Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 32 - Evidence - February 27, 2013
OTTAWA, Wednesday, February 27, 2013
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 4:15 p.m. to study prescription pharmaceuticals in Canada (topic: off-label use); and to consider draft budgets.
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[English]
The Chair: Honourable senators, to explain our procedure for the benefit of the witnesses, we will take a brief three to five minutes on a budget item and then go into the formal session. You are perfectly fine to be where you are, but I just wanted to let you know what is happening.
Honourable senators, we have circulated the budget preparations for the next fiscal year for the studies we have anticipated.
Senator Eggleton: So moved.
The Chair: Would you move them one at a time, just in case? Could you perhaps move the social inclusion budget first?
Senator Eggleton: Social inclusion, so moved.
The Chair: It has been moved by Senator Eggleton that the proposed budget for social inclusion be approved. I can assure honourable senators that the steering committee has been through this very carefully. If there are any questions, we would be pleased to answer them. Are you ready for the question?
Hon. Senators: Yes.
The Chair: Carried?
Hon. Senators: Agreed.
The Chair: Thank you.
Next is the budget for the study of prescription pharmaceuticals.
Senator Eggleton: I will move that too.
The Chair: So moved. Any discussion? Ready for the question?
Hon. Senators: Agreed.
The Chair: Thank you very much. Those are both approved.
[Translation]
Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
I am Kelvin Ogilvie, a senator from Nova Scotia and chair of the committee. I will invite my colleagues to introduce themselves starting on my left.
Senator Eggleton: Art Eggleton, senator from Toronto and deputy chair of the committee.
Senator Dyck: Lillian Dyck, senator from Saskatchewan.
Senator Cordy: Jane Cordy from Nova Scotia.
Senator Enverga: Tobias Enverga, senator from Ontario.
Senator Seth: Asha Seth, Toronto, Ontario.
Senator Martin: Yonah Martin from British Columbia. Welcome.
Senator Seidman: Judith Seidman, from Montreal, Quebec.
The Chair: We have three witnesses with us today, but before I invite them to make their presentations, since this is the first meeting of this study, I thought it would be important for us all, and our audience, to understand that this is the first meeting on phase three of a four-phase study into prescription pharmaceutical issues in Canada. We have completed the first two phases on clinical trials and post-approval monitoring, and we are now looking specifically at off-label use.
While the committee is becoming quite familiar with the terminology here, the label refers to the official label, which is the one Health Canada gives. It describes the way in which the drug can be administered in terms of dosage and, indeed, in terms of the population to which it can be prescribed. Off-label refers to uses outside of those, and we will specifically look into that in detail in this study.
To start off this study, I am very pleased to have with us three excellent witnesses with regard to this particular subject. They have agreed that I will call them from left to right as I face them, and that would mean that I will first introduce and call Dr. Jeff Poston, President of the Canadian Pharmacists Association, to make a presentation.
Dr. Jeff Poston, President, Canadian Pharmacists Association: I would like to thank the committee for the opportunity the Canadian Pharmacists Association has to appear before the committee today as part of your ongoing deliberations into prescription pharmaceuticals and in particular the issue of off-label use. As you know, CPhA represents the interests of the pharmacy profession in Canada. Through its publications, CPhA also supports clinical decision making through the provision of evidence-based drug and therapeutic information.
Off-label use refers to the use of medications for indications that have not received regulatory approval from Health Canada. It is different from the use of an unauthorized medicine or from unlicensed use.
Off-label use is fairly common practice amongst health care providers. Estimates indicate that approximately one third of all prescriptions are for off-label use, although the estimates vary from 11 per cent to 50 per cent of prescriptions, depending on the scope of the study and the country where it is carried out. For certain patient groups such as children and the elderly, and in certain diseases such as cancer, off-label use is common.
Overall, CPhA is supportive of off-label use when clinical and scientific evidence has suggested that beneficial patient outcomes might outweigh potential risks. Patient safety should always remain the top priority of health care providers.
Guidelines and educational programs are being developed to support the appropriate use of drugs off-label in order to reduce any risks. However, despite these guidelines, there remain challenges associated with off-label use that need to be addressed. These include the fact that there is sometimes a lack of valid scientific evidence to support the off-label prescription. A 2012 McGill University study found that of drugs prescribed off-label, 79 per cent lacked what they called "strong scientific evidence." This lack of evidence could put patients at risk for inappropriate exposure to medication and potential side effects. However, I should add that, in that study, meeting the criteria for strong scientific evidence required that the drug had been studied in at least one randomized control trial, and we know that that is seldom the case with off- label use.
Another issue is that there is no formal monitoring mechanism in place to record and monitor the impact or effectiveness of a drug used off-label. This inhibits the ability of health regulators to be able to track or record the effects of off-label use.
It is also possible that practitioners could be held liable for off-label use if it can be demonstrated that the prescribed treatment of care was not supported by evidence and if a patient was shown to be harmed by being exposed to the treatment.
With certain drugs that are reimbursed by private and public drug plans and classified as limited- or exceptional-use products, there may be restrictions on payment regarding off-label use.
In order to reduce the risks and challenges associated with off-label use and to promote best practices, CPhA would recommend the following: First, health care providers should only prescribe medications for off-label uses when there is valid scientific information to support the use of the medication for that indication and when the potential benefits to the patient clearly outweigh the risks. Liability insurance should cover health care practitioners prescribing drugs off- label unless there is evidence of negligence or use has an insufficient scientific basis.
Second, better guidelines and educational support for health care providers should be developed to support off-label use. Health providers, including physicians and pharmacists, need to disclose to patients when medications are being prescribed off-label and discuss any potential pitfalls associated with off-label use. Informed consent should be obtained.
Third, physicians and pharmacists should report adverse events or side effects with the use of off-label prescriptions to Health Canada, who should in turn make information available to health care providers to better inform clinical decisions.
Fourth, support needs to be given to implementing e-prescribing and e-health systems so that information can be more readily shared between physician and pharmacist in the event of off-label use. Also, off-label prescriptions should be clearly documented in the patient's medical record. The capture of e-health data would also help to inform the evidence supporting off-label use.
Fifth, when pharmaceutical companies learn of the off-label use of their products, they should be encouraged to conduct research to determine efficacy for that indication and, ideally, to submit to Health Canada for formal recognition of the use of the drug for that indication. Consideration should be given to incentives to support this type of research by industry.
Sixth, a dialogue should occur between payers, health providers and governments to determine eligibility and reimbursement policies with respect to medications off-label use. In general, reimbursement policies should cover off- label use that is medically appropriate.
I would like to add that the CPhA would be happy to work with governments and other stakeholders to implement policies and programs that would improve the use of off-label prescribed medication and reduce associated risks.
We very much appreciate the opportunity to appear before the Senate committee today, and I look forward to answering any questions you might have.
The Chair: Thank you, Dr. Poston.
I will now turn to Dr. Kara Laing, President of the Canadian Association of Medical Oncologists.
Dr. Kara Laing, President, Canadian Association of Medical Oncologists: Good afternoon. I am very pleased to be here today representing the Canadian Association of Medical Oncologists. Thank you for the opportunity to present on off-label drug use in oncology.
Medical oncologists work within a multidisciplinary cancer care team, are involved in the treatment of patients with various malignancies, and prescribe a broad range of systemic drug therapies, including chemotherapy, hormonal therapy and other targeted treatments.
There has been a significant increase in the number of new drug therapies in oncology in the last several years due to a greater understanding of the biology of this disease. This era of personalized medicine is based on providing the right drug to the right patient at the right time.
Cancer patients may be treated in the neo-adjuvant or adjuvant setting, in which they are given treatments before or after potentially curative surgeries in order to improve their disease-free and overall survival. As well, many patients are treated in the metastatic setting, where the goals of treatment are to palliate symptoms, to control the disease, to improve quality of life and to prolong life. In fact, many cancer patients might live for several years and might have several different lines of therapy.
