health products are sold in Canada, manufacturers and Health Canada monitor their safety. The adverse event reports collected by Health Canada from manufacturers, health care professionals and the public cover all uses, including off-label use. These reports may be used to detect safety signals. If at any time serious safety concerns are raised, Health Canada may pursue action, including changes to the labelling, communication to practitioners or to the public, or removal of the product from sale.
If there are early suggestions of a safety issue arising from an off-label use, the department can ask the Drug Safety and Effectiveness Network to fill gaps in drug safety information to conduct studies. To date, there have been several proposed DSEN studies for off-label use in children and pregnant or nursing women.
As another way of providing useful information to health care practitioners and other Canadians, the department recently announced that it will be publishing negative decisions about products whose submissions for new indications or whose use in other populations were reviewed and rejected by Health Canada. This information would be useful to practitioners considering off-label uses in these treatment areas.
Health Canada is also taking steps to update its regulations to align with international best practices on risk management and monitoring at all stages of a product's life cycle.
In conclusion, all authorized drugs have benefits and risks, whether they are used on-label or off-label. Health Canada works to provide physicians and patients with current information to enable optimal decisions about prescribing and use of medications. Health Canada is taking measures to continuously improve its drug safety monitoring processes.
Where safety issues are identified with pharmaceuticals for either on- or off-label use, Health Canada will take action to protect the safety of Canadians.
I thank you very much for your attention and I look forward to your questions.
The Chair: Thank you very much. I will now open the floor up to my colleagues.
Senator Eggleton: Thank you for being here. We have gone through a process and we have heard a lot of disturbing things. We have heard that Health Canada does not currently monitor use of the off-label use of drugs, although several coroners' juries have recommended they do so. They say Health Canada's involvement with this issue is largely limited to posting occasional warnings or advisories about the dangers of particular off-label uses of certain drugs. It sounds like that is very inadequate. We also heard in the testimony from at least a couple of researchers that 79 per cent — I think Dr. Beaudet repeated that again today in his submission — of the drugs prescribed off-label have no evidence base. It sounds pretty dreadful and quite frightening that 79 per cent do not have an evidence base.
We also learned that while off-label use may be around an 11 per cent level overall, for certain drugs it is much higher. For example, it is 60 per cent for antipsychotics, and various other statistics were given to us as well about very extensive use. That is not to mention, of course, in terms of children, pregnant women, et cetera, very substantial use of off-label drugs, and without the clinical trial benefits of them having been involved.
We also heard about insufficient information going to doctors. There are two kinds of labels. There is one on the container. Then there is another, more extensive label, and according to one person who did survey work, only about 1 per cent of doctors actually read it and follow it. There is a question of how we can get more and better information. Someone suggested that the Australian model might offer better information to doctors about off-label use.
We are also being told that pharmaceutical companies have engaged in illegal practice. In the United States, big pharma companies on the list have been fined $8.9 billion in the last few years. GlaxoSmithKline, Johnson & Johnson and Eli Lilly are all in there. They end up agreeing to these fines as a result of prosecutions, but they are still making a lot of money. It is simply a cost of doing business. In the United States, they even have a piece of legislation called the False Claims Act. It is whistle-blower legislation whereby someone who blows the whistle can get part of the award that the government takes from some of these drug companies, which is an interesting possibility. In France, they are taking criminal action against the head of one of their largest drug companies. He is being charged with manslaughter because 2,000 deaths occurred in the activities of that particular company. We have heard about some very bad performances.
What do we have in Canada in terms of prosecutions or fines? I am told it is absolutely zero, nothing, and I would like to know why that is. I would like to know whether any of these other experiences in the United States with the False Claims Act or the action being taken in France should be considered here. Why have we not done more in terms of enforcement of the actions of these companies in Canada? They are the same ones as elsewhere and are producing the same drugs. Do not tell me they are bad in the United States and they are clean here. Nothing is being done about it, and I would like an explanation.
Dr. Sharma: That is a lot of information.
I will start by speaking to off-label use. This is in no way minimizes the concerns you have with off-label use when products are not used appropriately. The key words are ``appropriate use of medications'' because there are good off- label uses where patients benefit from early information or information that is very much customizable to their specific case; and there are incidents where off-label use could introduce a risk. The challenge is that we do not have a lot of studies. The one study you referred to came out of McGill, specifically the 79 per cent was looking at an indication — a drug that was not approved for a specific type of disease.
Off-label use spans a much larger spectrum of treatment. For example, if someone's kidney function changes and you have to change the dose on the label because their kidney function is different, that is off-label use. Certainly, many uses are for illnesses that are difficult to treat. A patient may have multiple treatments and try the approved products, while there may be a case of a physician and patient faced with limited choices.
I am not saying we do not have an issue with potential associated risks, but when you look at the numbers, you see that there is a huge span. Studies in Canada and the United States indicate numbers of 3 per cent to 65 per cent off- label use in the same population. Even in pediatrics, the numbers often talked about are the percentage of drugs that have off-label uses. However, most of the drugs commonly prescribed for children are on-label. The volumes as well are different when looking only at off-label instead of at all drugs as a whole. It underlines the complexity we are dealing with when we talk about the issue.
With respect specifically to your question on the prosecutions, we have a system such that when a product is advertised or promoted to a physician and is off-label, it is reportable to Health Canada and is technically against the law. In anticipation of these questions, we went back to see how many complaints we received over the last 10 years that specifically talk about promotion of off-label uses. There were fewer than 10 complaints. It is a good question but is it that we are seeing less of that? Is it that we have less direct-to-consumer advertising like they have in the U.S? We have not seen that, but if we do, we take steps to correct it to ensure that no harm occurs from the promotion of something that is not in accordance with the appropriately labeled product in Canada.
Senator Eggleton: I find that hard to believe. That is not credible. You are saying that what is happening in the U.S. is not really happening here. You are saying that no evidence is being provided, but you are not looking for anything or trying to make sure they follow the rules, which is what I think you need to do.
Let me ask you about the information that goes to doctors that is then passed on to their patients. We could be doing an awful lot better in that area in terms of off-label use. Could you do more in that regard?
Dr. Sharma: I believe we can always do more. I do not think there is an area where we would not say there is more that we can do. We are making sure that physicians and the public have as much information as they can have to make the appropriate choices. Doctors will get information from a variety of sources. Certainly, when Health Canada speaks to the products it approves, it is taking greater steps to put that information out. As Dr. Berthiaume mentioned, we put a summary basis of decisions up, and we have that information available, as well as the information that Health Canada has when they make that decision to authorize the product. Now, we are moving to put out information that explains the basis of the decision when we do not authorize a product.
