Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 33 - Evidence - March 7, 2013
OTTAWA, Thursday, March 7, 2013
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 10:30 a.m. to study prescription pharmaceuticals in Canada (topic: Off-label use).
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
The Chair: Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie. I am a senator from Nova Scotia and the chair of the committee. I will invite my colleagues to introduce themselves, starting on my right.
Senator Seidman: Judith Seidman, from Montreal, Quebec.
[Translation]
Senator Verner: Josée Verner from Quebec.
[English]
Senator Martin: Yonah Martin from British Columbia.
Senator Enverga: Tobias Enverga from Ontario.
Senator Campbell: Larry Campbell British Columbia.
The Chair: Just before I welcome our guests this morning, I want to remind everyone that we are in our study on off- label use of prescription pharmaceuticals, the third phase of a four-part study on prescription pharmaceuticals in Canada. We have some distinguished visitors with us this morning, and I will introduce them as I invite them to make their presentations. By earlier agreement, I will start with Dr. Brian O'Rourke, President and Chief Executive Officer of the Canadian Agency for Drugs and Technologies in Health.
[Translation]
Dr. Brian O'Rourke: President and Chief Executive Officer, Canadian Agency for Drugs and Technologies in Health: Mr. Chair, thank you for inviting me to appear before the committee.
[English]
Let me begin by telling you a bit about the Canadian Agency for Drugs and Technologies in Health, CADTH. We are an independent, not-for-profit technology assessment organization that was established in 1989. We provide federal, provincial and territorial health care decision makers with evidence-based assessments of the clinical and cost effectiveness of pharmaceuticals, diagnostics and medical, dental and surgical devices and procedures.
The members or owners of CADTH are the federal, provincial and territorial deputy ministers of health who fund the agency, that being Health Canada and all of the provinces and territories, with the exception of Quebec, which runs its own agency called INESSS. Mr. Chair, CADTH operates with a dual value proposition. First, we are a producer of evidence, advice, tools and recommendations that promote the optimal use of drugs and other health technologies. Second, we operate as a broker of Canadian and international health technology assessment initiatives.
As a producer, CADTH provides a range of services to support the effective management of pharmaceuticals and other health technologies in Canada. One of our flagship programs is the Common Drug Review, a federal-provincial- territorial process used to review the clinical effectiveness, cost-effectiveness and patient-group input for new drugs and existing drugs with new indications. The Common Drug Review supports coverage decisions by 18 of the 19 publicly funded drug plans in Canada. Once again, Quebec has its own agency to support its drug review listing system.
We also conduct therapeutic class reviews on pharmaceuticals and conduct optimal-use projects, products that are the result of expert deliberative processes that provide the evidentiary foundation for jurisdictions to promote the appropriate prescribing and utilization of drugs and other health technologies.
Another valuable service provided is quick summaries of the dauntingly large and complex medical literature, our Rapid Response Service. This service is extremely helpful to jurisdictions in that it addresses their urgent needs for clear and balanced information that informs policy and practice decisions about drugs and other health technologies.
We also conduct more comprehensive and complex health technology assessments when warranted. Some examples include robotic surgery, magnetic resonance imaging units, pharmacological based therapies for smoking cessation, and medical isotopes, just to name a few.
[Translation]
As I mentioned, in addition to being a major producer of health technology assessments, the agency also operates as a broker, helping to create and nurture an environment for evidence generation and adoption across Canada.
As a pan-Canadian body, we are well positioned to work collaboratively with health technology assessment organizations operating at the provincial level, in academia, and within hospitals.
[English]
As an organization involved in promoting the optimal use of health technologies, CADTH is on occasion asked to provide evidence and advice on the off-label use of pharmaceuticals. It is not surprising that we receive these requests about off-label drug use given its prevalence in Canada and other countries. A 2012 study by McGill University researchers found that 11 per cent of medications prescribed by primary care physicians in Quebec were for off-label use. The researchers also found that 79 per cent of the off-label prescribing identified in their study was not supported by strong scientific evidence, defined as at least one controlled clinical trial.
While much of the media attention surrounding off-label use is focused on safety, a compelling argument can be made that the quality of health care Canadians receive would actually be diminished if off-label drug use was completely curtailed. Since clinical trials involving children are rare, many drugs are used off-label for pediatric patients based on evidence from trials involving adult populations, with physicians adjusting dosages for children based on anecdotal reports, experience and clinical judgment.
In addition, there are situations where off-label drugs are the only option to address life-threatening or terminal conditions. Drugs are used off-label in psychiatry, in geriatrics, in cardiology and in most other clinical disciplines. Finally, the use of older drugs for new indications, even when they are used off-label, can in some cases reduce costs without impacting patient care.
In many cases, there is a substantial body of evidence supporting the off-label use of a drug. This is particularly true in the case of older drugs, where real world evidence has been generated over time and appropriately documented in medical journals. This evidence rarely includes randomized controlled clinical trials, but it does provide sufficient evidence upon which clinicians can make an informed decision. CADTH has responded to a number of requests for information on off-label drug use from provincial governments and from regional health authorities and individual practitioners.
As an example, we conducted a systematic review of intravitreal bevacizumab, a drug commercially known as Avastin, for the treatment of diabetic macular edema, or DME. DME is a serious complication of diabetes, in which the centre of the retina swells, causing vision loss. A drug called ranibizumab, commercially known as Lucentis, is the drug that is approved for use in treating patients with DME. Avastin was approved, by Health Canada, for use as an anti-cancer agent, but because it has a similar mechanism of action to Lucentis, it is also being used to treat DME off- label, primarily because it is available at a much lower cost. We identified a recent indirect comparison, which actually concluded that Avastin may have similar efficacy to Lucentis in treating patients with DME. As you can imagine, the possibility of achieving cost savings without negatively impacting patient care is of significant concern and interest to drug plans across the country.
[Translation]
We stand ready to respond to requests from our customers for evidence on off-label drug use and other topics related to the optimal use of drugs and other health technologies.
[English]
I would like to leave you with two messages. First, off-label drug use is common in Canada, and while there are concerns about safety, it offers some benefits to patients and the overall health system. Some off-label prescribing should be permitted. Second, where data exists, health technology assessment organizations like CADTH and INESSS in Quebec are able to support decision makers by providing evidence-based analysis, information and advice regarding off-label drug use.
Thank you, Mr. Chair, for allowing me to present to you today. I welcome any questions that you might have.
The Chair: I will turn now to Dr. Paula Rochon, Senior Scientist with the Institute for Clinical Evaluative Sciences.
Dr. Paula Rochon, Senior Scientist, Institute for Clinical Evaluative Sciences: Thank you for asking me to present. I am a health services researcher and a specialist in geriatric medicine, with almost 20 years experience studying and caring for frail older adults. Today I will be talking about off-label prescribing, particularly as it relates to older adults. Some of the research I will discuss comes from CIHR funded research studies.