Cancer care programs face many challenges related to drug delivery. These include the significant cost of these drugs, especially the newer targeted agents, and an increase in the number of patients requiring treatment due to an increase in both the incidence and prevalence of cancer in our country, to our aging population and to the fact that the successes of treatment mean that many people are living longer with cancer.
Access to cancer drugs for patients across this country is an issue, as is the timeliness of approval of drugs through Health Canada and through the review process of the pan-Canadian Oncology Drug Review and, ultimately, of provincial funding agency decisions for these drugs.
Off-label use is a very important issue in oncology. Cancer drugs often have a very specific indication related to the clinical trial data that initially supports the approval of that drug. For example, the label for a cancer drug might read, "For first-line treatment of metastatic breast cancer." Any use other than this, therefore, would be considered off-label.
There are three main situations in oncology where off-label drug use occurs. The first is when a drug is already licensed and available for use in the clinic and is being used with a specific disease site. New clinical trial data might come along that indicates a broader use of that drug. There might be very good safety and efficacy data for that use. However, the pharmaceutical company responsible for that drug might or might not seek additional approval for that indication, which would then be added to the label. If that is not done, the use of that drug is considered off-label.
The new indication for this drug might be approved at a provincial cancer level within a disease site group. There might be national guidelines indicating that that use is appropriate. It might be reimbursed by cancer programs and by third parties and might even become the standard of care, but it would still be considered an off-label use. There are many examples of this today in oncology. However, in this situation, the use of these drugs is evidence-based.
The second situation arises when there is less evidence for a drug, and this is usually in a situation with a more uncommon tumour. In this case, there might only be phase I or phase II clinical trial data — and not the randomized trial data as Dr. Poston mentioned — or expert opinion that guides treatment for those patients, yet it might be very appropriate for a particular patient, with a particular stage of cancer, to receive a certain drug in that setting.
Many cancer care programs that reimburse for drugs in this situation require that these cases be reviewed at multidisciplinary case conferences, or a special approval process might need to be gone through.
The final situation occurs when there is little or no data to support the use of that drug in a particular indication. In this case, the potential harm to the patient may outweigh the benefit, and we do not recommend that drug use off-label be supported in that situation.
When considering off-label drug use, the potential risk benefit ratio must always be examined. For the individual patient, the chance of benefit must outweigh the potential risks. Off-label use should also not be encouraged when there are ongoing clinical trials looking at that specific drug in a specific clinical situation. Instead, patients should be encouraged to participate in those clinical trials.
Finally, with limited resources available, decisions about off-label drug use must be fiscally responsible. Other jurisdictions outside this country have also recognized this as an important issue in oncology. The European Society of Medical Oncology, ESMO, published a position paper in 2007 addressing this issue. They called for more involvement of regulatory agencies, for a list or a compendium of anti-cancer drugs with acceptable indications, some of which may be off-label, and a mechanism to expand a drug's indication that could be done not only by the pharmaceutical company but by other interested parties.
A recent publication in our Journal of Clinical Oncology examined the off-label use of 10 patent-protected, intravenous cancer therapies in the United States in 2010. Prescribing data was compiled from a pharmacy order entry and billing system that looked at 122 medical oncology practices that were across 35 states and ultimately had approximately 135,000 drug administrations. They determined that 30 per cent of the drug use was off-label, while 70 per cent conformed to the FDA indication based on the cancer site, the cancer stage and on the line of therapy. Of the off-label use identified, approximately 15 per cent were concurrent with NCCN, which are national guidelines in the U.S., and another 10 per cent were within the same cancer disease site. They estimated, based on this study, that the cost of off-label drugs in the U.S. for these oncology drugs was approximately $4.5 billion. The overall drug budget was $12 billion. As you can see, it did take up a fair amount of that.
Oral drugs are also a concern. An increasing number of anti-cancer therapies, particularly most of our new targeted therapies, are actually oral agents. Not all of these are covered by provincial cancer care budgets, by provincial formularies or by third-party private insurers. Reimbursement for these is often an issue, and this leads to inequality in access in cancer patients, and it also makes it very difficult for us to know how much off-label use occurs with oral anti-cancer drugs. This does need to be addressed.
In conclusion, off-label drug use does occur frequently in oncology, but it is both evidence-based and appropriate in many of these situations. It does, however, need to be better defined, and I agree with all of the statements made by Dr. Poston in terms of what we would support. This has a great impact on access to care for cancer patients living across this country, the potential risks and benefits of the treatments that they receive, cancer care program budgets, reimbursement and, of course, regular industry agencies.
I thank you again for the opportunity to present to you today, and I am happy to address any questions or concerns you may have.
Dr. Jitender Sareen, Chair, Research Committee, Canadian Psychiatric Association: Good afternoon. I would like to thank the committee for giving the Canadian Psychiatric Association an opportunity to address the important issue of off-label use of medications for mental disorders. I would like to acknowledge the efforts of our research committee members for the substantial input they have given into the comments that I will make today.
What is off-label prescribing? It is the use of licensed medication outside of the condition or indication for which the licence was issued. Pharmaceutical companies apply for approval to promote medications for specific conditions. These licensing regulations are designed to regulate the claims pharmaceutical companies can make about their medications. Although it is illegal for pharmaceutical companies to promote the use of medications for off-label conditions, it is legal for physicians to prescribe medications off-label.
Off-label prescribing is common in all medical practice and is often required to help patients who suffer with residual symptoms. Although many clinicians consider whether the medication is licensed for treating the condition, they rely more heavily on the clinical practice guidelines, systematic reviews and clinical experience.
The Canadian Medical Protective Association has issued recommendations to physicians on the off-label use of medications and devices. They suggest that physicians should review the medical literature and consider if the proposed off-label use of the medication has gained enough acceptance among peers, that they should take reasonable precautions to ensure that the off-label use is appropriate for the patient's condition, that they should advise the patients that the drug is not approved for their particular condition and, finally, that they should obtain and document informed consent before using the off-label medication.
Turning to mental disorders, what are the reasons for off-label use for mental disorders? Off-label prescribing is very common and essential in medical practice in treating mental disorders, and there are some key reasons.
First, with the reduction in stigma over last number of years, there is an increased willingness to seek treatment for mental health problems. Mental disorders offer present with complex symptoms that affect multiple brain systems. Most medications approved for common mental disorders are associated with only a partial reduction of the symptoms, so off-label prescribing is used to treat residual symptoms and improve functioning.
Second, off-label prescribing of antidepressants and antipsychotics in children and the elderly has been increasing over last 10 years. Pharmaceutical companies often do not seek approval for medications for children and the elderly due to financial concerns. Studies in these groups are difficult to do and outcomes are difficult to measure. Clinicians will often use medications that have been approved for the condition in an adult in children and the elderly. However, there is an urgent need for research in children and the elderly on the safety of off-label medication use.
Third, the majority of people treated for mental disorders in Canada are treated by their family physician who does not have the time or the training to provide psychotherapy. Long waiting lists for psychiatric assessments and limited availability of psychotherapy mean that patients often receive medications to treat their disorder and do not get the additional psychotherapy.
Finally, there is little data to guide clinicians on the length of treatment that a person requires. This means patients often receive multiple medications, some on-label and some off-label, to reduce their symptoms. To obtain approval, pharmaceutical companies usually conduct short-term studies, usually six weeks to a year. However, the appropriate length of required treatment and the long-term safety of medications often remain unknown.