The process for a new drug takes a year to go through all the information. The paper for all the information on one drug submission would fill this room. The information is in place at the time of initial authorization and all the information that goes into making the decision is reflected in the Canadian product monograph. The monograph goes through what the product is indicated for, any contraindications, how the product should be used, adverse reactions and a section for consumers. We moved to put that up on the website to make it more readily available. We are also looking at further improvements to it.
We are trying to put out as much information as we can. When it comes down to a physician in an office with a patient, there are numerous ways for the patient to access information for the prescribing. That part of the practise of medicine is definitely unique and varies from practitioner to practitioner, and it is different for each patient. Health Canada has a large body of information. We are not expecting a physician, given the tens of thousands of products out there, to go through a room full of information for each product, so the information is synthesized and put out.
Companies may make changes to the product monograph, such as adding an indication or a risk. In that case, we update the information available and put out any required notification. We are always trying to reach physicians and patients with information, but we are always looking to see how we can do that more effectively and get more information at the point of care when they are making decisions.
Senator Eggleton: You might look at how to do it more effectively.
On adverse drug reaction reports, why not require that information in the case of off-label be provided on age, patient gender, dosing information, indication, et cetera. That would give you more information about the off-label application and on adverse drug reactions. We found in previous discussions that it also needed considerable improvement. This could be done on an electronic reporting system.
Dr. Berthiaume: The challenge around off-label use from a regulatory perspective is information generation. That part could be addressed partially by an electronic system. It is also the interpretation of the data. Off-label involves a number of players. We regulators receive information from drug manufacturers, review that information and look at the benefit risk. The benefit risk part that is positive becomes an indication; the benefit risk part that is negative becomes a contraindication. For example, if there are documented side effects in children that make it contraindicated, we will have that in a product monograph. The reality is there is a grey zone where there is basically limited information on the benefits of the drug because it is not the study group or groups for which harm has been demonstrated.
When you collect adverse event reactions about these groups, the practical challenge is that it is difficult to interpret that harm information; that is, you are getting adverse event information in the absence of any supportive benefit information. The real advancement to be able to analyze off-label use should integrate information not only about harm but also about benefits, as my colleagues from CIHR have suggested, which enables advancement of the knowledge. You are then able to say that this indication may be beneficial and that this indication should not be an off- label use and should be contraindicated. When we are talking about off-label use, we are often talking about this grey zone.
I have listened a lot to the deliberations of the committee and you have had good speakers here who have offered a whole spectrum of things. You have heard that off-label is not always negative, that there are positive aspects. An example raised before this committee was taking Aspirin for cardiovascular prevention. That was going on for 10 years before it was approved officially. If you would have done a study, you would have captured this off-label use in Canada in tens of thousands of patients, but it was not to their detriment. This is why to be able to interpret the information around off-label use wet need a broader piece of information, namely the information about the potential benefits. That is usually done in a setting that is more complex than ADR collection. It will usually involve collecting information about patient conditions and the indication of use, so a broader range of information that is usually done through some research organization, because you need a lot of information to be able to come up with the interpretation of the data.
Senator Eggleton: You have to do more for public safety.
Dr. Sharma: All the information you mentioned about age, gender, et cetera, is definitely valuable. The more information, the better quality information you have on an adverse reaction report, the better you are able to interpret it.
Health Canada does not receive only adverse reactions of on-label use but both. It is any serious adverse reaction associated with that product. There have been times when we have seen those adverse reactions. As Dr. Berthiaume said, you have to put that into context with the rest of the information. We then put contraindications or advisories out if that has been a concern.
In terms of the electronic receipt of it, we are moving to be able to receive adverse reaction reports electronically. By next month, we will be receiving our first ones electronically. I know that the committee has heard, and certainly we have heard, that part of it is that you need to make the process by which you submit this information to Canada as quick and easy as possible. We were moving to do that for companies, and the next phase will be to do it for a broader web-based approach so that companies, physicians or hospitals can submit that information to Health Canada quicker and easier.
Senator Seidman: I would like to pick up where we just left off in the sense that there is no question that we have heard over the course of these hearings that off-label use is important, and in certain population groups it is critical or there would be no treatment at all. I would like to ask a couple of questions with that in mind.
We heard testimony here from Dr. Rowan-Legg, who said that ``provincial formularies do not reflect contemporary prescribing practices, especially in pediatric populations where 75 per cent of the drugs used are off-label.'' In your presentation to us, Dr. Peterson, you referred to this very issue, and I would like to ask you about it in more detail. You said that the evidence exists from databases, whether internationally, different provinces, or the U.S., and you recommend action on the part of Canadian lawmakers to mandate the submission of such evidence to Canadian authorities. Would you explain this to us?
Dr. Peterson: More than a decade ago the United States took action to address the issue of off-label use in pediatrics through legislation referred to as the ``Best Medicines Act,'' which went through a series of renewals at that time that effectively required manufacturers to submit to the FDA the information on appropriate dosing and dosing frequency and effectively the information that would be required for appropriate use in the pediatric population, if the medicine was likely to be used in a pediatric population. They did that by virtue of specifying that experts would create a list as to what those medicines are at the present time so that important medicines could be identified in advance for the FDA. The companies would then apply to the FDA seeking authorization to fall under the other part of this legislation, which I will get to in a moment. The FDA has granted well in excess of 200 such authorizations for companies to submit data to them on the extension of the trials.
They had a companion provision where they were able to provide extension of the exclusive marketing of that product for all age groups, adults as well as children, for an additional six months following the end of other intellectual property — effectively, the patent on the product. There was a tremendous economic stimulus on the part of manufacturers to seek an additional six months of market exclusivity. If you look at a revenue driver in the United States, this could amount to the better part of $1 billion, and that would be the revenue gained as a consequence of doing this in exchange for an investment of a few hundred thousand dollars to do the clinical trials in children.
When I indicate that we know that evidence exists in the case of more than 200 drugs, it is related to fact that the FDA has announced that the product has had a label extension to say it is safe for use in the pediatric population. When we looked at this last year — and I know you are familiar with the editorial in the Canadian Medical Association Journal, where we drew attention to this differential — the response from Canadian manufacturers was they felt they had 25 products on that list that had sought and achieved authorization for in Canada. There is evidence in that regard.
The companion incentive to the U.S. FDA six-month extension of market exclusivity has been on the Canadian regulatory framework since 2006, which provides an additional six months of data protection. In other words, from the time of market authorization the regulator will not engage in an application with a generic manufacturer for an additional six months beyond when their data protection would otherwise expire. That has been in Canada for some time. As of last year, when we reviewed the status of significance of that, we found the differential to be well over 200 products in the United States and 25 or so in Canada. It does not appear to many of us who are actively engaged in this area that the incentive has been sufficient to drive the applications in Canadian.
The other part of the legislation in the United States was done in regulation in Europe, so it was not necessary to pass or amend an act to provide the same requirement, which have both resulted in a bit of misalignment between what the expectations are in Canada for appropriate labelling for use in children or not.