Off-label prescribing is the prescribing of a drug therapy in a way that has not been approved by a regulatory agency. This can mean prescribing a drug for an unapproved indication or to an unapproved subpopulation. It can also mean using a dose outside the recommended range.
Federal agencies review clinical trial evidence to identify indications for drug licences. Drugs are often used for other indications. This is ``off-label.'' Off-label is far more common than people realize. In some circumstances it can be necessary and beneficial, but it should only be done with careful consideration of the risks and benefits.
I would like to make three points about off-label prescribing. First I will explain why off-label prescribing is particularly common and concerning for older adults. Approved drugs and drug doses may not be evaluated in conditions experienced by older adults, yet older adults are often the group most likely to be prescribed these drug therapies in real life. Off-label use is of particular concern when the drug therapy is associated with important adverse events. Ideally, drug therapy should be tested in the population that is most likely to use this therapy.
Second, I will talk about the magnitude of the problem of off-label prescribing, using the example of antipsychotic therapy. Antipsychotics are widely used off-label. These drugs are approved for the treatment of schizophrenia. However, in older adults, this therapy is often used to manage behavioural problems associated with dementia. Of the three widely used atypical antipsychotic therapies in Canada, only one has a labelled indication for this use.
There is substantial evidence from post-marketing surveillance of high rates of off-label antipsychotic use and indications of serious adverse events. This is particularly relevant in long-term care settings where antipsychotic therapy is frequently associated with what have been called ``preventable adverse events.'' These include falls, Parkinsonism and other events that are serious enough to require hospitalization. Our work has estimated that about a third of long-term care residents are being prescribed one of these therapies.
Third, I will talk about a strategy that could reduce adverse events caused by off-label prescribing in vulnerable older people. The first strategy is to use post-marketing surveillance to build the evidence of the risks and benefits associated with off-label use. In Canada, as a result of our single-payer health care system, we have outstanding administrative data that can be used for observational studies. We are in an excellent position to use these data more effectively to monitor off-label prescribing and to inform our prescribing practices. Research can help us to identify high risk off-label prescribing practices. Targeting and reducing these high risk prescriptions can prevent adverse events that are very costly.
The second strategy is to increase doctors' awareness of common off-label prescribing patterns and to enhance the impact of safety warnings where required. Prescribers may not recognize that they are prescribing a drug that is not approved for use in the context. To communicate the risks of important prescribing concerns, federal agencies can issue safety warnings.
In Canada and the United States a series of such warnings have targeted antipsychotic drug use by older adults with dementia. The main message from both of these regulators was consistent: Atypical antipsychotic drugs used by older people with dementia are associated with serious risk, and most of these therapies were not approved for use in dementia.
These messages from regulatory agencies appear to have insufficient effect on prescribing practices. One issue is that these warnings are non-specific, leaving the prescriber with no clear direction.
Finally, we need to make information available to physicians at the point of their prescribing. The increased availability of electronic health records could help in this regard. In an ideal world, a prescriber who selects a therapy like an antipsychotic therapy for dementia would be electronically alerted to potential problems. The system would suggest alternative strategies to inform their decision making.
Another opportunity is to more actively include pharmacists on clinical teams. Pharmacists are the experts on drug therapy and can alert physicians to off-label prescribing and provide guidance.
To close, I will restate a few points. First, off-label use of drug therapy is common, particularly in older adults. Antipsychotic drug therapy illustrates the frequency and the concerns that can be associated with off-label drug use.
Post-marketing surveillance can provide important information about drug safety, particularly as it relates to off- label use.
Finally, and perhaps most important, remember that our overall goal is to create strategies to optimize the use of drug therapy. To achieve this goal, we will require the collaborative efforts of groups including researchers, regulators and professional organizations.
The Chair: I will now turn to Dr. Stuart MacLeod, appearing as an individual. He is a professor of the Child & Family Research Institute of the University of British Columbia.
Dr. Stuart MacLeod, Professor, Child & Family Research Institute, University of British Columbia, as an individual: I appreciate the opportunity to speak to the committee. I was here about a year ago speaking to the clinical trials part of your mandate. I am happy to report back to you, from the outside world, that those of us who are interested in improving the clinical trial environment in Canada were greatly encouraged by your report. I think it is a very useful document.
I see the topic that you are addressing today as being perhaps a special case within that broader environment of clinical investigation. I am here as a professor of pediatrics at the University of British Columbia, but probably more importantly as someone who has spent more than 40 years studying drugs in children and addressing the kinds of issues you have before you.
I should start by saying that everything Dr. O'Rourke and Dr. Rochon said resonates with me. All of it is true in the child health world as well. I think, though, the stakes are perhaps a little higher when you focus down on very young children and the range of issues that confront us in looking after those children with treatable diseases.
Those of us who work in pediatric pharmacology have been concerned with this issue for at least the last four decades, and there is quite a bit written on the subject, as you will find when you look at the literature. Most of it is valid and authoritative. Everyone agrees it is a problem. The only thing in dispute is how best to solve it.
As I said, it is particularly a problem in the child and youth field because in the majority of cases where we prescribe drugs for children or adolescents we do not have a full evidence base, based on authoritative research, to support what we are doing. In fact, the drugs have often not been labelled with full information that would allow a prescriber to make the best choice. Notwithstanding that, of course, choices must be made, so they are made on the basis of imperfect information.
You will read all kinds of figures in the literature. The most common one you see is that 75 per cent of drugs have never been appropriately studied in children. It is a broad generalization, and I think what you find depends on where you look. If you are talking about adolescents, for instance, the figure would be considerably lower. Maybe 25 per cent of drugs have not been studied in adolescents or do not have data that could reasonably be extrapolated to the care of adolescents.
If you look at a 1,000-gram baby in a neonatal intensive care unit, the numbers are much worse because it is categorically impossible to conduct a good, scientific study on 1,000-gram babies, or at least to do it quickly. Most of the information we have that supports prescribing for those low-birth-weight infants is based on experience from neonatal intensive care units. In truth, I think we do very well. There are very few misadventures in prescribing for those infants, but it is done on the basis of experience, some very limited research, and a good understanding of the disabilities and conditions affecting those babies.
We all know the problem. The solution is better research on children of all ages, starting in particular with newborns and low-birth-weight newborns, but we need more clinical trials conducted in child care environments to produce high- quality evidence that we can then translate into prescribing guidelines, which is really what drug labelling represents.
One of the problems, as I said in my briefing note, is that children are not a homogeneous group. Obviously, you start with babies of 500 grams, 700 grams, the very lowest-birth-weight infants who can survive, and you go from there up to 18-year-olds who look like all of us, just a little bit younger. When you want to produce good evidence to support prescribing in children, it is a very complex undertaking. You need to do five, six or seven studies in order to get prescribing information for the full range of children. I think it is self-evident that this is an expensive and complicated undertaking from a scientific perspective.