What are the suggestions for future research and policy? First, a strong investment in research that aims to understand the underlying causes of mental disorders is required. Until we discover the cause of the illness, medications will continue to target the reduction of symptoms rather than curing the actual illness. Similar to the heavy investments in research in cardiovascular disease, cancer and AIDS that have led to important discoveries and better treatment of these conditions, there needs to be a similar increase in funding to support understanding the underlying causes of mental disorders. Furthermore, investment in innovative ways to treat mental health problems is also urgently needed.
Second, governments rely too heavily on pharmaceutical companies to conduct research on medications. We need to create an independent, non-biased research capacity to conduct trials on medications after they have gained approval. This research should focus on the long-term safety and efficacy of these medications and specifically target youth and the elderly.
Finally, Canada needs to invest in unbiased physician education focused on the benefits and risks of medications. In the last 20 years, most physician education has been sponsored by pharmaceutical companies and has been criticized for being biased. There have been substantial policy changes to reduce the potential bias in educating physicians. Nonetheless, there remains a need for education and best practices that are not profit-driven. This education should take a comprehensive approach that includes medications and psychotherapy.
In summary, the off-label use of medication is an essential tool in treating people suffering from severe and disabling mental disorders. Governments cannot rely on pharmaceutical companies to conduct research on long-term safety and efficacy of medications. They must invest in education and research into the causes and appropriate treatments of mental disorders. This investment will improve treatment and reduce the burden of mental illness for Canadian society.
The Chair: I will now open up the floor for questions.
Senator Eggleton: Thank you very much for your presentations. I have a lot of questions; I will get in as many as I can at this stage.
This question is for Dr. Sareen, but I think all of you have mentioned this. You say in your submission that physicians should review the medical literature and consider if the proposed off-label use of the medication has gained acceptance. They should take reasonable precautions and ensure it is appropriate. They should advise patients. It is also something that Dr. Poston said in his submission needed to be disclosed to patients when medications are being prescribed off-label. Informed consent should be involved.
As I understand them, these things come under the jurisdiction of the provinces because we are dealing with physicians. Physicians do this; they decide on the prescriptions under the regulatory control of the provinces. Do you know of any provinces that are doing this now? How would you see this unrolling in terms of federal involvement? Are any provinces doing this?
Dr. Poston: The provinces have some effect on this where they control reimbursement practices. For example, provinces may have control over what gets funded out of a provincial drug plan. Certainly, for expensive drugs or new drugs, they will have conditions applied to their use. They are also called "limited use" or "exceptional use" drugs. Often the limitations are that they limit use to actually only on-label use.
My colleagues described it, but a lot of the guidelines do fall under the practice of medicine. We are reliant on specialist medical societies or groups like the Canadian Medical Protective Association for actually providing guidelines in relation to use.
Senator Eggleton: You all agree with that, do you? Okay.
Dr. Poston, you had six points. Your first point was that health providers should only prescribe medications for off- label uses where there is valid scientific information to support the use of the medication. How much of the judgment that physicians make today is based on that? How much of that is there? I agree with you that it should exist — I think we would all agree — but how much of it does exist today versus it being them just talking to other doctors or reading about it? How can we help to ensure that valid scientific information is provided to the doctors?
Dr. Laing: I will tackle that question. Certainly, in my own field, this comes up a lot in the treatment of uncommon tumours, where we do to have robust phase III randomized trials to look at the best way to care for a patient. In that situation, we do a lot of different things.
When you review the literature, what is out there in those situations is often earlier-phase trials. Phase I is where they look at the safety of drugs. Phase II trials seem to be more specific to a particular cancer disease site. Often you can look at provincial guidelines or provincial websites to see what chemotherapy protocols or regimens are approved for a different disease site and gain information that way.
A lot of us do talk to colleagues across the hall, across the province and nationally to ask for opinions for things that might not be published. In that case, you are looking at a level of evidence that comes as expert opinion.
Senator Eggleton: That exists now, right?
Dr. Laing: That is what we do.
Senator Eggleton: Right, but how do you think it should be strengthened?
Dr. Laing: In a lot of those situations, that will be the best evidence you have. There will not be a situation where you will be able to have a randomized trial because these are tumour sites for which there are just not enough patients to be able to conduct such research.
In Canada, reimbursement ultimately limits a lot of off-label drug use. In order for me to prescribe an IV cancer therapy in my cancer centre, it has to be funded; it has to be a proved drug that has a funding mechanism. In most places, that is provincial. For many provinces, there is a provincial budget. In some provinces it is broken up into cancer care programs, but for many of us it is a provincial budget.
If you want to make a case to use a drug in an off-label indication for an uncommon or rare tumour site, you have to do your homework, which includes a review of the literature and talking to your colleagues across the country. Then many of us have a mechanism where that is presented to a group that often includes other physicians who are non- cancer specialists, ethicists and those who look at it from a research point of view.
A lot of times, those off-label uses actually have a layer of approval that is different in various provinces. We have a one-page form that you have to fill out. In Ontario oncology it is called a section 8. B.C. has a special form. There are mechanisms at the provincial level to look at a lot of this off-label use, particularly in rare tumour types.
Senator Eggleton: If you see a national role, where do you see it?
Dr. Laing: Where there is a national role in oncology is that we are fortunate in many respects that we actually have a pan-Canadian oncology drug review process. That looks at any new compounds coming for any new indications. That is a mechanism where you already have a structure that exists to look at some of these issues more carefully.
Senator Eggleton: Does that offer guidance to physicians?
Dr. Laing: It looks at the new compound and it makes a recommendation on two levels. It looks at the clinical efficacy and the pharmaco-economics. That is reported back; this is an agreement among ministries of health across the country and the territories, except for Quebec.
A recommendation is made back to the provinces. Ultimately, it is up to the province to decide whether they agree with that recommendation. Most often they do. The issue is funding.
Dr. Sareen: This is a challenge. The Canadian Institutes of Health Research has also said this; namely, that when there is new science, it takes about 10 to 15 years for new scientific evidence to actually get to the clinician practitioner. They have really tried to create better ways so that a rapid knowledge exchange can happen.
One of the comments I was making is that we have relied too heavily on pharmaceutical companies to educate physicians about medications. We need to have better ways that are non-biased through associations like the Canadian Psychiatric Association and the CMPA to have clearer evidence that is given to the practitioner. I think there is a significant role in that.
Dr. Poston: Dr. Laing described it fairly well. We rely on the continuing professional development mechanisms that the professions have to keep up to date for a lot of this. However, the recent work by the Council of the Federation, for example, is explicitly looking at clinical practice guidelines and how they get produced, disseminated and used. That is a piece of work that is under way in an attempt to resolve this issue of striking the balance between the regulatory role of the federal government and provincial governments' roles in relation to medical practice.
Senator Eggleton: Our researcher tells us that in the U.S. as much as 75 per cent of cancer drugs or biologic therapy is off-label. I did not see figures that high in any of your presentations. Now I realize this is relevant to oncology and it is higher. I understand that and I understand why, but 75 per cent? Is it anything like that here?
Dr. Laing: I think it depends if you look at a specific drug. The trial that I mentioned in the Journal of Clinical Oncology looked at 10 different drugs. One of them, a drug called bevacizumab, had the most off-label use. The newer drugs are the ones that are often the most expensive and are often the ones for which there is ongoing research but not enough data to recommend them across the different cancer sites. The hype is there, as we call it, and there is a great interest amongst patients, their families and practitioners to have these drugs available to those patients. We are often dealing with people who have an incurable malignancy and have already had the standard of care and know there is a new drug and evidence for its use in lung cancer or in colorectal cancer, for example, and they have a different malignancy. That happens more in the United States because of how drugs are reimbursed. That is less likely to happen in Canada, except there are mechanisms for patients in some provinces to "private pay" for oncology drugs, but not all provinces.