This, by the way, is one of the most exciting ways to address off-label prescribing that has appeared, and to begin to focus this in that fashion would be quite relevant.
Senator Seidman: I do have another question. I will take that as a strong response, and I appreciate that. I am not sure if there is more detail that we need about this in terms of the kind of action that would be necessary. You state here: ``Action on the part of Canadian lawmakers to mandate the submission of such evidence to Canadian authorities would align Canadian regulatory requirements with other jurisdictions.'' You have explained what you mean by that. I will leave it for now because I have a question for Dr. Beaudet, and I have very limited time. If there are any other details about that that we are missing here, I would really appreciate having them. You could send them to the clerk at some later time.
Dr. Peterson: I will do so.
Senator Seidman: Thank you.
Dr. Beaudet, if I have time, I would like to ask you about something you referred to. On the whole issue of the sharing of information, data collection, aggregation, analysis, electronic records and, as you said, registering, we have heard it all here, over the course of these hearings. However, there is no question that the sharing of data, in some form or another, would ensure what we all know is so important for off-label use, and that is the best certainty of safety and expert prescription for the people who are prescribed off-label.
You say here: ``As an example, we are providing ongoing support for research on an electronic health record network.'' You talked about that in your presentation to us. I would really like to hear you tell us a little more about what this means, what exactly it will be.
Dr. Beaudet: I will ask Dr. Peterson to answer because he knows more about it than I do.
Dr. Peterson: I would be happy to do that.
This full electronic medical record has been the Holy Grail for several decades for all of those individuals engaged in assessing appropriate utilization and research into new uses, for example. There has been a fair amount of support for researchers who have looked at pilot studies around this area.
I can answer very specifically from the Drug Safety and Effectiveness Network perspective. We have heard that a passive reporting of adverse drug reactions does not give a very high return rate for that, and the question is whether there should be a requirement in order for that to take place. We have the ability in Canada now, using methodology funded by DSEN since 2010, to examine the administrative health records linked together that provide diagnostic information, pharmacy prescribing information and, to a certain extent, a fair amount of information about serious, adverse reactions when they result in hospitalizations.
We would be able to focus a specific query on any class of drugs using our linked administrative health records and be able to garner a good deal of information about off-label use, on-label use and the benefits and harms. In fact, we have done that in a number of circumstances, albeit with on-label use of medicines as the focus.
Our limitations are what is not present in an administrative health record — laboratory data, clear details of outcomes and more specific issues associated with whether this is an expected adverse event or a new adverse event. We could only garner that if this were a true electronic health record. There are several areas of Canada right now where electronic medical records have been implemented or nearly implemented, both in pilot studies and in the ability of provinces to link data from their laboratory measurements and other outcomes into their diagnostic information. There are many areas where we are beginning to have access to that now. We could set this up, and this could become an ongoing review and monitoring of events that could take place electronically.
I agree fully that the ability to get electronic medical records is ultimately where we would like to be. On the way to that, I can tell you that we are developing some very powerful and sophisticated methodology in epidemiology studies. This is not RCT. It does not require an RCT. It does not limit the population. In fact, you want very large numbers, and, at the outcome of that study, you get a relative risk. Is there a 20 per cent risk of an additional adverse event or harm with this drug? Is it 30? Is it 50? The reality is that when we get odds ratios that are greater than 2, which means doubling of the rate, usually you do not have to have these big population studies to do that. We know that that is the case just from our clinical experience.
The Chair: Dr. Peterson, would you explain for the viewing audience what you meant by RCT?
Dr. Peterson: A randomized clinical trial. This would be the structured investigation that excludes a large number of patients who might ultimately get the drug in the real world.
Dr. Beaudet: I just wanted to add that what Dr. Peterson has been describing is extremely important to us. I am encouraged by, first of all, the achievements of DSEN in terms of being able to access data from various jurisdictions. What we are realizing now, as we are developing the patient-oriented research strategy, is that one of the foci for all jurisdictions is realizing the importance of access to data to respond to exactly these questions and prominently putting an accent on making this access easier for researchers so that we can truly benefit from our universal health care system that provides us with so much data that we are not accessing and properly looking at right now. I think you will see a huge difference in the coming years.
Senator Seidman: I want to clarify one thing you said, Dr. Peterson, because it is a good thing, I think. You are saying that you would see taking responsibility for this electronic recording or this health record network as a role for DSEN. I am trying to understand whether you have taken the responsibility.
Dr. Peterson: Thank you for the opportunity to clarify that. No, is the very short answer to your suggestion. Quite honestly, you are accurate in that we said that we would access electronic health records if there were a question about the use of antipsychotics in children. We do that in the form of administrative health records now, and we can garner a very large amount of information from that. There is no necessity for mandating additional adverse drug reactions.
I will send you some information about how access to electronic records such as this was able to actually correct a misperception about a new anticoagulant that has been in use in the United States, where the reporting system suggested a major problem with bleeding. In fact, when the counterpart to DSEN in the United States was able to go into the electronic health records, they found that there was no difference in frequency between that and the comparison drug. It is exciting for us to believe that we will be able to extend the resources that we have now. Others who are given the responsibility for general monitoring would be able to capitalize on the methodology that is being developed now and to apply that.
Senator Seidman: You are demand driven. Basically, that is the point here.
Dr. Peterson: We are very responsive to the needs of the regulator who gives us focused questions and to whom, therefore, we give very specific answers.
Senator Martin: I wish to ask one question related to what Senator Seidman was asking. There is a focus on developing methodology and ensuring that, once we can use the technology in our systems, it can be applied and used in an effective way. My question is in regard to the technology itself. Do we have the right tools in Canada or access to them? Does technology exist, once we have found the right methodology and all the stakeholders are ready, or is the tool available for us to implement that?
Dr. Beaudet: First, you are talking about methodology from an electronic standpoint and whether we can ensure that we can create proper linkages, because they are totally key. I think we do. The complexity, of course, is that the systems are variable between jurisdictions, and that is what complicates it a bit. I think the methodology is there. I think technically we can do it. However, it is not always as easy as we would like it to be because we are trying to establish linkages between systems that may not always be, let us say, readily compatible.
However, that is really the ``e'' part. When we are talking methodology, we have to think more broadly about looking at different methodologies for trials if we want to carry out the number of trials that will be necessary to address many of those questions. I am thinking particularly about cases of rare diseases, where you have actually very few patients, which is one of the reasons they are a small market. The industry is obviously not that keen on funding big trials, plus it is difficult to do these trials because of the small number of patients. Methodology on being able to devise meaningful trials on smaller populations will really change the way we look at the efficiency of drugs.