Obviously, we have found ways of working around this dilemma. One of them is to extrapolate from what we know about how these drugs act in adult populations. Drugs are much better studied in adult populations than in childhood age groups, although as Dr. Rochon has pointed out, that does not extend to the other extreme of life either. We do usually have a lot of data on adults between the ages of 18 and maybe 50 that can be extrapolated. What we need is better rules or better scientific guidance that would instruct us on how to do that in an accurate fashion. There is a great deal of interest at the moment in looking at new methods of studying drugs in this age group so that we can get better information that will guide us in extrapolating back from what we know in the adult world.
There is another huge problem in pediatrics, and that is rare genetic disorders, most of which present at this early stage in life. We are under an obligation to study those conditions in young children because the trajectory of the disease is such that the effects will sometimes appear 20, 30 or 50 years later. It is a good investment to study outcomes at an early stage in young children.
Let me conclude with my major point, which I think is evident, and that is that we have to invest in the kind of research that you need in order to get the evidence that will allow us to label most drugs for use in children.
There is some reason to be hopeful. In the last seven years in Canada we have created something called the Maternal Infant Child & Youth Research Network, which is a cooperative venture of all 17 academic health science centres in the country. It creates a platform on which you can do these kinds of studies, beginning in pregnancy and proceeding through adolescence. I think we need some financial encouragement for the Maternal Infant Child & Youth Research Network in order that it can produce the kind of results that have made a difference in other jurisdictions, particularly the United States and Europe, where they are somewhat ahead of us in this game.
My final point is that awareness of this issue does extend to Health Canada. Two years ago they petitioned the Council of Canadian Academies to do a report on this subject, looking particularly at innovative trial methods that would help us get better information. That panel is now meeting, and I am actually the chair of it. We have had two meetings, three more are scheduled, and we will produce a report for the Council of Canadian Academies probably toward the end of this year or the beginning of 2014. It will address some of your issues.
The Chair: Thank you very much.
Senator Seidman: We have heard a lot during these hearings that off-label use is necessary, and you have confirmed that as well; and, in fact, it is quite common in vulnerable subgroups like children, the elderly and pregnant women. As you have said, we must always be aware of the necessity to maximize safety, that we have expert prescription information and that we can share that information among patients, doctors and pharmacists.
Dr. Rochon, in 2006 you co-authored an article that profiled the CPOE CDS system. It is an electronic prescribing program that provides physicians with immediate feedback about clinically important information that may improve their prescribing decisions. My question is quite similar to what we discussed yesterday here, and the whole issue has to do with motivating physicians to participate and the idea that if they had some kind of immediate feedback, then it would be more than just a chore for them to enter data.
You described the system in this commentary piece that was published in the CMAJ, and you are the lead author. I would like to know if the system is in operation in Canada and, if so, could you provide us with some idea of how it would function specifically with regard to off-label use?
Dr. Rochon: Thank you very much for your question. I will start by saying that I think the idea of using electronic records and clinical decision support is a really important way that we can help guide prescribing. It is maybe something that is very feasible, in a sense. Most health care organizations now have electronic records, and most if not all of the prescribing is being done through these electronic systems.
We have the opportunity to add to those systems what we call clinical decision supports. The idea is that you want to make it easy for the physician to know how to do the right thing at the time when they are making those prescribing decisions.
By using clinical decision support as a person enters a particular drug, you can feed back all sorts of information to them, whether it is that the patient is allergic to the drug at one level or that the dose is inappropriate based perhaps on kidney function or another problem they might have. As well, you can let them know that the drug is potentially off- label and there might be concerns about this drug, and you can alert them to other things they might want to do.
The nice thing about that system is that it is relatively seamless and happens as a part of what physicians are already using and needing to do. It is potentially out there and fairly widely available. There is the ability to customize it in a way that can provide help to provide even more good information.
One of the problems with this whole issue around off-label prescribing is that people often do not know they are doing it. These kinds of systems would make people aware of that. Even if they know they are doing it, they often are left with the situation of wondering what they should be doing. These kinds of systems could help to provide that information.
Senator Seidman: You are saying that the system is used now by physicians when they prescribe medication. Is there a way to indicate in the system that this is off-label?
Dr. Rochon: I would say the system is used in various ways in different facilities. Some have fairly advanced systems, like the one that was described in that particular article, while others have less advanced systems. Others simply prescribe the drug and can do so electronically; and they might get some assistance with selecting doses and so on. What I am saying is that there is the potential to advance where people are with those systems to achieve something that is better than we currently have.
Senator Seidman: Is the system linked with pharmacies?
Dr. Rochon: Yes. That particular system was hospital based and automatically interfaced with the pharmacy. When the person placed the order, it would automatically go to pharmacy. The physician in that case would get the high priority alert for the things that were brought to the physician's attention that we thought they ought to know about. There are often many other issues around the drug that need to be thought about that can be done behind the scenes, and the pharmacist would still do that. It interfaced between the physician and the pharmacy and with lab systems, so it automatically picked up information related to lab values and other kinds of flags that would be relevant to that patient.
Senator Seidman: I will not go into more detail about it, but is there some kind of written documentation about how the system functions that the committee could receive to help us in writing our final report?
Dr. Rochon: We could give you some helpful information that talks about how that kind of system and other systems function, which could be quite useful.
Senator Seidman: Dr. O'Rourke, you have defined well the role that your organization plays in evaluating and analyzing for your clients, as you call them. You say that you respond to a number of requests for information on off- label drug use from provincial governments and regional health authorities. When you receive these requests, what process do you use to evaluate the evidence and to do your analysis in order to feed it back to the people who make those requests?
Dr. O'Rourke: With any request that we get, one of the first things we look at is the timeline. In many cases there is an urgent requirement for the information. We have a whole series of different types of products that we can provide based on the timelines. We have a good staff of information specialists who are very good at searching the medical literature, including grey literature, which is unpublished literature. The amazing amount of literature then goes to some of our scientists and clinicians to analyze. They look at the scope of the literature and grade the evidence as well to know whether it comes from a clinical trial or observations or an anecdote that appears in a journal. They put that information together in a format that is useful to anyone looking for the information, whether a policy-maker on the use of off-label drug or clinicians in a hospital who need immediate information on it. We will package it together based on their specific needs.
Senator Seidman: I might be missing something. How do you get the information? Do you conduct a review of the literature?
Dr. O'Rourke: It is a literature search. Our librarians, information specialists, search the medical literature and all the different databases out there on clinical trials.
Senator Seidman: That means you use information from other jurisdictions, including international information.
Dr. O'Rourke: Absolutely. There are major databases for the literature search.
Senator Seidman: This issue of mining globally came up yesterday, specifically, and perhaps even last week in our discussions. In off-label use we have to make decisions based on small populations and population subgroups that are never tested. You are telling me that you do that.
Dr. O'Rourke: We do that.
Senator Seidman: You mine globally and then you send that evidence and an analysis or a final summary, with a judgment call?
Dr. O'Rourke: Yes, depending on the timelines. In some cases, requestors are searching for the evidence and do their own reading and assessment of it, while in other cases we look at the abstracts and put a short summary together. At times, we do a critical appraisal of the actual evidence as well and then provide guidance to the requestor, depending on the scope of what they seek and how much uncertainty is involved with the typical drug they are assessing; and then we put that together. If it was something of major concern or a major report, we might even seek some peer review or put an expert panel together to do a more deliberate expert review of the evidence.