Senator Seidman: Dr. Poston, there is no question that pharmacists play a really important role in this whole area. In fact we heard this in the previous areas of study on our pharma study, which is in four parts. In Quebec recently, in 2011, the role of pharmacists was significantly increased in terms of their activities and the things that they were allowed to do.
There is no question that pharmacists have access to the patient record of medications. They have one-on-one relationships with patients who come into the pharmacy to fill their prescriptions, and they provide instructions to those patients about how to take the medications and about the potential side effects and problems.
In the recommendations of your association, I would like to choose two things here given the statement I made about the role of pharmacists. You say that there is no formal monitoring mechanism for adverse events or side effects in the use of off labels. You also talk about the importance of the whole electronic system, e-prescribing and e-health patient records, and so on. In this very long-winded way, I would like you to speak to this and to the future possibilities in improving what we do in monitoring off-label use and its safety.
Dr. Poston: That is a good question. Like Quebec, many provinces in Canada recently passed legislation expanding the scope of practice for pharmacists.
I will pick up specifically on e-health. The paper on the 2012 study by the group at McGill was made possible because of the research group in Montreal that actually have a group of physicians all networked through an e- prescribing system, the so-called medical office of the 21st century. In that e-prescribing system the physician, as well as picking the drug and the dose, has to pick the indication that the drug is being used for.
In everyday general community practice there is no linkage between the drug and the indication. Pharmacists get an order for the drug but do not get any indication of what it is for. Through their own records and through discussions with patients they may have that information and may be in a position to make a judgment about appropriateness. However, I think the experience with the so-called MOXXI project in Montreal is a good example of where, in that system, the physician makes the choice for the drug and also makes the indication of the choice it is used for. That is why they were able to publish the research paper because it indicates the indication. If we had systems like that, then we would be able to create a database of patients who were getting drugs off-label and follow them up and monitor them.
What happens I think in everyday practice currently is that the pharmacist will have an understanding of the patient as to what the drug will be used for and will often be in a position to reinforce the physician's prescribing position. If it is a situation where there are concerns about the appropriateness, then they are in a position to raise those questions with the physician. Currently that documentation and the availability of that information are not there.
Senator Seidman: That is helpful.
Did you have any recommendation, for example, in how one could facilitate the provision of the kind of information we are talking about? I know you used the e-health system in Montreal as a fine example.
Dr. Poston: The other area where we are seeing progress made is where primary health care reform has moved forward in this country and multidisciplinary family health care teams have been established. Pretty well every province has an initiative going on around family health teams. Those teams are usually employing a pharmacist or several of them. I think we are beginning to see the evolution of what I would call local prescribing policies within practices that will cover issues like off-label use where it may apply to children or to pain management or to a number of areas.
Dr. Laing mentioned the development and the use of oral cancer drugs. Many patients, if the reimbursement regimen allows it, are able to be treated outside of the hospital. Recently, for example at our last conference, a pharmacist oncology specialist spoke about oral drugs being used in the community as a way of trying to ensure that community pharmacists are aware of some of the newer cancer therapies being used in practice.
It really comes down to collaborative practice arrangements that enable the sharing of the relevant information and whether that done is through the way of practices or through electronic means. That better sharing of information and better capture of information is something that we all have to work on.
Senator Seidman: I think the key is always in discussing this: Who will enter the central data for this information and who will make sure it is accurate? That is always the basic issue. You are correct that sharing is important, but then you have to have a depository that everyone can use to share the information.
Dr. Poston: In the study that I quoted from MOXXI and in the example that Dr. Laing quoted, both pieces of research were enabled through the fact that there was — and this is the technical term used for hospitals — "computerized physician order entry." There were e-prescribing systems. The study was done because the data was captured in an e-prescribing system.
Senator Seth: I wish to thank all of you for some great information.
I see that off-label medications are becoming commonly used for different diseases and their use is increasing. However, there is a significant off-label use of drugs in cancer patients. Can you explain why cancer treatment involves so much off-label use of this drug? Do you also use off-label medication or drugs for trial purposes, that is, for treatment?
Dr. Laing: That is a very good question. I think there are two main reasons. One is that many of the chemotherapy drugs we use are older drugs that have been around for a long time.
Most of the new drugs in oncology are not standard, cytotoxic chemotherapies. They are what are called targeted therapies. They ask these questions: What is the mistake that caused the cancer to develop, and how do we block, fix or stop that mistake?
Many of our treatments rely on a combination of the newer and the older. If you look at many of these older medications, they have been around for 20 or 30 years. They are generic, and the indication may be for one cancer, one particular disease site, but there are many different kinds of cancers.
For example, there is a drug called cisplatin, which was one of the very first chemotherapies prescribed, and it is used now to treat head and neck cancers. It is given with another biological drug. If you look at the label indication for cisplatin, which is 30 years old, nowhere will it tell you that you can use it for head and neck cancer, and nowhere will it ever tell you that because no one will ever go back to a regulatory authority and say, "I would like to submit cisplatin to be used in head and neck cancer." That is the one issue.
That is why whenever we hear discussions at the pharmacy and therapeutic level in our hospital about how we must never use a drug that is off-label, we always put our hand up and say, "But there many different reasons."
There is also another example. There are so many different malignancies, but many of them share the same problem. For example, a drug called trastuzumab, which targets something called HER2, a growth factor, was initially prescribed in breast cancer, but we found that it also is very important in gastric cancer. The initial indication for trastuzumab is breast cancer. There are many good trials now showing a benefit in gastric cancer, but then it is up to the pharmaceutical company to go back and ask for that indication to be added. They will do it and they will do it, and then eventually they will not do it anymore. It is that requirement for a lengthy process on the behalf of the pharmaceutical company. Also, in all instances at the regulatory level, it has to come from the pharmaceutical company.
In our pan-Canadian drug oncology review process that has recently been established, there is a mechanism for cancer care programs, cancer agencies and provincial tumour groups to make a submission, which is good, because it allows someone other than the pharmaceutical industry to bring forth something to be looked at.
That is the reason. It is because many of these drugs have been around for a long time, and many drugs have numerous indications across numerous tumors and even numerous treatment lines and combinations within the same disease site.
Senator Seth: My question was also about trials, supposing it is a cancer patient not responding to any treatment.
Dr. Laing: Going to the second part of your question, in oncology we are very supportive of clinical trials research. We contribute nationally to our National Cancer Institute of Canada clinical trials group, and we also do some industry-sponsored trials. Whenever we can, we would prefer in that situation to encourage participation in a clinical trial. If we do have a situation where we have a patient who has had all the standard treatments, there would need to be a certain level of evidence, perhaps not phase III evidence, but there would have to be some level of evidence to indicate that the safety and the efficacy of the drug would outweigh the benefits before we would use it. We would not just pick a drug that had never been used for a particular cancer site and say, "Okay, we have run out of options, so I am going to try this on you." We follow the same guidelines that have been articulated here in terms of what the CMPA recommends. For many of us, we have a process to go through where we would have to review the literature that is available, present it at a case conference and then maybe use something that there is some evidence of, although it may not be randomized trial evidence. Certainly if there was no evidence, we would not use the drug.
[Translation]
Senator Verner: I will speak to you in French. I will follow up on the question asked by Senator Eggleton, as we are in the same range of questioning. You have already provided part of the answer to the question I wanted to ask you about how health care professionals identify the risks and benefits for a patient's health when a drug is used off-label.
My understanding is that there is a lot of consultation among colleagues, and the national association of oncologists provides a great deal of information. Is that the case for all health care professionals?
Do other countries' clinical studies serve as a base for deciding whether a medication can be prescribed outside the terms indicated by Health Canada?
[English]
Dr. Laing: First, to address the question regarding determining risk and benefit, the risk of a drug is similar regardless of the indication. Often we will know about a drug because it has been used in another tumour site, so we will have a fair amount of knowledge about the potential side effects of a drug.