Dr. Peterson: I agree completely with the assessment that the technology is there and the linkages can be put in place, if necessary. I will report to you that our largest challenge in DSEN in accessing health records is not the technology. We can allow for those platforms to talk to each other, and we do that for more than eight provinces plus the general practice research database from the United Kingdom, the Medicare database in the United States. I can go on and on with that. It is a challenge, but we can get beyond that.
Our biggest difficulty now is privacy legislation at the regional level and the interpretation of that on the part of the actual data custodian. For Canada to move forward in this is partly the investment in the technology, the willingness to have the information recorded but beyond that, a means forward that allows for the understanding of how you can protect the data and how you can share the data to come forward. As I say, we purchased information from the United Kingdom in order to garner a population equivalent to what we have now as we go through our studies.
Senator Martin: That leads me to a question I had for Dr. Sharma and Health Canada. In terms of looking at privacy legislation at the regional level that would need to be addressed, is there a role for Health Canada in looking at this as a public health safety matter? For Canada to move forward, this is a very important piece. I do not know if there is such a role for Health Canada. If so, are you aware of any work that has been done to bring the regional stakeholders together for such a conversation?
Dr. Sharma: I think the electronic part of it has been interesting because that has been one of the areas we have had the most focus on. We have been working with Health Canada Infoway, for example, and they are looking at standardizing the way information comes into the system. A lot of that standardization is focused in two different parts. One is the technical standardization and whether one computer can send to another. Dr. Peterson said that is not the major barrier for them, but for us that has been the big hurdle.
When it comes to what we receive, we can get information into the system, but once you start sharing information across jurisdictions, that is where the individual privacy legislation comes into play. We have talked to researchers and they say, ``We can send you our information from British Columbia. My colleague from Alberta can send you the information, but I cannot send my information to my colleague from Alberta.''
One part is the role that we work with through Infoway to be able to do that breadth of sharing information and getting information across the different jurisdictions, but the other part is Health Canada's role in getting that information and what we do with it from a centralized place. We are looking at it in both respects, but the challenges exist on a province-by-province basis.
Senator Martin: I have one more question, then, and I would like to probe more on that. We know the challenges are there, so I wish you well on all fronts to try to move it forward.
The question is regarding a role for Health Canada or the federal government in terms of public education around off-label drugs and adverse effects. I will truthfully say, having been part of this committee and being involved in the care of someone in my family, I have been able to advocate and ask questions. I think education is important, although it is provincial jurisdiction. I think just as we had elder abuse campaigns that really brought that issue to the public's attention through TV ads, even understanding what ``off-label'' and ``adverse effects'' mean and being able to ask those questions at the time of prescribing is important.
Dr. Sharma, you said the practice of prescribing is unique to the physician and to the patient. There is that piece for the patient, and I wonder about Health Canada or the federal government's role in raising that awareness.
Dr. Sharma: I will start and then have my colleague join.
I think way you framed it in terms of needing to be an advocate for your own health, and being an advocate for the health of your loved ones, when you are equipped with more information — and information in a way that you can use it and assimilate it and be able to use it when you are having that discussion — is really important. We are faced with so many different places where we get information that Canadians look to places like Health Canada to say, ``Okay, I can go to 20,000 different places on the web, but I want information that is there, that I know has been authorized by a body that I trust, and it is in a format that I understand.''
We are always looking at different ways to do that. One of the things I mentioned was our product monograph. That is the summary of all the information that Health Canada looks at when we authorize a product. There is a section, part 3, that is actually written in more — I do not want to say lay language, because it makes it sound it is not as important as other language — accessible language. We always struggle with how much information and in what format we need to put it in so people can access it. That is up on the web. We certainly encourage Canadians. You can search the database, look for your product, look at that section and take it with you.
We have had comments around information at the point-of-sale. When you go into a pharmacy to pick up your prescription, you get information. That information is not necessarily the information that Health Canada authorizes. We are working with the different pharmacies, provinces and territories to make sure it is the right information — it should be Canadian information — and to ensure it is written in a way that people can understand.
It also speaks to the label itself and the information that comes with it. We have an initiative called plain language labelling to have information that goes out to Canadians be more accessible.
It is even as simple as the names of products. We have had areas where the naming of a product led to confusion. When a prescription is given either over the phone or when it is written, it looks similar to another product. People can potentially get the wrong product because they are so similar. We are putting out guidelines to show how you can do your assessment for your products to say whether or not they are too similar, to ensure they are not mixed up. I think there is a lot of information that we can put out. We would certainly welcome any recommendations or advice from the committee as to how we can do that better and how to better reach both Canadians as consumers and the people who are prescribing and using the product.
Senator Cordy: For the benefit of the viewing audience, the acronym CIHR stands for Canadian Institutes of Health Research.
Dr. Beaudet, you are the President of CIHR. Your position is a Governor-in-Council appointment made by cabinet. Is that correct?
Dr. Beaudet: That is correct.
Senator Cordy: According to the legislation of June 2000, CIHR is an arm's-length agency of government. You do not perform the studies yourself, but I think many Canadians believe you do. Perhaps you could explain the process in the arm's-length agency of government and how you deal with that.
Dr. Beaudet: With pleasure.
Indeed, we do not do the research. We give grants to researchers in our universities, hospitals and academic health sciences centres to do the research. The money is distributed based on excellence — excellent researchers, excellent projects, excellent proposals and excellent methodologies. All the requests for funding mean that the researcher has to send us a full proposal explaining, for example, the objectives of the trial; the past literature with information on what is known to make sure that it is truly novel research; an explanation of the methodology of the research; and the expected results of the research.
Committees of peers — i.e., researchers who are expert in that area — review the proposals. They receive several thousand proposals a year, and we fund 800. About 18 per cent of the proposals that we receive are funded. We are talking about a stringent process whereby only the very best science is supported. The researchers are expected to carry out their proposed research to ensure that the research is published and that it benefits the Canadian public.
In addition, we have taken a number of steps to ensure that there would truly be what we call a ``knowledge translation,'' ensuring that the results of the research are translated into better health and better health care; that there is a review of the results; that these results are disseminated; that there is an uptake by the decision makers and practitioners of those results; that they are available; and that they are informed of the latest data in the health sector.
Senator Cordy: The legislation says that it is supposed to be arm's length.
Dr. Sharma, you said that patients should have as much information as possible for off-label use — and so they should, whether it is on-label or off-label — and that one should be an advocate of one's health. I agree with that. Unfortunately, not everyone is in the position of those around this table for being an advocate for one's health. Certainly, I agree with your comments.
We heard a discussion from some panel members about someone receiving an off-label drug and whether they should sign an informed consent that they are aware of it being an off-label drug. In the case of a child, the parent or the guardian would sign. We discovered that part of the challenge is that doctors often do not know that the drug is being used off-label.