Senator Seidman: Does it mean that you have a direct impact on what drugs are included in public drug plan formularies?
Dr. O'Rourke: Yes. Every new drug that comes into Canada — the drugs in the provincial/territorial formularies used in communities — is submitted through us. We provide, through an expert committee review, a recommendation to all of the drug plans except for Quebec, which has its own process in place. Most often, the decisions made on listing those drugs are consistent and congruent, with our recommendation.
Senator Munson: Dr. MacLeod, I was at UBC recently. I do a lot of advocacy work for autism. The work carried out by Dr. Daniel Goldowitz and his team is incredible. We may see some emerging themes coming in terms of what is happening. I am thrilled to be at UBC.
Dr. MacLeod: We hope that will bear fruit.
Senator Munson: The pharmaceutical industry has told this committee that drug approval requires considerable time and money. A drug's approval is for a specific condition and a specific dosage within a specific population. In order to get Health Canada's approval broadened for any of these specifications, a company must submit a Supplemental New Drug Submission and require additional clinical trials. Perhaps the witnesses could comment on the financial incentive for manufacturers to submit an SNDS in light of the off-label prescribing being permitted. There is a limited market share, I understand.
Dr. MacLeod: The financial incentive in most cases is limited, in particular because often we are talking about small populations or small numbers of patients with a particular condition — the same conditions that make it difficult to conduct a clinical trial and to find adequate numbers of patients to produce authoritative evidence. Those same conditions limit the financial incentive for actually submitting supplemental information and seeking a labelling change.
I would not say that the vicious circle is unbreakable, but it is difficult. I do not think that financial incentive related to specific products is likely to be the answer for most of these situations. It might work better in geriatrics — Dr. Rochon might speak to that — with larger numbers of patients who have common conditions, circumstances under which a substantial market might open up if supplemental information were to be submitted.
Dr. Rochon: I think the situation in the elderly might be different because there are large groups of people using drugs for conditions that perhaps have not been part of the initial indication. There might be different incentives there.
Dr. O'Rourke: Building on what Dr. MacLeod stated, the financial incentive for them is likely related to expanding the population where their drug can be used through an approved indication. Some countries — I believe the United States — offer an extension to their patent if they do studies in the pediatric population, which also creates a fairly good, substantial financial incentive.
The other factor here is that market authorization is only one hurdle for the pharmaceutical industry. That gives them the ability to sell their product in Canada, but they are still required to have it paid for by someone. Typically, that requires them to come through us, through our Common Drug Review, and requires a decision by the individual drug plans across Canada. That is a three-step hurdle for the pharmaceutical industry.
Senator Munson: Thank you for that.
I have two other questions. I think this has been answered, but I would like to have more clarity on the off-label prescribing of drugs. It is not illegal in this country, but it is illegal to advertise this sort of thing. I think you answered, but how do physicians learn of the off-label applications of approved drugs, in your experience?
Dr. MacLeod: I can answer again in the context of child health. You could not be engaged in child health care in Canada without using pharmaceutical products off-label because the majority of them have not been studied, at least not in all conditions, in all age groups. In fact, the information about how to prescribe is spread in things like the Handbook of the Hospital for Sick Children in Toronto, which has pages and pages of information about drug prescribing, most of which would not be allowed to be printed in the official prescribing information because it is not supported by a sufficiently substantial evidence base. That does not mean it is wrong, and it is certainly not illegal for a practitioner to choose to prescribe a drug based on his or her knowledge of what is in the scientific literature or what has been done in a small local study. That is what happens. In the pediatric world, there is an informal set of prescribing guidelines that certainly does not have legal validity but represents a kind of informal labelling.
Dr. Rochon: In the elderly, for some of the drugs that are widely prescribed, I think some of it is done because people see that that is what other people are doing in that context. I think that is potentially problematic if people are doing those things in the absence of evidence.
Senator Munson: That leads me to my last question and to the statement you emphasized today. We have it in our notes as well. You talked about off-label use being necessary and beneficial, but you said that it should be pursued after ``careful consideration.'' You used that term. What does ``careful consideration'' mean? Is it changing regulations? Would it have anything to do with new legislation, which takes time? I would just like to know what ``careful consideration'' means.
Dr. Rochon: I guess careful consideration can start at a variety of levels. It can start at the prescriber level, when you are right down there at the bedside. It can be thinking about what is required in that situation. Careful consideration can be weighing the risks and benefits. Normally, what we suggest are things like whether there other approaches. For example, is the drug required at all in the first place, or are there non-pharmacologic approaches? From a clinical perspective you can consider what the relative risks and benefits are of taking any one of those.
At a larger level, one of the things we need to think about more deeply is the role of getting evidence out there and getting evidence that can be brought back to prescribers to make their decisions much more informed. In Canada we have an opportunity to access a wealth of data on everyone because of our single-payer system. We have the potential to quickly look at drugs that are used off-label in the real world setting. We can, fairly quickly after their release, look at who is getting them and find out what is happening with those patients. Are the drugs well tolerated? Are there problems arising? We can identify things that might not have been anticipated. In that way, we can really learn about the risks and benefits in a much more detailed way that can actually go back to informed prescribing.
Senator Martin: Dr. Rochon, I will continue the line of questioning from Senator Munson in terms of what you just said about there being an opportunity. What do we need to do to actually capitalize on this opportunity or take the next step to use the system that is in place to utilize the data that has been collected so that it is ensuring greater safety and better monitoring of these off-label drugs? I am speaking from direct experience of recently having placed my mother in a long-term care facility, where I see the kind of administrative data that is collected every day, the kind of real-time daily observations that care workers are making of my mother's progress and the observations I have made. There is a real opportunity. What are some of those steps, or what is the first step that we need to take? As you say, systems are in place and we have an opportunity here. I am curious about the how, the next steps.
Dr. Rochon: As you have eloquently said, we have amazing data. We have basic data on everyone who gets health services in the country. Within the Ontario context, we know about everyone who gets health services in Ontario. The data and the information are growing. As you say, in the long-term care setting, we now have detailed data on functional status, cognitive status and a whole lot of rich pieces or information that help us to get an amazing understanding.
How do we pull that information out? I think it happens at a number of different levels. One is through research. Our federal funder, CIHR, plays an important role in supporting investigators who often work in those clinical settings and are also researchers, so they see clinical issues. They see, for example, how drugs are being used. They see things that are good and things that are concerning. They want a better understanding. They can use that data to get that kind of information. Individual scientists should be encouraged use that core source of data to answer those kinds of questions.
Also, I think there is an opportunity to make it somewhat more systematic so that when new drugs are brought on the market and you anticipate or think that they will be used by populations that were not studied — and it often happens in the elderly that they move from being used in one context to another — or even if you do not know how they will be used in the real-world setting, you can automatically start to monitor the drug use in the population and see the indications that it is being used for. You can then map whether those indications are being helped by the drug or whether unforeseen problems are arising. I think it is a combination of supporting curiosity and the important investigator-initiated research that happens in this area, but also taking advantage of a more systematic approach.