In terms of the benefit, it depends on the clinical situation. When we are treating patients adjuvantly for a cure, we want to ensure that there are no long-term side effects and that there is good data to suggest that this will help patients to live longer and to live without cancer.
Senator Verner: Where do you find that data?
Dr. Laing: It may be from trials that are not phase III trials, so phase II trials where we look at things like response rate and something called progression-free survival, which refers to how long is it from when a patient starts a treatment until when their cancer progresses or gets worse and they have to switch to another treatment. In the metastatic setting, we do not always have overall survival data.
As to other practices of medicine, I think many of my colleagues who deal with other areas would go through the same risk and benefit analysis. I think we do it a lot more in oncology because of the types of drugs that we use. We do informed consent, and that is part of what we do because of the toxicity of the drugs that we have used for several years. These newer drugs that we call targeted therapy, even though they are oral, still have a lot of toxicities associated with them.
We certainly do rely on clinical trials from other countries, very much so. Many of the larger trials that are done are done in the U.S. We rely a lot on our European counterparts. For many things that we do, Canadian and European medical oncologists are very similar. We attend their meetings and look at their trials. We look at recommendations from the EMEA. We base a lot of our decisions on information from other countries.
[Translation]
Senator Verner: Regarding reports of side effects related to the prescription of off-label medication, producers and health care professionals can currently report adverse side effects to Health Canada. There is a process for doing that.
Do you think it is conceivable to ask health care professionals to indicate — when reporting adverse side effects — whether the medication was used off-label, in order to gather a bit of information on that kind of use?
[English]
Dr. Laing: Yes.
[Translation]
Senator Verner: Do you think health care professionals in general would agree to do that if they were asked?
[English]
Dr. Laing: Yes.
Dr. Poston: I think what happens is that in practice, the form asks for the indication that is being used. I think that data does get captured.
Dr. Laing: Whenever we provide that sort of information, we provide as much detail as we can. The issue is that we are not always very good at doing that. I will admit that there are instances where there are toxicities, and I do not think we report post-marketing toxicities back to Health Canada as much as we should.
Senator Cordy: You have been excellent witness and certainly very knowledgeable in answering the questions that have been asked. It is great to have a first panel of this high calibre.
The drugs that are being used off-label have already gone through clinical trials but not for the usage that you are expecting. I know that you, Dr. Laing, spoke earlier about the challenges of trying to go back to the regulators and the time it would take, but should there be a time limit on how long a drug should be used off-label? Should we be collecting data and monitoring? When I heard you, my question was: Should there be a time limit? Then, when I heard your response about sending it back to the regulators, in that period of time, I would think that you would not be able to use it. However, I am not sure that it would take long. Should off-label use for a drug that has been approved for another use go on forever?
Dr. Laing: I think it depends on how different the off-label use is. A lot of the off-label use in oncology is because of the very specific way the label is written. It might say that it is only to be used in the first line. It might say that it is to be used only in combination with another drug. It might say only in a certain setting. I think, in many instances in oncology, if a drug is going to be moved from being used in the metastatic setting to being used in the adjuvant or curative setting, there would need to be a new indication sought from Health Canada. If you were going to move from one disease site to another disease site, such as going from using a drug in breast cancer to using it in colorectal cancer, there is often an expectation that that drug would go through an approval process and have a new indication for a new tumour site added.
When they become too restrictive and then we gain clinical experience in using the drug or when new studies come out, that makes it difficult to go back and keep adding one indication after another.
Dr. Poston: I think it depends on the prevalence of the disease. If it is a very common disease and if the drug that is being used off-label seems to be very effective, it is probably in many people's interests for the clinic trial and the research work to be done and for the indication to be added.
The other area where there is potentially a case for it is where it is of questionable benefit, where there are patients who appear to benefit from the off-label use and others who might have side effects or adverse effects. In that situation, I think there is clearly a case for research to be done to add to the off-label use.
The irony is that we see most off-label use with old drugs that have been around a long time. Often they are off- patent, and so there is very little incentive for anyone to support clinical research to do that. One of the interesting innovations is what Dr. Laing talked about where physician groups are being allowed to make the case that research should be done and an indication should be added.
Senator Cordy: Every drug has side effects, so it does not matter? You hope that the benefits outweigh of risks? That always makes me nervous when I think of some of the off-label use.
Pharmaceutical companies cannot advertise off-label, but can they have professional development sessions for pharmacists and for doctors to tell them about off-label use? I guess what I am asking is this: Is there a way around the law?
Dr. Poston: It would be interesting for the physicians to comment. It is kind of a difficult area to find a balance. In the U.S, there has been a lot of legislation recently and many discussions around this. I think that where people are trying to find the balance is to allow the exchange of information so that physicians and pharmacists can be informed. However, the drug must not be promoted. The challenge from the pharmaceutical companies' perspective is that in one hospital there might be somebody using a drug differently and getting good results with it, yet they are not seeing many patients. In order to do the research, you need more patients, so you have to go out and talk to other physicians who are treating those sorts of patients in order to assemble enough people for a clinical trial. There is a fine line between the exchange of information and promotion. One of the challenges in sorting that issue out is where you draw the line.
Senator Cordy: Dr. Sareen, I know there is a fair amount of off-label use in psychiatry, in dealing with psychotic episodes. How do you determine the effectiveness of an off-label use when many people who are undergoing psychiatric treatment are on more than one medication and when much of the off-label treatment is to treat residual symptoms — the side effects — and to improve the quality of life? How do you know whether the off-label use is actually working?
Dr. Sareen: That is a really good question. Often the aim is to follow up with the patient and their family member. Off-label use in psychiatry can be for residual symptoms of the main illness, for people with depression or psychotic illness who have partially responded to one medication and then have side effects so that you cannot go up on that medication and who use another medication to try to improve the symptoms.
It is about trying to review clinical guidelines and research, not only nationally but also internationally, to see whether the addition of these medications is useful and beneficial. It is also about reviewing those guidelines and listening to the patients. The patients that I treat will tell you. I sit with my patients and follow them. I have a patient right now who has manic depression, and she says that she has had one episode of depression and wants to know whether she should take the medication long term or not. It is very important that we suggest that we follow people and see how they do on and off the medications.
This comes up in pregnancy quite a bit as well with moms who have had an episode of illness and are now stable and wonder whether they should stay on the medication or not. If you look at the evidence that guides you, there is very little evidence that guides whether people should stay on or go off of their meds. They are guidelines, so that is a real decision between the patient and the physician. The proof is in the pudding when you talk to the patient about how they are doing when they go off the medication. It is really about following them with or without the medication.
Senator Cordy: Sometimes for conditions like schizophrenia the side effects of the medication itself can be debilitating, which means that the person wants to come off the medication because of dryness of the mouth or whatever. That is often when the off-label use drugs are used. Is that correct?
Dr. Sareen: Right. That is always the challenge. The good news now is that for psychiatric medications there is a lot of choice. From the 1950s to the 1970s there were basically one or two antidepressants and one or two antipsychotics. Now there are almost too many. When I sit with a person with depression, I have a list of 20 antidepressants that I could use, all of which have indications. None of them are off-label. I am trying to figure out which medication is going to help. We are far behind oncology in that we do not have any guidance as far as biological tests or genetic profiling that would say, "This medication will work." It is a bit of trial and error, but for the majority of things, especially schizophrenia and major depression, there is a lot of on-label use, much more on-label use than off-label use.
Senator Enverga: It looks like we have gone a long way on research. We have spent billions of dollars on all of these medicines and other forms of investigation. How confident are you with our off-label drugs? How sure are you when you decide whether to use off-label or on-label? How confident are you, as a practitioner, with off-label or on label drugs?