Would you comment on that? Knowledge is important for the patient, but certainly doctors should be aware that a drug is being used off-label. Sometimes when we talk about off-label use, we say that it is wrong. Well, it is not all wrong. Some off-label use, such as baby aspirin, is beneficial. It is probably one of the best things you can do for a healthy heart. However, we should be aware that we are using a drug off-label. Certainly, I would like to trust that my doctor is aware that the use is off-label.
Dr. Sharma: I will turn that over to Dr. Berthiaume, who writes prescriptions every week.
Dr. Berthiaume: I am still a practising physician. I have practised medicine full time for more than 10 years, and I have practised part time for more than 10 years. I would tend to disagree with the statement that some people put forward that doctors do not know when a prescribed drug is off-label. As a physician, and as knowing many physicians, I would tend to think that physicians, most of the time, are aware that they are prescribing a drug off-label. They do so deliberately because they have assessed that there would be potential benefits for a specific patient.
Based on that, the best opportunity for getting information is during interaction between the health care practitioner and the patient. Patients should be made aware that a drug is used off-label because that is part of an informed decision about taking a drug. That would be true for the discussion about the benefit risk of the drug for non-label use, too. It is a good practice of medicine or pharmacy to provide information at the point of care and for the patient to ask the relevant questions about the benefits and risks of a drug. Even for drugs on-label, there might be significant benefits for a patient. That is a valuable opportunity to have such a discussion.
Senator Cordy: I agree that, whether it is on-label or off-label, the patient should have as much information as possible. I have never asked my doctor whether a drug I take, and luckily there have not been many, is off-label. I have never asked that question.
Dr. Sharma, you talked about the information that we can access. Sometimes we are overwhelmed with information, such as in 20,000 different places on the web. Conceivably, if you wanted to sit down and do research, that could happen. However, we know that technology is a positive thing and that you can access a lot of information electronically. I was reading an article in the New York Times about how you can get so much information about drug use through people replying to things online.
How much information is there about off-label use in the United States? The people most likely to use off-label would be children, those with rare diseases, pregnant women and seniors. It is difficult to have a clinical drug trial on a pregnant woman. I do not know of a pregnant woman who would agree to such a thing; and for children it would be the same. Those with rare diseases who have nothing left would probably say, ``Yes, I will do a clinical trial. Give me anything. Let me try.'' How much information sharing is there and how much good, strong, scientific data is coming from the United States?
Dr. Sharma: I will divide that into two parts. For the clinical trial data, we refer to different populations and how it can be difficult to get that information. Certainly, when Health Canada looks at a product submission either to market a product, to change an indication, or to add an indication to a product, we look at the information provided to us, which can come in a variety of forms. As we have discussed, a clinical trial is the highest bar for information. In Canada, we do not say that those trials have to be done in Canada on Canadians because we understand that we are a smaller population, there is a large world out there and the companies are global. We will take information from clinical trials done in other countries. As long as those results are generalizable to the Canadian population, we will accept them.
For example, if a pediatric study is done in the United States and a company wants to market that product in Canada, they can submit that trial to us with the rest of the information and we will look at it.
I want to ensure that people know that we are not looking at only Canadian information, but it is the highest-level information. That goes with all information. If something from a database shows that a risk is associated with an off- label use in a population, it comes to our attention. We would not say, ``That is happening in the United States. We do not know what is happening in Canada. We are not going to do something about it.'' We would take that information and put it in the Canadian context and then communicate it out.
From a regulator-to-regulator perspective, we have ongoing dialogue with the FDA, with the TGA in Australia and a with number of other regulatory authorities about what risks they are seeing, what adverse reactions they are picking up and what types of things they are seeing that we need to be able look at. They might have larger populations. They might be seeing things that we are not seeing and vice versa.
There is a lot of information out there, and it does not have to be in the form of a clinical trial to be able to be added to the body of information that we have.
Having said that, if you are really looking at putting a new indication in, marketing a product for a new disease, we do want a certain level of that information. You want to ensure that you have trials, that how the product works is very well demonstrated and that the risks are minimized to the point where the benefits outweigh the risks. You still want to do that.
That leaves this area of off-label use. You have some information. You have people who have published, for example, that a series of patients they have treated have responded well to a product and have not shown a lot of adverse events. Then it comes down to the individual physician as well. I am seeing this information and looking at the rest of the information available to me through studies, Health Canada or wherever. I have a patient in front of me, and I need to make a decision as to whether, even though this is not on the label, I think that my patient can benefit from it and that I am not putting them at undue risk.
It is very fluid and very flexible in terms of that information. Again, you want the patient to have information, but you do not expect them to do everything that a physician would have to do to assimilate that information. A physician is not expected to do everything that Health Canada does as an organization. It is all part of the overall drug system, and we are all there to ensure that people have information to make the appropriate choices about the products they take.
Dr. Peterson: I would like to give the researcher's perspective — that of a clinician-scientist — about the dilemma you have alluded to in not wishing to do clinical trials in vulnerable populations or populations in which there might be uncertainties around the safety of the product.
We do clinical trials in pregnant women for drugs used in the treatment of pregnancy. Examples would be medicines used to stop pre-term labour. By extrapolation, I can refer to pediatric trials as well. For the drugs used in children, we do trials in children, particularly when it is a medicine to be used on the child and not on adults. We can manage the benefits and the harms and the protection of the individual within the clinical trials.
The alternative, of course, is this perpetuation of individuals prescribing without the additional information that you would garner in a structured approach to identifying those issues. Researchers and research ethics boards can address these questions.
I bring to your attention the fact that women are highly under-represented in clinical trials. That does not mean that when you prescribe a medicine approved for adults to a woman you are prescribing off-label. However, the reality is that the body of evidence to support any differential harms or benefits that would exist within a woman does not exist, and, unless you enroll those patients in the clinical trials, you will not have that.
We have a very structured approach in pediatric work such that if the drug is going to be used on children but not exclusively on children, then the clinical trials are done on adults first. We are able, having garnered the safety issues and the caveats, to extend the work into that area. I appreciate the dilemma apparent to the committee. We can address that.
The Chair: Dr. Peterson, to clarify a bit, it is my understanding that when Health Canada gives approval for the use of a drug, it refers directly to the population that was included in the clinical trial. I am seeing nods of different types here. This is an important issue because that is what literature suggests, and you have just indicated that if women were not included in the trial, the subsequent prescription of drugs to women is not an off-label use.
Dr. Peterson: I will defer to my colleagues who are currently regulators because I rely upon my prior experience. However, I can tell you that — and I use the example of HIV drugs in adults today — most of the clinical trials that lead to market authorization of an HIV drug are 90 per cent or greater on men. It does not mean that those drugs are not indicated for use in women.