Dr. MacLeod: To go a step further on what Dr. Rochon was saying, in pediatrics there is a tradition of doing what people call opportunistic trials. Children are being treated with off-label drugs every day of the week, sometimes in specialized situations. If you intervene early enough, it is possible to collect accurate data on the drug's effect in that child, both beneficial and adverse effects. We need to improve our capacity for capturing and disseminating that information.
It is actually a very rich information base and our colleagues south of the border have managed this quite well. They have the Pediatric Trials Network, funded by the National Institutes of Health, which specifically devotes itself to these opportunistic trials. They are limited because they can only look at products that are off-patent, so they cannot look at new products. In an ideal world we would look at both old and new products.
Dr. O'Rourke: I wanted to build on the comments here and on an opportunity that we have with these administrative data sets. Health Canada created or funded the creation of the Drug Safety and Effectiveness Network a few years ago, and they have created a number of collaborating centres. One of them is called CNODES, the Canadian Network for Observational Drug Effect Studies. It is being led by David Henry from ICES. It is trying to collectively bring all of that information together with a series of researchers across the country. We have linked closely with DSEN. Our experts, when we are evaluating drugs or doing projects on classes, are identifying gaps in evidence and then we will feed that into the DSEN network and the research community in Canada to try and close those gaps. An effective network has been created.
Senator Martin: Thank you so much. I have so many other questions in my head.
Dr. Rochon, in terms of making it more systematic, I watched the care workers at a recently installed computer terminal at various points, and they were constantly doing something. Are there software programs that organize their data entry so it can then be used by physicians or the prescribers to inform them? I do not know if that is what they are doing. I obviously have not looked at how they are entering the data, but are those programs available or being used at this time? Do any of you know?
Dr. Rochon: I cannot speak specifically to organizations, but different pieces of data from that information are being pulled into helping with prescribing decisions.
To go back to one of the earlier questions on computer terminals, data related to weight or things like that would come in from those sorts of entries and be used to calculate appropriate doses for the drug. One piece of data can be used in a variety of different ways. It often feeds back to let them know how people are doing, if their function continues to be stable, if it is improving, to give them some sense of feedback. It is used in a variety of different ways, but it would be fair to say that there are many more ways this data can be used.
Senator Martin: Dr. MacLeod, you mentioned that you are part of a working group for the innovative trial methods; is that correct?
Dr. MacLeod: Yes.
Senator Martin: I am wondering if that is what you are speaking to when you are talking about opportunistic trials or if it is very different. For instance, could we use the opportunity we have with the data you are collecting — because it is hard to include the elderly, young children and pregnant women in the clinical trials themselves — for creative ways to get this information that is not standard, scientific evidence but absolutely valid evidence? Is the work that you do with the innovative trial methods working towards achieving this end? Could you speak a bit more about that?
Dr. MacLeod: I was with you all the way until you said ``absolute evidence.'' There is a hierarchy of evidence. It is well-known. Of course, the best evidence is something that comes from a randomized, double-blind, controlled trial — the kinds of trials you were talking about in your last mission. It is clear that in some of these special populations we have to deal with, whether it is newborns or the frail elderly, you cannot do those randomized controlled trials, so you need to look at steps in between.
There are some quite robust scientific methods that will give you good evidence. No one would call it ``absolute'' in its validity, but it is nonetheless good evidence. Then down near the bottom are these so-called opportunistic trials, which are really just taking advantage of experiments that occur in the normal course of looking after patients. The evidence is valuable. The data is valuable, but it does not meet the same standard as that obtained from a randomized controlled trial.
Senator Martin: Are innovative trial methods recognized by physicians and by Health Canada? Are you moving in that direction?
Dr. MacLeod: I mentioned a panel that I am chairing for the Council of Canadian Academies. The crux of what we are looking at is how Health Canada can use these alternative trial designs, understanding that in many cases full- blown, randomized controlled trials will not be feasible. All the drug regulators in the world are concerned with how to use data from what they call ``small'' trials. Instead of having 20,000 people in a trial of a new antihypertensive drug, you might have 200 children in the trial of a new drug for treating some condition in prematurity. Clearly, you need a different scientific approach to validate that data from 200 subjects instead of 20,000.
Senator Martin: We are making progress.
Dr. MacLeod: It is a big challenge but it will be done, and there is a lot of consensus on how to do it. It just does not have the force of law. It is not yet written into the regulations of the Food and Drugs Act.
Senator Martin: Is that where there needs to be a regulatory —
Dr. MacLeod: I believe eventually you will at least need regulations. I think ideally you need legislation, but I understand that may be a tall order.
Senator Seth: First, I would like to apologize for being late. I missed a little bit. Thank you for giving such a knowledgeable presentation.
Dr. MacLeod, in the two phases of the prescription pharmaceutical study, this committee has heard that drugs are frequently prescribed off-label to children, since market approval for the drugs rarely extend to the pediatric population. What strategies have been developed to minimize the uncertainty associated with the off-label drug use in children?
Dr. MacLeod: The best way to minimize off-label use is to improve the evidence base on which prescribing guidelines are written. It really just comes back to research. Other jurisdictions, particularly the European community and the United States, have brought in legislation over the last 15 years that looks at new pharmaceutical products that may be used in children, and they make a decision. If they really think it is important for children, then they can order the pharmaceutical companies or manufacturer to conduct trials that will eventually produce the kind of evidence we are looking for.
Senator Seth: Are there any strategies to follow that routine?
Dr. MacLeod: As Dr. O'Rourke said, the strategy in the United States has been to offer an incentive. It could be a large financial incentive. If you conduct the experiment in children as requested by the regulator, you do not just get an extension of your patent for children but it is extended for the whole population. Even though a drug widely used in adults may only have a very small use in children, if you do the studies, you may then get access to a market that is worth $1 billion a year, which is a very substantial amount.
In Europe, they have taken more of a stick approach. It is simply a legislated requirement. Anyone who wishes to license a new drug must put it before the European Medicines Agency. If they feel that it will be used in children, they have the legal right to require what is called a PIP, a pediatric investigation plan. The plan does not have to be executed immediately and it does not have to be done at the time the drug is approved for adult use, but it must be done within a certain time frame. That is a pretty strong requirement.
Dr. O'Rourke: Building on some of the frameworks in Europe, France has created a new regulatory pathway for regulating off-label use where they grant temporary recommendations for use, giving three years on a new drug or on a drug that does not have that indication. The manufacturer does not have to submit and do all these major studies, but it allows a time to collect observational data on the use of that drug in a supervised fashion.
Senator Seth: Dr. Rochon, in the aging population, you have said that although the off-label drug use may be necessary and beneficial, it should be only pursued after careful consideration. I understand that. In your view, should the off-label use of drugs be limited until there is a sufficient evidence base?