Dr. Sareen: For off-label use, I guess it really depends. As Dr. Laing said, some of the medications have been around a long time. That they are off-label does not mean they are ineffective. They actually might be more effective than some of the newer medications. Most physicians, especially in psychiatry, look more heavily at the systematic reviews and clinical practice guidelines to choose a medication than at whether it is on-label or off-label.
Senator Enverga: It looks like everything about oncology treatment is individualized; am I right? Do you have a database for everyone that says "this is for this drug"?
Dr. Sareen: Yes.
Senator Enverga: For individuals?
Dr. Laing: You are right. When we look at the treatment of patients in oncology today, we talk a lot about individualized care. I may do a clinic and have 15 patients with breast cancer. They will be treated very differently. It will depend on the biology of their tumour, and we are very fortunate to be able to look at not just things like hormone receptors but another test called Oncotype DX is now available to us. It really gives us an indication of what is driving that cancer.
I also then have to look at the patient and ask: What co-morbidities does she have? What drug coverage does she have? Where does she live? How important is it for her to get back and forth to the cancer centre, et cetera. There are many different things.
It is very individualized. We are fortunate in oncology that we have a lot of good biology to guide the treatments that we provide. Much of it is still trial and error, but a lot is very specific.
I would say that we are very comfortable with 90 per cent of the drugs that we use off-label. We have a lot of clinical experience with these drugs; we use them all the time. There are very good randomized phase III trials that say you can, for example, give a drug called docetaxel in combination with another drug and it improves overall survival. That may not be on the label, but there is a lot of very good evidence. We have that, which I think in many situations is more important than what the prescribing label says. That comes from very good level 1 evidence.
Senator Enverga: If you said it is already 90 per cent sure, or you are comfortable with it, why do we not make it on- label now?
Dr. Laing: The process to put it on-label relies on the pharmaceutical company going back and asking for it to be added on, and that does not always happen. They have moved on. The drug is now generic. They have gone on to developing in a different disease site, and they know it is being used. There is a clinical practice guideline that supports it. It is being reimbursed at the provincial cancer level. Therefore, there is no real impetus for them to go back.
That is something like a listing to say that although it might not be an on-label use, it is a very appropriate use.
The other instances are when we just do not have the luxury of that amount of data. That is when you have the rarer tumours, and that is when you really have to look at the evidence that is out there, discuss it with your colleagues, and present it to the patient.
However, we learn from that; we learn from those experiences. I think the impetus is on us to share that. We share that when we meet and discuss these things as groups. We share that through publications.
I have a patient with a rare tumour who went from the pediatric to the adult world. I could find one report from Japan about using a drug that I use all the time in oncology. It is called temozolomide. I sat down with this 20-year-old boy and said, "I have never seen anyone with what you have. I have seen it described in the literature. I can find one case, but I know how to give this drug." I gave it to him and he had a brilliant response, so I wrote that up. That is how we share the data so that other people can learn from it.
There is an impetus on us to share what we know and to be responsible for how we use that information. If someone comes to me and says, "I have breast cancer and I want drug X," I may say that there is no evidence, but they are doing a study in MD Anderson Cancer Centre, a phase I trial. I say, "Yes, but I do not have the level of evidence that is indicated to treat you for this." That is the kind of off-label use you want to avoid.
I do not know if any of you are familiar with a drug called bevacizumab, or Avastin. It is very interesting for many reasons. One, it was one of the first drugs in Canada that allowed for patients to private pay. When it came out for the treatment of metastatic colorectal cancer, not all provinces funded it, so it allowed for private clinics to set up and challenge the Canada Health Act.
The FDA gave it conditional approval for breast cancer. We never went after that approval in Canada and never used it for breast cancer. Then the FDA withdrew the approval. The toxicities were well known for the drug, and they were the same whether you give it to someone with lung cancer, colon cancer or a brain tumour. The benefit is very different.
In breast cancer, the benefit was very small: a matter of three to four weeks of progression-free survival at the metastatic setting, yet they could have bleeding and perforation of the bowel, so that was withdrawn. It worked very well in metastatic colorectal cancer, but it does not work at all in the adjuvant setting.
We learn more about these drugs as time goes on. That impacts things. It is then our responsibility as prescribers, but also as regulatory agencies, to have that ability to follow these drugs and to change your mind, if you will.
Senator Martin: Your last response, Dr. Laing, is helpful in guiding some of my questions. One of the most alarming or impactful statements that I heard was from Dr. Sareen when he said that although it is illegal for pharmaceutical companies to promote the use of the medication for off-label conditions, it is legal for physicians to prescribe medications. I was trying to wrestle with this statement and say that you are representing your professions or your fields well, but in every profession there are always those who may not be as well informed and as knowledgeable. I have several questions. Is it a lack of information, having enough information, or is it the coordination of it? What are the gaps in our current system?
At one point I had to be the navigator in optimizing the meds for my father. I did not realize that he was on 15 different medications. Some counteracted others and there were adverse side effects.
Is it too much information or not enough? How does that coordination happen and where are the gaps? When you describe what you prescribe to your patients, our hope is that everyone does that. However, what happens in the case when it does not happen and meds are not optimized and there is off-label use? You say 90 per cent are very effective, but that 10 per cent is concerning. It is a tool that can be used very effectively or it could be very damaging.
I am curious about the gaps and the concerns. How would we address that?
Dr. Sareen: The off-label use, as I said, is very important. Usually, as has been described by my colleagues, it has an evidence base. The challenge in emotional problems — and it goes back to some of the questions around schizophrenia as well — is that often the illnesses have multi-layered symptoms. We do not have a good understanding of why the illness is happening; we see a range of symptoms. Often physicians prescribe medications to try to reduce the symptoms and there are common side effects. People do land on multiple medications at times.
Often the challenge is that we do not have a good understanding of which medications will be useful and protective over a long period of time. People do stay on five or six different medications, and it is very important. The clinical practice guidelines often say for physicians to review the medications and to think about whether this medication is actually needed. Do you need two antipsychotics? Do you need three medications for sleep? Do you need two different antidepressants? There is a move to try to reduce poly-pharmacy, a number of different medications.
In Manitoba, the Improve Project is looking at this. It is kind of like electronic prescriptions that come to the Manitoba government. For example, a physician may be prescribing outside of the guidelines, say benzodiazepines in the elderly for more than 90 days. They are doing an education trial to send out letters to the physician saying, "This patient is beyond the guidelines, and here are some recommendations that you can think about around how to come back within the guidelines." It is really to provide information. This is a new program. In Manitoba, they are looking at seeing whether that can actually have an impact on practice.
As you were saying, the knowledge gap takes 10 to 15 years. People often end up on multiple medications. Family doctors are busy and have a short amount of time. If someone is on six medications for depression, anxiety and alcohol, which one is working and which one is not? It requires quite a bit of thinking and follow-up.
Dr. Poston: You ask a really important question about the gaps. The big gaps are between hospital and community. The continuum-of-care issue is where the gaps are. The specialists working in a hospital or clinic setting — a very well- defined setting — have a lot of control over what is happening with their patients. Some of the gaps begin when that patient gets out into the community.
The Canadian Patient Safety Institute has been developing and promoting — and has become and standard for accreditation in lots of hospitals — a process called medication reconciliation, where, on discharge, the patients' discharge medications are coordinated and reconciled with what they have received during their stay in hospital. Out in the community, community pharmacists will often reconcile that. Often, the patient in the hospital will have had drugs added to their treatment. They might have had drugs stopped. A whole host of things might have happened in their drug treatment while they were in hospital.
This process of medication reconciliation, both on admission and discharge, is being developed by the Canadian Patient Safety Institute as one the tools to ensure that there are no gaps in treatment as changes made are carried on along that continuum of care.