The Chair: Dr. Peterson, we are not going to get into a debate over this. The issue is whether women were included or not. I am not talking about how many women. The inference was that when woman are not included in the trial, it is not a question of 10 per cent, 50 per cent or whatever. If women are not included in a clinical trial and the drug is approved for use and subsequently prescribed to an adult woman, is that an off-label use of the drug?
Dr. Sharma: If it is a product intended for use in both men and women, it would be extremely rare to ever have a study that did not include both genders.
The Chair: We understand all of those things. The question is simple. I do not want you to go into ``ifs''; it is a simple, straightforward question. If women were not included in the clinical trial and subsequently the drug was approved and prescribed by a physician for a woman, for use by that woman, is that an off-label use?
Dr. Sharma: It would not be an off-label use unless the product indication said, ``To be used in men only.''
If the indication was that the product should only be used in men and then the product was prescribed to a woman, that would be off-label. If it did not specify and was prescribed to a woman, it would not be off-label.
The Chair: If the application for approval is made to Health Canada for a drug to be used for adult men and women, no women were included in the clinical trial, but Health Canada approved it for use, then it is approved for what the applicant requested and, therefore, not off-label because they asked you to approve it for use in both men and women. Is that correct?
Dr. Sharma: Right. What they ask for and what they get might be different, so in terms of an approved product whatever they get is what the label says.
The Chair: We are not going into all of these different issues. This is a fundamental issue that has come through in three different areas, and I wanted it clarified. I think I understand the straightforward issue. It is that, based on what you have said so far, if an applicant requests authority to sell a drug to adult men and women, the clinical trials carried out have zero women involved and Health Canada approves the drug, then it can be prescribed for adult women. That is not an off-label use. However, if the applicant simply applied for authority to use the drug in adults, no women were included in the trial and Health Canada approved it, would Health Canada approve it for both men and women?
Dr. Sharma: Usually yes, with caveats because there are a limited number of effects that are actually gender specific. Most of the products would be approved for both men and women. It is interesting because we have had this debate around a specific product indicated only for women, and we had both men and women in the trials. In fact, having both men and women in the trials actually strengthened the body of information based on the way that the product is used in the body, so it was actually a good thing that you had both genders in the trials. It actually gave you more scientific weight for women.
The Chair: I want to ask some questions for further clarification of certain other issues.
Dr. Sharma and Dr. Berthiaume both referred to the issue where we have had various reports that 11 per cent of all medications are prescribed off-label; with subsets and children it may be 75. However, there is an important distinction here as well. That is the percentage of total medications prescribed, is it not? It is not the percentage of the total drugs on the market.
I want to use an example just for illustration. Baby Aspirin was prescribed off-label for nearly 10 years for heart issues. There were probably tens of thousands of such prescriptions written, but that is just one drug, right? However, the total number of prescriptions written would count in this overall number of the percentage of medications prescribed off-label, right?
To take a ridiculous example, it is possible that 2 drugs out of 1,000 on the formularies could account for all of the 11 per cent of off-label use. I am not saying it is; I am just using it as an example to clarify the distinction between the percentage of total drugs available to be used, because I am fairly certain that people are interpreting that number as meaning the percentage of the total drugs on the market and therefore this is a very important clarification. Could you respond to the examples I used?
Dr. Sharma: Specific to that study, the 11 per cent was referring to the percentage of prescriptions that involved an off-label indication and not an off-label use writ large. Not a dose necessarily on the label, not a root of administration that was not on the label, but an indication, a product used for an indication, a type of disease or condition that was not on the label. You are correct. It is not the number of drugs; it is the number of prescriptions. In that case it was from 2005 to 2009, in that practice, with that population that was monitored.
The Chair: Thank you very much. This has occurred over the course, and you people will give the correct clarification and I wanted to get that on the record.
Dr. Berthiaume, at the bottom of page 3 of your presentation you referred to off-label use and you said ``when a formal research program to examine this use is funded, it no longer constitutes off-label prescribing.'' I would like you to clarify that.
I am sorry Dr. Berthiaume. It is Dr. Peterson who said that. I had you in my mind because I was actually going to ask you a slightly different question. Dr. Peterson, it is your report on page 3.
Could you clarify for that for me? What do you mean by a research program and how does that lead to it being identified in a way that subsequent use of the drug for that previous off-label use is no longer off-label?
Dr. Peterson: I shall try to do so briefly.
If you agree that the term ``off-label'' refers to the unauthorized use of the drug from a regulatory perspective, it does not have an approval by Health Canada for that use. There are ways in which products can be authorized for use in Canada that do not require market authorization and the actual label for that purpose. A clinical trial application is one of those. Division 5 of the Food and Drug Regulations, which authorizes the use of a substance within the context of a clinical trial, does mean that is now authorized for use within the clinical trial.
The organization of this prescribing practice where, as a physician, I prescribe for one or for two patients and there may be many months or years between those is not an organized trial per se, but once you begin to address that question —
In the context I was giving, it was an application to a funding agency to support that type of a clinical trial — randomized or not —and that the authorization of that clinical trial by Health Canada, having had a clinical trial application filed and not objected to, allows for that product to be used within the purposes of that clinical trial and it is not off-label in the context that I am using as a definition. It is important to therefore distinguish wide prescribing practices which may in fact be in violation of Division 5 of the Food and Drug Regulations. If I decide as a practitioner that I will do my own trial on a cohort of patients, then I am required under the regulations in Canada to actually ask for clinical trial authorization and to carry out my research on that basis.
The Chair: If I have understood you, you are referring to a research program that has subsequently been identified as an authorized clinical trial. Well, that is a whole lot different than the inference I took from your presentation.
Dr. Peterson: I beg your pardon.
The Chair: I know CIHR funds many research programs, and in rare diseases, for example, most of it is in fact ``research program'' but not ``clinical trial.'' That is why my question was for you to clarify. You brought it back into the context that once it is authorized, but authorized within the context of an identified clinical trial.
Dr. Peterson: That is correct.
The Chair: Dr. Berthiaume, in your presentation you referred to information available from the summary basis for decisions or actions of Health Canada. If I heard you correctly, you indicated that you will soon be reporting on such decisions where there was a negative decision. Did I hear you correctly in that regard? If so, I have this feeling that I have been hearing this for a while and I wonder if you could indicate when the summary decisions that were negative with regard to an application will actually be published.
Dr. Berthiaume: The summary bases of decisions are currently, and have been, published. My understanding is that since October 2012 some negative decisions have been published. Perhaps Dr. Sharma can provide more details around that.
Dr. Sharma: The summary bases of decisions is not just for drugs but medical devices as well. It is the information in a summary form that went into the authorization of that the product. Phase I looked at new products and active substances coming to Canada and provided that information. That was expanded to all the new products and since September 2012, phase II started. Again, those would be the products that were coming through and if there was a negative decision.