Dr. Rochon: I think you are asking whether drugs should only be used for so-called on-label indications. Is that what you are getting at?
The Chair: That is implication of the question.
Dr. Rochon: This is a bigger challenge. There is so much need for evidence around particular indications where drugs are being used by the elderly that you almost wonder if it is possible to get the labelled indications for all of the potential uses, which raises a different issue.
Ideally, if there is an indication you have to look at that carefully. If it is being used outside of that indication, that is potentially a concern because you are in an area where you really do not know.
I do believe that for many of those situations we do have to think carefully. Often there is other evidence out there that has come from other sources that might be helpful to guide the prescribing. It may not have a labelled indication, but there could be evidence out there, for example, from observational studies or other things that help inform that decision making. The concern is particularly when there is evidence of potential harm or there is no evidence on which to make the decision. People find that particularly problematic.
Senator Raine: I am not a full-time member on this committee, but this is a subject that interests all Canadians so I am happy to be here. I hope my questions have not already been answered by other panels.
We all recognize that off-label prescribing is happening and that it is necessary in certain populations. When you are gathering the best information for the physicians, adverse drug effects and drug reactions are obviously very important. You need to know that this has done harm. If you as a physician are considering off-label prescribing, is there a way to find out what those adverse reactions are?
Dr. O'Rourke: When we are looking at drugs for whatever reason, we are very concerned with both how the drug works, the efficacy or effectiveness of the drug, but also the safety, the safety individually or safety in comparison with other therapies and treatments. We are constantly looking and trying to find those anecdotes and those individual reports on patients that have had an adverse reaction to a drug. We have a system in place where we monitor that. If we have given a recommendation strongly that a drug can be used, we will continue to monitor the literature for that and have alerts produced for as long as we can do it. That is extremely important to the experts that are reviewing these drugs, the efficacy as well as the adverse effects.
Dr. MacLeod: In some ways, it is easier to get access to reliable data about safety than it is about efficacy. Safety is rarely studied prospectively, particularly in the context of a clinical trial. You cannot do a safety trial. You have to wait for a certain number of patients to be exposed.
However, there are relevant programs in Canada. The Canadian Paediatric Society has run a passive surveillance program for about 10 years now in which practising pediatricians are asked to report all adverse reactions in their practices. There are ways of gathering this data, and it is quite accessible using the Internet. The problem is that a risk- benefit decision is required, and you do not always have the countervailing information that you need about benefit.
Dr. Rochon: There are also things that are really severe, and there are concerns about safety. There is the warning system, so warnings can be issued and people can access those as well.
Senator Raine: I do not believe you are obliged to report adverse drug reactions, especially if you are doing off-label. In your database, that is the grey area.
Dr. Rochon: The idea that everyone is going to report the adverse event is a little optimistic, shall we say. Some people report things if they see them, and that is important. Often people do not recognize that things are adverse events, which can be even more problematic. Things happen and people do not necessarily think that there is a link with a drug. They may not make that connection. Again, that is where it is useful to have observational data as a source to identify some of these safety concerns.
When you are looking at the entire population and everyone who gets a drug, you can start to see patterns emerge that an individual physician may not recognize or see. That information again feeds back to these various sources and provides a body of evidence that people can use to help with their decision making.
Senator Raine: It is obvious that medicine is an art.
Dr. Rochon: Yes.
Senator Raine: ``Do no harm'' is probably in every physician's mind all the time but, as a system, the more we can gather information and have that information readily available so that people do find out what is not working, the better.
The Chair: For your information, we will do a whole study on that next. We have had a great deal of issues with regard to post-market surveillance already. You are on the right track. We will get into that, and we hope to write a separate report on it.
Senator Cordy: Thank you for being here today. We know that off-label use is pretty common. We know that it is necessary, especially with the subgroups that you are representing here today.
Going back to the adverse reactions, unfortunately if someone does not feel well when they are taking a medication, they often just throw it in their drawer and no one knows about the adverse reaction because they just stop taking the medication. Does a patient know that a drug that they are being prescribed is off-label? In the case of children, would a parent know that the drug they are being prescribed is actually being prescribed in an off-label way?
Dr. MacLeod: I think the best answer would be ``sometimes.'' There is a lot of off-label use in pediatrics that is very common. Drugs have been used in a certain way for sometimes decades. They are officially off-label, but it probably would not occur to a practitioner to have a discussion with the child or the child's family about the particular use.
On the other hand, if you are really breaking new ground, if you are using an old drug in some particularly novel way in a child, then it is not a legal obligation but most practitioners would feel obligated to have a discussion with the family and point out what they were doing. It stops short of asking for, say, written consent because off-label use is not the same as experimentation. It is going in that direction, but it is not really experimentation. You are not randomizing the patient to receive or not receive a treatment. There is not that kind of a legal context. However, in the spirit of good communication, families should be told that off-label treatment is occurring.
Dr. O'Rourke: The other aspect is that in some cases even the physician does not know that the drug is being prescribed off-label. I would say that there are many good information sources available for patients through the Internet and their pharmacist. They can get the information on whether a drug is on-label or off-label and, if it is used off-label, what evidence there is to support it.
Dr. Rochon: When a drug being prescribed off-label has known concerns about adverse events, it is important to have conversations with patients. That is another issue and is particularly relevant for the elderly.
Senator Cordy: Dr. MacLeod, you spoke earlier about information sharing or how a doctor would know that a drug is used frequently and successfully with children or other groups. How is the information shared? You talked about a booklet in a hospital, for example. Do the doctors in your hospital share with the doctors at the IWK Health Centre? What do you do internationally? I ask this particularly in terms of subgroups such as children, pregnant women and seniors. Those subgroups are much smaller and drug studies tend not to include them. How is the sharing done and is it done successfully?
Dr. MacLeod: As Dr. O'Rourke said, we have made a lot of progress over the last 20 years in validating information and making it available for sharing.
Many publications focus on evaluating the level of evidence and translating that into recommendations about treatment. Possibly the best known enterprise in Canada is the Canadian Cochrane Centre, which has been supported by CIHR and is committed entirely to looking at the evidence on contentious points in treatment. Obviously, they are looking at exactly the situations where off-label use is occurring because they are situations usually where the evidence base is not adequate to permit full labeling. They package the information on their conclusions about a drug's therapeutic validity, strength of evidence, et cetera. All of that information is available. I wish I could say that it is available to the entire Canadian public but it is not because there is not a license for The Cochrane Library in Canada. Certainly, it is available to the vast majority of practitioners who get it through their electronic libraries in their institutions or through their medical associations or pharmacy associations and so on.
Dr. O'Rourke: The challenge is that physicians and clinicians in general are bombarded with information. How much of that information can they read, process and put into their practice? Many younger physicians walk around hospitals and clinics with their smartphones and use a program such as Up toDate to get their information. We hope that the information they are getting is strongly based on evidence. It is very challenging for physicians to keep up to date.
Senator Cordy: I can well imagine.