Work is going on to really try to address some of the gaps that occur in care. If a patient has done well on an off-label use of a drug in hospital, then that will get carried over into the community. Likewise, if they have been receiving a drug off-label in the community and it is not working well, that will get picked up and perhaps changed when they are in the hospital setting.
Senator Martin: You say it is being developed, so it will be dealt with differently depending on the province. Once it is fully developed with a mechanism or template that is effective, will it be shared across Canada?
Dr. Poston: It is pretty well developed at the moment. I think that for Accreditation Canada, which accredits hospitals, it is now required or strongly advised or recommended to hospitals in their accreditation process. Oncologists and psychiatrists have probably done more work in the area than anyone else.
Senator Martin: That is good to hear.
Senator Munson: I just have one question because there have been so many good questions and excellent answers to a serious issue.
To Dr. Poston and others who want to answer it, you use the word "encourage" in your discourse about recommendations and guidelines. I am curious about how serious this matter is. As the Standing Senate Committee on Social Affairs, Science and Technology, we love doing these studies and recommending to government what it or what a health minister should do. Beyond encouraging and beyond better guidelines and support, should we be encouraging the government to enact a new law and come up with something new to address this issue? Is there a legal ramification here that can make this issue a better place for everybody who has to use these kinds of drugs?
Dr. Poston: That is a really great question. I think we are stuck with this regulatory divide in that a lot of what we are talking about relates to the practice of medicine and the practice of pharmacy, and it sits with the regulatory colleges relating to those professions and to the role of provincial governments in that.
There is potentially a role for government in finding ways to better measure and monitor what is happening. I think a lot of that would benefit from a central approach. Rather than having the somewhat piecemeal approach we have at the moment — if it happens — it would be helpful to have that done nationally. There might not be many patients in Canada of the sort that Dr. Laing talked about — the one-off patient — but if we could capture the experience of all of them and share that information, it would help. Better mentoring and monitoring is one of the things that governments have a role in.
We have heard of the work that Health Canada has been doing around progressive licensing as an approach. It sometimes gets referred to as a life-cycle approach to drug regulation. That concept has a great deal to offer in this area because you would be systematically collecting data, on an ongoing basis, during the life cycle of the drug. That type of regulatory approach could really support the development of information and could improve use in this sort of area.
Senator Munson: Better measuring and monitoring rather than, as you say, a piecemeal approach. Should these be enforceable guidelines from a federal perspective? In other words, "You must follow."
Dr. Poston: I think it is difficult to make these things enforceable. If you establish best practices and there is support for them happening, my sense would be that you try that approach first. That is where you would start.
However, a very important discussion point around the development of e-health and e-prescribing is that voluntary systems to try to make that happen have not been very successful. We are seeing a serious debate emerge about whether this should become mandatory in some form. You have to try the voluntary, best-practice-guidelines approach and see where that takes you first.
The Chair: I would like to come back to a theme that has run through a number of the questions. In prefacing the question, I note that in oncology we have rather a unique situation in terms of an area in which there is often not a large number of people in a given situation — in all of the subcategories of cancer and so on — and one that is often close to the research-base activities in hospitals, through CIHR. Dr. Laing described very well the degree of information transfer that occurs in that area.
We have been looking at this issue in the population with regard to all of the prescription pharmaceuticals. When a prescription is assigned to a child, it is, for most pharmaceuticals, an off-label use. The same is true, in general, for pregnant women. In fact, it is often the case for women, regardless of their state, and certainly for the elderly.
You have been implying that the collection of information is really quite good and that in the case of oncology you have a 90 per cent confidence level. What we know from the record is that in the off-label use of drugs in psychiatry — for children, for example — and in many other cases, there can be significant, unintended consequences, which can be life threatening.
We have also heard, in our previous two study phases, that the collection of data is not very robust across the spectrum of pharmaceuticals at this time. Dr. Poston, Dr. Laing and Dr. Sareen have referred to the issue of e-health collection, but we know that the status of the e-collection is not where it needs to be to get to this.
I want to come to a specific question to you, Dr. Poston. Pharmacists will know that when they are presented with a prescription for a drug for a youth, the flag goes up immediately that this may well be an off-label use, unless they are familiar with extensive experience as Dr. Laing as pointed out. We heard in previous studies that a deliberate follow-up with new drug prescriptions is starting to enter the activity. In fact we heard of one in the U.S. and one in Canada, and from the data collected, apparently initial results suggest that is a very good thing. If I can use the example I used in those studies, it is like taking your car in for service and within a month they follow up: "How has it worked?"
We also know from another study we did that pharmacists are quite good at using the e-system for data. I want to come specifically to the issue where there is a high likelihood in the pharmacist's mind that the drug is being prescribed off-label. In the wide breadth of prescription pharmaceuticals that are available, only a small number go to oncology. Most of them go to the large general population.
In cases where there is a reasonable expectation on the part of pharmacists, if we had a system in place where the pharmacist is referred back to the prescribing physician with a requirement for a follow-up, perhaps within a month or a longer period of time, depending on the drug, can you envision some sort of reasonable e-system of follow-up that might allow for the much larger degree of collection of the data?
We also heard that this is really important even in the general population because once you are out of clinical trial and enter the general population, you are entering the subsets that do not occur just in cancer areas but in the population as a whole.
Dr. Poston, can you suggest a reasonable e-system follow-up? We did hear in our other studies that making it a law that you must do this has not worked out very well in other countries. In fact, the results have tended to go down in some of those countries.
Dr. Poston: Often the pharmacists may actually not know whether it is for a child or a youth unless it is a privately paid prescription. If it is in a provincial drug plan and it is the mother or the father picking it up, unless the pharmacist asks, it may not be evident on the prescription. You will have a patient's name. Obviously if you have the family record you will know. If it is a private prescription you will often end up knowing because the drug plan will not pay unless they have the information that it is a child.
The Chair: The name of the patient is not always there.
Dr. Poston: The name of the patient is there but the age is not.
I have never been licensed to practise pharmacy in Canada. I am licensed in the U.K. In NHS prescriptions, because medication is covered free by the NHS for children under 16, the pharmacist has to write in the age of the child. In private prescriptions in Canada you usually know it is a child because the drug plan will not pay for it if that is not confirmed.
One of the banes of pharmacy practice — this is for the men in the room — is that men are notoriously bad at actually knowing the date of birth of their children, and that is one of the most common problems in pharmacy practice.
To get to your question, there is a process. The United Kingdom has just launched a new initiative in the National Health Service that they are calling a "newly prescribed medicine service." I think there are some limits on it by either drug or disease, but to your example, it could easily relate to a child population. For children under 12 you could create a newly prescribed medicine service where the pharmacist is required, and they get a fee for the service, to follow up with a patient. First, they only dispense a limited quantity of the medication, usually 7 days or 10 days, and then I believe they are required within 28 days to follow up with the patient and the family physician to make sure the medication is working and is successful.
It is not a sophisticated e-system. It is a basic telephone call or, if necessary, the patient is asked to come back to the pharmacy. We are seeing services emerge around newly prescribed medicine in an effort to fill in some of the gaps and to better capture data around utilization of drugs that perhaps have risks associated with them or drugs that have been used in certain populations.
The Chair: This business that it is not clear what category of person the prescription is for, would it be not be reasonable for there to be a requirement that prescribing physicians indicate youth, senior citizen or some category like that?
Dr. Poston: In practice, the pharmacist will usually know and the pharmacist will ask, but it is not necessarily documented.
The Chair: Your first statements were fairly clear. Now you have qualified that by saying the pharmacist will likely know. My question was designed with the idea that the pharmacist likely knew. Would it not be reasonable to have a signal? If in fact the pharmacists do not know because they are in a big city and have no idea about people, would it not be reasonable that there be a requirement for an indication of some category on the prescription?