The timeline is interesting because it takes a year for a new drug submission, so you may not necessarily see a negative decision coming out on September or October 1. However, the program to do that second phase where negative decisions will be published started as of September 2012. It has been a long time in coming, but it is here.
The Chair: That applies to all negative decisions, does it?
Dr. Sharma: Yes, that is right.
The Chair: Thank you. That is very important to us.
I have a question with regard to the information technology, but I want to make sure I get my colleague's questions out.
Senator Dyck: Thank you for your presentations this evening. It has been a long day and you have answered questions from a dozen external examiners.
My question relates back to what Senator Seidman asked Dr. Peterson. In your answer to her you talked about the situation in the U.S. You mentioned that there were drugs that went to a committee to look at drugs that were likely to be used off-label in children. They would look at them and essentially approve them for a specific use so they would become on-label. You also mentioned the Best Pharmaceuticals for Children Act.
In Canada, what are we missing? We have a six-month data protection plan, but for some reason we do not seem to have the mechanism to facilitate the transfer of off-label drugs and approved on-label to children. What are we missing? What are the key elements, or is it the act that is missing? Could you pinpoint what we need to do?
Dr. Peterson: The act in the United States was referred to as having both a carrot and a stick. The carrot was the six- month extension of market exclusivity across all age ranges for that product should you submit applications to the FDA. The stick was the provision in the act that said you must present this information to the FDA if the drug is to be used in pediatrics.
With the examples I gave you and the large amount of profit that could be garnered within the six months, it was anticipated there might be a large number of applications coming from industry to avail themselves of that. The FDA put in place an expert committee that said, ``We will help you create a list of those medicines that you can refer to reliably as drugs that will have a strong pediatric utilization.'' The FDA permitted companies to make applications for market exclusivity only if the drug was on that list. There was no committee of experts to say, ``Yes, this drug is okay,'' thereby circumventing the regulatory process.
Canada has passed a form of the benefit — an incentive — in order to do this. It has not been taken up widely by industry and, therefore, we are lacking the stick, the actual statement that if drugs are to be used in Canadian children, then the information will be submitted to Health Canada.
I have modified that a bit in my presentation to say ``not if the drug is going to be used.'' What I have said is, ``If evidence exists on the appropriate use of the drug in Canada,'' and you could go beyond that to say,'' and has been submitted to other regulatory agencies, it will be submitted to the Canadian regulatory authorities in order for your product to be marketed in Canada.''
Senator Dyck: Would you make it a recommendation that there be a form of stick in a piece of legislation? It looked like you were saying that in your submission on page 3, but it does not actually state it clearly or strongly.
Dr. Peterson: A caveat with a disclaimer here: I would be making that recommendation as a pediatrician and as a former practising clinician in Canada. That would be a very strong recommendation that I would make personally. The disclaimer here is that my prior affiliation with Health Canada or my current affiliation with CIHR does not necessarily reflect that.
Senator Dyck: In your opinion, that sort of legislation would likely improve the ability to treat children more effectively so that they would get out of this guessing game or use data from other sources without having that approved or authorized by Health Canada.
Dr. Peterson: It immediately solves the off-label issue. It will improve the distribution of information, as has been referred to many times here, on the appropriate dosing frequency and utilization of the products.
Senator Enverga: Dr. Sharma, you said that you have been involved with or have been speaking with countries like Australia and the U.S. with regard to off-label use. Can that information be accessed by a regular doctor? Is it being used?
Dr. Sharma: To clarify, what specific information are you asking about?
Senator Enverga: You have been talking about off-label drugs and comparing notes with practitioners from other countries. Is that information available to Canadian doctors?
Dr. Sharma: I was talking about the regular meetings or teleconferences with four large jurisdictions to look at the adverse reactions and adverse events that they see. For example, we can raise something that has come up in Canada that we would like to get information on from another country. Australia might say they have done an analysis of this information, which they present. Health Canada takes all that information and puts it into the Canadian context. We take the information and determine what is relevant and add it to our database. All of that information from studies, from what other people have published and from our databases goes into making a decision.
The information we get is not shared directly with people because it needs to be put through more analysis and put into a Canadian context. We then disseminate the information.
Senator Enverga: It will take more studies before you can put it into a database that will be available.
Dr. Sharma: Right.
Senator Enverga: Let us say there are medicines that were off-label. After so many clinical trials and your investigation, is it possible for Health Canada or DSEN to declare that off-label drug as on-label if everything is okay?
Dr. Sharma: The short answer is no. The decision to market a drug or to market it for a specific indication is up to the pharmaceutical company. The company that wants to market the drug would bring that information to Health Canada. That is for the positive part of it. What are you going to market the drug for? If there is a risk that speaks to our patient safety or health protection functions, we raise that. Certainly, we work with the companies to change that. Often, it will be Health Canada who raises an issue on something that needs to be added to the label or to be communicated publicly. Certainly, for a new indication or to market a product, the responsibility is that of the pharmaceutical company.
Dr. Berthiaume: I want to add a practical consideration. Sometimes for all their drugs physicians will look at the product monograph but also at other sources of information. Off-label use approved in other countries may make its way into some of the documents that they will access. Software exists so that a physician can be registered to provide an overview of specific treatment areas on a regular basis. When a physician prescribes a drug, he or she may look at the product monograph but may also find some information about off-label use in other formats so they can make a decision. Much of the discussion here is focused on the product monograph, which is an important document.
However, I want to ensure that the committee is fully aware that physicians use information from other sources, even from pregnant women, for example. As a physician, if I want to prescribe a drug to a pregnant woman and the product monograph has no information, I can go to a number of other information sources online and by phone. I can call and ask what they know about the use of a drug in pregnant women. They collect all the information about the use of that drug in a specific group and provide information to help with the decision and to share with the patient. I want to broaden the discussion with the fact that there are other means for other information for off-label use application.
Senator Enverga: Let us say you find that an off-label drug is very good for patients. Would you recommend that drug? Would you recommend the manufacturer to make it on-label so it will be distributed easily to practitioners to help the general population?
Dr. Berthiaume: Dr. Sharma answered that previously. The system in Canada, as in other jurisdictions, is manufacturer dependent. The manufacturer has to present a submission so that an indication makes its way to a product monograph. However, the other sources of information do provide a capacity to go beyond the product monograph. The product monograph is the official document, but it is not the only tool used by physicians out there. That would be my answer.
Dr. Sharma: We provide incentives. If you have a product used in a patient population that does not have any other treatment options or a product you want to market and it shows a significant benefit to the patient — either a significant improvement in the way it works or in decreasing the risks — then you can get a priority review in Health Canada. That priority review is a much shorter time span to look at that product. We are trying to encourage manufacturers to come in with submissions for products that are really showing health benefits.