Dr. Rochon: That goes back to the idea of how to make it easy for people to get that information and how to take this world information and put it at their fingertips, which is where the computerized opportunity is for prescribing.
Senator Cordy: We have all talked about off-label use of drug therapy being common. Do we have data on how common that is?
Dr. O'Rourke: One study in Quebec, which I referred to in my remarks, showed that in family practice, 11 per cent of the prescriptions over a period of time were off-label. In about 79 per cent to 80 per cent of those, there was no evidence to support the use of the off-label. A number of reports have come out of the U.S. as well that quote numbers in the range of 20 per cent of all prescriptions are off-label. In the U.S., that would mean over 150 million prescriptions being used off-label.
The Chair: Dr. O'Rourke, to clarify your comment about no evidence, I think the report said no strong scientific evidence.
Dr. O'Rourke: That is correct.
Dr. MacLeod: Certainly, there are figures in pediatrics, although they are all over the map. On average in outpatient pediatrics, something in the order of 25 per cent of prescribing is off-label. In hospital pediatrics, where it varies the higher-up you go in the intensive care chain, it is probably more like 50 per cent to 60 per cent.
Senator Eggleton: I am sorry that I could not be here earlier to hear your presentations; I was at another meeting. I hope my questions will not duplicate those of my colleagues.
Should there be a requirement for a doctor to write ``off-label'' on a prescription and anything in addition to ``off- label,'' such as the category information about the patient? Should the patient and the doctor know that this is an off- label prescription?
Dr. MacLeod: I am willing to bite the bullet. I think it would be a nightmare. As Dr. Rochon said a few minutes ago, the majority of doctors often do not know when they are prescribing off-label. There are shades of grey within off-label with non-approved uses, such as an adult formulation for a child, which is not exactly ``off-label'' but is ``non- approved.'' As well, in pediatrics frequently there are extemporaneously prepared products. Compounding pharmacies make something up that is clearly not a labelled product. I guess the patient would know they are getting such a product, but so much prescribing is off-label that you would be writing this all the time. Prescribers would soon require a stamp.
Dr. Rochon: That is an interesting idea that could be thought through a little more. For example, should we pay and reimburse for drugs being given off-label when there is potentially no evidence or little evidence and there are potential serious concerns for those drugs? Should there be a halt or something put into the process so you have to justify why you are using that? That might be something to think about.
Dr. O'Rourke: That is exactly what is in place.
There is another hurdle, as I mentioned. When we make the recommendations on the listing of it for public reimbursement, in many cases we will put criteria that restrict the indication even further. In those cases, the physician typically has to justify it if they want to use it for something broader than the criteria we have put in place. The indication that Health Canada approves may be this big, our criteria restrict the drug even further because of cost- effectiveness and other factors. It would be challenging to do, but I like this approach.
Senator Eggleton: Dr. MacLeod pointed out that the doctor has to know in the first place that it is off-label. It therefore has to start with that information flow.
Dr. MacLeod: There is another player in this case — the pharmacist. Pharmacists probably could flag, to some extent, the use of off-label approaches as they are dispensing the medication. However, when you write a prescription you do not have to explain on it why you are prescribing the drug. Pharmacists do not consistently know, although they may guess.
Dr. Rochon: Most drugs for the elderly are reimbursed through provincial drug mechanisms. There is an opportunity when they are going forward for reimbursement to bring it to attention and to request additional clarification before it is funded.
Senator Eggleton: On the issue of what drug company sales representatives tell to doctors, they are supposed to talk only about the indication of the drug that is approved, not about the off-label use. However, we see reports in the United States where some of the major drug manufacturers have agreed to pay horrendous fines, most of us would think but perhaps petty cash to them, because they have crossed that boundary. They are actually promoting or selling off-label use.
The fact that sales representatives are going to see the doctors and presenting their products is not only an issue for off-label but perhaps a general issue as well. What should we do in terms of monitoring that? Should a different agency take over from the sales representatives to ensure the doctors get the right information about drugs? This is not to suggest the sales representatives are giving them bad information, but of course they have a different motivation. They are trying to sell their drugs. Would you see any changes or better way of controlling that information flow?
Dr. O'Rourke: Certainly we are a source of good evidence-based information for practitioners and policy-makers. When it comes to the sales reps and the information they are allowed to share, it does typically have to be only about the approved indications. However, in many cases the physicians or pharmacists will ask them about off-label use as well. I do not believe sales reps are allowed to give that information. That has to come from the medical information specialist within the manufacturer, within the company. It cannot come through sales and market access people. It is a challenge. It goes back to this aspect of where clinicians and physicians get this information from, and they are bombarded. There are all kinds of sources of information. Using good independent bodies like the Cochrane Collaboration, like CADTH, like INESSS in Quebec, are good sources for clinicians.
Senator Eggleton: One of our presenters said that one way of getting better information is to look at what the Australians or the British are doing. The Australians have an Australian Medicines Handbook, and there is the British National Formulary. These apparently have more descriptive information and are more helpful in terms of off-label information. I guess what doctors have here is the CPS blue book, which does not seem to meet that need. Can we learn from what the Australians or British have done in terms of getting that information to doctors?
Dr. MacLeod: There is some problem in going beyond what is legally approved as prescribing information so we do have a legal document, official prescribing information. In order to have some impact in the world of off-label prescribing, you really have to go beyond what has been legally approved. That creates problems.
For instance, in the U.K. there is a British National Formulary for Children. There is one for adults. It has been there for years. Since off-label prescribing is so common in pediatrics, you can be sure that the British National Formulary for Children makes all kinds of recommendations that would not be supported by evidence that would be considered adequate by Health Canada, the FDA or by the European Medicines Agency. However, they do it on the understanding that some information is better than no information.
Whether it is correct to call it a formulary and imply that it is better than any other kind of information is perhaps debatable, but it is not beyond human ingenuity to produce a good compendium of informal prescribing information in some of the fields like we have been talking about, geriatrics, pediatrics, rare diseases.
Dr. Rochon: There are some of those in the various subspecialties too, and you can access them through electronic means. How to bring that level back to the point of prescribing or point of decision making is important. It is also important to think about how to get people like pharmacists — who often are a little removed from that process — to be actively engaged in helping to make that decision with the physician.
Senator Eggleton: I think one of you mentioned the new French procedure, the Temporary Recommendations for Use, or TRU. Do you think that could be applicable here?
Dr. MacLeod: That approach has been looked at in most developed countries, recognizing that there will always be situations where it will take time to accumulate the necessary evidence base. There are situations where you would not want to deprive the patient of access to those medications while you were gathering evidence.
The real issue comes around reimbursement for the medication. In Canada, it is a provincial issue. I think Health Canada would have no problem with saying we could have some kind of a temporary approval with continuing collection of evidence. The problem is that in some cases it creates an impossible situation for the provinces that may then be looking at paying for a drug that costs $1 million a year while we continue to collect evidence.