Another program we have moved forward with is the orphan drug program. These drugs treat orphan diseases, which are diseases or conditions that are in very small populations. There is a program where if you have been given the designation of an orphan drug, you will get a priority review, so a shorter time. We will waive the fee we would normally charge for processing that. There is a modified review to take into account the fact that you will have a smaller, tighter body of evidence that you would be looking at. We look at market exclusivity, with an extension of six months for data protection for pediatric populations. Then there is appropriate monitoring or different monitoring that goes on with that product once it is on the market for those specific indications.
It is not specific to off-label use, but if there are areas where we find companies are not coming in, we are trying to put incentives in place to get them to submit that information to Health Canada for review so that we can have them for Canadians to use, but with a label that really describes how they should be used and all the information that has gone in to support that authorization.
Senator Enverga: Dr. Beaudet, you mentioned that there were some cost savings resulting in clinical trials, like Avastin and Lucentis, done by the same manufacturer. Obviously the company knows something that we do not — chemical composition. Maybe it is for great economic benefit. We do not know about that. Can you comment on this? How many more times have you seen this?
Dr. Beaudet: This is perhaps an extreme example of really two drugs that were marketed for different purposes, one for macular degeneration and the other for cancer. The very cheap one was for cancer. Several rigorous, well-done trials demonstrated clearly that these two drugs, under trial conditions, were equally safe and equally effective. I mentioned the difference in price. There was a huge incentive, obviously, for the company to allow the use of the cheapest drug, also using macular degeneration as an additional indication.
The problem is that because that drug was for cancer, it was meant to be injected not in the eye but in the veins. In the real world, when it started being used off-label, it was actually found to give rise to higher incidence of eye infections, even leading to blindness in certain cases. For those reasons, Health Canada has put a cautionary note in using, under these packaging conditions, the cheapest drugs.
There were two messages there. First, off-label does not mean bad. In some cases you may, through a rigorous trial, realize that an off-label use may be not only as efficient but can actually turn out to be cheaper. Second, under the rigorous trial conditions, you may have a result that is suggestive that they are exactly the same, but in the real world you may find that there are differences.
Senator Enverga: I was thinking that maybe Health Canada can give a better incentive to manufacturers to ensure they make the off-label drug as labelled. Maybe you should bring more information.
The Chair: We will not go further down that road because the issue of patent protection life, et cetera, is a complicated business decision. We will stick to the health-related aspects here. I will see how many of the second-round questions we can get in. I will ask you to be brief. We only have a few minutes left in responding to questions.
I will start and I will try to be clear. One of the things we have been pushing very hard throughout this particular study, and indeed all three of the studies, is the issue of use of information technology and the awareness that the so- called electronic health record, which in my opinion is not being used correctly in terms of what percentage of the population has one. It means your total health record is really limited electronic medical records that people are referring to in that regard, and that is a very different set of data.
Those are not available to us to collect data and return information on the kind of basis that the promise holds and you referred to a couple of real reasons for that. One of them is the jurisdictional issue, the provinces and so on. To some large degree that is often technological, but you have indicated correctly there are ways to overcome the technological issue. You also referred to the privacy of information.
Today there was an important information conference in Ottawa, and most of the morning session dealt with issues that can directly relate to health care. Two of us attended those meetings this morning. In fact, the people presenting identified the kinds of issues that occur in Canada that are preventing these electronic databases to develop as fast as they can as being typically Canadian problems. If we want to end a discussion on moving forward in an area, all we have to do is yell ``privacy concerns.'' That was stated explicitly. I will add two to that, ``two-tier'' and ``private delivery.'' Those things will end discussion on important issues in Canada faster than almost anything else.
They indicated that, as you have suggested, the technology is available to move information forward much more rapidly but that the issues are the reluctance of anyone to move forward in a number of these areas because of the concern over privacy. In other jurisdictions, the Veterans Benefits Administration in the United States, the Mayo Clinic and so on are collecting tens of thousands of patients' information in an electronic form and interacting deliberately. The specific example of the Veterans Benefits Administration is one that has gone from being the ``bottom-feeder'' of American health delivery to one of the tops in terms of access to information. I will stop and let Senator Eggleton take over for the few minutes that are left here.
With regard to the examples we have heard throughout the study — the idea of drop-down menus in doctor's offices to indicate when it is off-label and so on, through to the other end giving the patient e-access to Health Canada to report on their response to a drug, for example — there is no reason why we cannot do much better in those areas. If any of our experts here who deal with this have suggestions for us in this area after you leave here, I would welcome you bringing them forward.
I will not put my question on for further dialogue at this point because I want Senator Eggleton to at least get his questions on the table before we run out of time.
Senator Eggleton: We had representation amongst our witnesses to the effect that since the pharmaceutical companies are profiting from off-label use, they should be required to go through some sort of authorization, some testing process, something that Health Canada, presumably, would administer. However, there is not much incentive for them to do that. They already have their formal approval and off-label is determined by the physicians. Particularly towards the end of a patent life there is even less inclination to want to go through that.
However, a couple of other examples came to our attention of what is being done in other countries. Would either one of these models have merit? In France, they have produced Temporary Recommendations for Use, TRUs, with respect to off-label uses. They can be granted for a maximum of three years, during which time a drug that has been approved for use for a given indication can be used off-label for stated indications.
In the United Kingdom, the National Institute for Clinical Excellence recently launched a new program called Evidence summaries: unlicensed/off-label medicines — nationally available critical reviews to help professionals and patients of existing evidence regarding off-label use of selected drugs.
Perhaps there is a third one. Earlier I mentioned the Australian model because Dr. Joel Lexchin, a practising physician and professor at York, said that according to a national survey only 1 per cent of the medical profession read the monographs. If you bring it right down to doctors only, it is about 4 per cent, but that is low. We have to find a better way of getting information to these doctors.
Do you think some of those international practices could have application in Canada?
The Chair: If the witnesses require more than a yes or no, I will ask you to follow up with a written response.
Dr. Sharma: We need more than a yes or no.
The Chair: I would ask both groups to follow up with written responses to the clerk of the committee.
Dr. Sharma: Yes.
Senator Eggleton: We are at the end of our study. Recommendations are coming.
The Chair: We are at the end of our time, colleagues. We have put a good range of questions to the witnesses. We have attempted to push hard on some of these issues because they are the authorities on these matters. As we indicated, we attempted to use a different approach this time to hear from the various witnesses throughout, so the witnesses had access to other testimony. It is my view that the committee could review this approach for the future. The nature of the questions and the responses has helped us a great deal as a result of our being more informed coming into this session.
We will see you again on various issues over time, as we have seen you before. On behalf of the committee, thank you so much for being so willing to address the questions put to you.
Colleagues, thank you for the thorough and thoughtful questions.
(The committee adjourned.)