There are some real financial impediments but, particularly in rare diseases, the only way in which we will improve the evidence base is to have some kind of coverage that must be based on at least presumptive evidence that the treatment will be effective and safe. You then gather data over perhaps 10 years, but someone will need to pay for the medication during that time period.
The Chair: I want to come to the overall issues we have talked about today. I really appreciate the insights and information you have brought to us. First, I want to clarify a couple of things.
Dr. O'Rourke, is the Cochrane database one of the documents that you use in developing your information?
Dr. O'Rourke: Yes, we would search the Cochrane database.
The Chair: In terms of a question to you, I think you have already conveyed the answer. However, in your presentation you say that we do therapeutic class reviews in pharmaceuticals and conduct optimal use projects and so on. You answered the question by saying you search the literature, including the grey literature. Yours is a search of the available information. Do you have an active pursuit of new information? Do you formally approach the collection of new information from your organization?
Dr. O'Rourke: Yes, we do. For every drug that we review through the Common Drug Review we have an automatic alert system set up through our electronic information system. We will have access to any new study or report that comes out on that drug and it will help feed into our evidentiary package.
The Chair: You are still looking at reports. You are not going direct to the individual submission.
Dr. O'Rourke: No.
The Chair: I thought that was the answer but I wanted to be clear.
Dr. MacLeod, you have covered the pediatric area exceedingly well in terms of the challenges and approaches to dealing with this particular area. You made a comment earlier about doing deliberate trials in infants, very young children, and then you added more clarification to that later in terms of research. The issue is whether society is ready to do what we would call a normal trial in infants. That requires giving the medicine to healthy infants as well, when we think of the true randomized kind of trial.
Dr. MacLeod: This is a situation where we need alternative trial methods. I do not think society will accept randomizing 1,000-gram infants to either get treatment or not get treatment. I think you need to have some more observational study.
I do not think there is any problem with accepting the need for research and clinical trials in newborns, including the most vulnerable newborns or in pregnant women for that matter. We need this data.
Young children, of course, cannot consent. The ethicists have written volumes about this, and they all agree it is ethically unacceptable to not study drugs in young children. We must have better information if we are going to treat them properly.
The Chair: That brings me to the question I really want to put to you. It is clear that in these large categories and in the subcategories of off-label use the real issue, as you have described, is that these things are being prescribed on the basis of evidence but in a different population, the trial population, to a large degree. However, they are being prescribed. You have all touched on the need to capture the information regarding what happens when you do prescribe them off-label.
From the two studies we have already done — and we will go into it in more detail in the next study, as I have already indicated — we know about the issue of specific adverse reactions. Now we are talking about the drug being prescribed in the whole population. Less than 5 per cent of adverse reactions in the total prescribing arena are apparently captured. That is what the literature tends to suggest.
The other side of this, the much more positive side, is the capture of the positive results of using a drug off-label in infants, in the elderly and in pregnant women. You have all referred to the need to capture that kind of data. In fact, we have heard from specialty areas — oncologists, for example — that there is a very good network of communication among them with regard to the results obtained in a given situation; that is, word of mouth or the electronic word among professionals seems to be fairly active in some specialty areas of the off-label use of drugs and the positive results that come out. Indeed, we have already heard from witnesses that the observation of the use of drugs has led to deliberate off-label use in cases where it was simply obvious that patients were benefiting in a different way than the original prescription intended in terms of their health.
We have been hearing different approaches to attempt to collect this information, the kind of information that leads to the documents Dr. O'Rourke is able to search for and give advice to formularies and to physicians. We have been talking about some of the things that have come up here today, namely, the electronic prescription, the drop-down boxes with regard to prescribing, the possibility of off-label use, where it is appropriate, printed on an electronic script, and the ability to start the information collection process through a prescription that has a little more detail on it.
Let me come to that end. When it is prescribed, the patients receive the medication, most of whom hopefully benefit from the off-label use of the prescription. Dr. Rochon gave a specific example of a situation in which she is involved. Have you seen any novel ideas that might have potential in the capture of the information focused specifically on the off-label use of prescription pharmaceuticals? Are there any novel ideas that you think might really work here or are good ideas, beyond the good examples you have used today? Could one of you tackle that?
Dr. Rochon: Maybe it builds on some of the things I said. I think there is a huge opportunity to take the drug being used off-label and marry it with the indication, the reason that the clinician is prescribing this drug. If you added that additional piece into the data set, you could then track whether it is really working for that indication. As you have said, we know it is often off-label. We know people are using it in different circumstances, and they are probably doing it because they think it works in some way. How do we capture that information?
On so many levels, we do not know enough about why a drug was prescribed. Through following it passively in a data set, you could actually see what was happening and start to collect data on that. Even on a clinical level, it is often not clear why a drug is prescribed, and that leads to all sorts of issues later on: Should we continue it; was it ever really helpful? All sorts of issues arise. I think that additional piece of information and marrying those two bits could take us a long way.
Dr. MacLeod: I think there are some possibilities. The difficulty — and this is what you are intimating — is that we have relied heavily on passive surveillance, a physician or pharmacist or nurse reporting on adverse reactions they see. It is human nature that they are only likely to report on the most unusual reactions they see. They do not report on the common ones. If 5 per cent were said to be reported, that would probably be an optimistic estimate. We have shown that you can do much better if you drill down with active surveillance. You say, ``We want to know what happens the next 25,000 times this drug is given to that population.'' The U.K. has been experimenting with this for about 50 years now. They get quite good data by having people send in cards describing the reactions of their patients.
I actually think, though, that to get good data you have to go to a real active surveillance, which requires someone who is properly prepared to report on adverse reactions or safety issues that are of interest. One way it could be done would be to make use of the ubiquitous smartphone. It is not impossible to collect data on every adverse drug reaction that occurs in every Canadian taking a particular product in the next 12 months. You just have to give someone a cellphone and tell them how to report it.
The Chair: That is right. I will pick up on those two a little bit. The issue comes back to the fact that the person at the end with the smartphone has to have a thing that drops down and makes it easy for them to do that.
Dr. Rochon, we heard other suggestions with regard to this when I specifically asked whether we could have a drop- down menu that outlines the indication and the age group, for example. We have been told that the pharmacist might not always know what age group the name on the prescription is in if a parent picks it up for a child or a child picks it up for an elderly patient. The issue becomes getting that drop-down menu. That is the start. What information will we ultimately have the recipients look for in terms of the issue?
You have provided very thoughtful analysis, observations, experience and reference to a detailed examination of these matters for us. You have covered groups that are largely susceptible to deliberate off-label use, which is a positive thing, as you clearly indicated, in many cases. Our objective is to identify mechanisms that we could possibly recommend as being reasonable to achieve in regard to what we have just been talking about.
When you are driving down the highway and see a billboard that suddenly makes you think, ``Ah, that might work,'' I would ask you to note it. Because of your tremendous experience in the area of collecting and distributing information, if you could pop us off any thoughts that occur to you at any time in this regard, we would welcome it.
On behalf of my colleagues, I thank you for coming here today and for the calibre of your presentations and answers to our questions.
(The committee adjourned.)