Dr. Poston: Some countries do that. I think what happens, though, is it often becomes a major administrative issue.
South Africa, for example, requires ICD-10 codes to be entered on prescriptions as part of their control mechanisms. Very often physicians will not necessarily know or have an accurate ICD-10 code to go on the prescription, so often the prescriptions do not get filled or are delayed as they try to get ICD-10 codes.
It is a great idea, but in practice it can be difficult to implement.
With respect to the idea of a newly prescribed medicine service, particularly with respect to children, pharmacists will usually know where there is an issue relating to dose. In many cases with pediatrics there will be a reduced dose, and if pharmacists do not know they will always ask. They get that information. I think there is some potential for newly prescribed medicine services as a way of capturing these patients.
The Chair: I appreciate that you are also indicating the complications of various identities. It would seem to me there would be a way to deal with those kinds of things, but I appreciate that.
Dr. Laing: I will make a comment regarding the issue raised earlier about poly-pharmacy and how we address that issue. I think it comes down to time, resources and knowledge. The key people in terms of the practice of oncology are our pharmacists. Whenever we see a new patient in our cancer centre, they are seen by the pharmacist and a medication reconciliation is done. When we start a patient on oral chemotherapy, they are followed by a pharmacist and we have that same follow-up procedure.
If a patient gets chemotherapy, whether IV or oral, they are called by the pharmacist within 48 hours to ask how they made out. When they are given an oral drug, the pharmacist follows them. The pharmacist connects with the local pharmacy to ensure that the prescription is filled in a timely and accurate manner.
What does that take? It takes time and resources. The biggest challenge is funding, but we are very fortunate. How we did it was through research. We did a seamless care project and actually showed better outcomes for our patients. We showed that they were less likely to run into toxicity, less likely to need a follow-up visit in a chemotherapy unit for IV hydration, less likely to have renal impairment and less likely to be admitted to the hospital. That is how you have to show those things.
Senator Eggleton: I was reading an article in Maclean's magazine last May entitled "Off-label drugs are off the charts in Canada," and it contained a fair bit of interesting information. One item I found was that Pfizer was out to develop a cardiac drug but found the side effects would make it a lot more money, and that drug is Viagra.
I will not refer to that any further.
Senator Cordy: Let's hear your questions on that.
Senator Eggleton: Dr. Laing, you said you had a comfort level of about 90 per cent in terms of the evidence base for making decisions for off-label prescriptions, yet this article in Maclean's magazine quotes a couple of people, for example, Dr. Tewodrose Eguale from McGill University, who says that of the drugs prescribed off-label, 79 per cent lacked "scientific evidence."
According to the same Maclean's magazine article, "a shocking number of prescriptions are written on hazy evidence," and Dr. Joel Lexchin of York University says, "Although some drugs prescribed off label are done so appropriately, most of the off-label prescribing in Canada doesn't have a scientific basis." It sounds like that is really, if not the major issue, a very major issue.
Looking at this from our level here on this committee as a national entity, knowing that a lot of the jurisdiction is provincial, what is the best way to work our way through this? Maybe you disagree, Dr. Laing, with these numbers anyway.
Dr. Laing: I have not read the article, but I assume those are general numbers for prescriptions across many specialties and many disease sites. I am only speaking about oncology.
You also have to realize that when I prescribe a drug for a cancer patient, the majority of those drugs are funded by a provincial budget. That patient is not taking the drug down the street to the pharmacy. That happens more and more with oral drugs, but many times these are IV drugs that are administered in a hospital setting — in my cancer centre, in a satellite hospital, in a regional hospital. That drug cannot be given to that patient unless there is approval at some level, whether it is a standard of care that is reimbursed through our provincial cancer budget.
That is how it is in oncology, and that is why I said in my statement that I do not think it is as big an issue in oncology as it is in the United States. The only way for that drug to be paid for is by the provincial cancer program. If it does not have an on-label indication, you have to give a good reason for your off-label indication, and there is evidence for that. That is the difference.
Getting to your question, the only way to deal with this, and we have all been saying around this table in various different ways, is we have to have the information, and we do not have the information. We have bits and pieces and estimates. We think it is 79 per cent or whatever per cent, and that is based on a very small snapshot of what is happening maybe with a particular drug.
Some of the reports I looked at about drugs used in lymphoma said about 50 per cent of the use is off-label in the U.S., but they have a greater access to these drugs to be able to give them in situations that may be appropriate or in situations that may have little or no scientific evidence.
The first thing you need to do is have an idea of what is happening in this country, and we do not have a very good idea of the real amount of off-label use. The question is how to capture that. We have heard a description of people showing up at the pharmacy saying, "I am here with my Viagra." Why are you getting it? Are you getting it for an obvious reason, or are you getting it for some off-label indication? It is difficult for the pharmacist who is busy and has no incentive to code and enter it. You need a database so people can enter that information and say who is getting it, how old they are, and what is the indication. That is how to gather the information.
The example in the U.S. is an amazing example of the ability to do that, but it is because it is an order entry system for ordering the chemotherapy and for billing. Unless you have a similar robust data set — you can look at it as a research opportunity or look at it in a province that might already have a wide setup for e-prescribing — you have to have to start somewhere. You can start it as your McGill example. That is how to grow that knowledge and be able to apply it to the larger group.
Dr. Poston: I did read the study, and I thought the 79 per cent was a little high, so I dug further. The actual words they used in the study were that 79 per cent lacked "strong scientific evidence," so "strong" was a critical word. In the paper, they actually listed about four of the criteria that qualified as "strong." To get strong scientific evidence, the drug had to be involved in at least one randomized control clinical trial for the indication. It is rare with a lot of off-label uses to have actually been used in an RCT.
I think that the 79 per cent number needs to be put into that perspective. It is interesting because the study found only 11 per cent of prescriptions were off-label. They had a pretty narrow definition of "off-label," but given the fact that "strong" required it to be used in a randomized control trial, I am not surprised by the 79 per cent number when looking at the criteria.
Dr. Sareen: I would agree that research and information are really needed. Coming back to Senator Munson's comment, the encouragement or law changes that can happen are to consider broadening the capacity for approval of the medications as on-label. Right now, drug companies are the ones that usually ask for approvals, and they have no financial gain in spending enormous amounts of money looking at children and the elderly.
If we want to ensure there is little inappropriate use, we need to know whether an antidepressant that works in adults will work in kids and will work and be safe in the elderly. We cannot rely on pharmaceutical companies to do that work. They will not do it. Lack of evidence does not equal that it does not work.
One of the tongue-in-cheek articles written in the British Medical Journal talked about whether parachutes actually work in reducing gravitational challenge. When they did a systematic review of evidence, they did not find any studies that had randomized people getting into parachutes versus not doing so before dropping them from a plane. Parachutes are still used; it makes sense to use them. They were pointing to the fact that we have to act, especially when you have adolescent suicide, which in our First Nation communities is extremely high. We need to do something about it.
Oncology is a good example of how things have developed, and psychiatry and mental health are about 20 years behind. We need to invest to ensure that we are giving the right medications and the right interventions to the right people.
Maybe some people who are on an on-label use of an antidepressant do not need it. Maybe they would resolve on their own. It is one of the challenging pieces.
Senator Eggleton: Dr. Sareen, you said that Canada needs to invest in unbiased physician education focused on the benefits and risks of medications. It is an interesting point. I think we will pursue that further at this committee.
I also read in an article in the New York Times that GlaxoSmithKline agreed to pay $3 billion in fines in part for promoting antidepressant drugs unapproved for off-label uses. Then, Johnson & Johnson reached a $181 million consumer fraud settlement with 36 states and the District of Columbia over its marketing of Risperdal, an antipsychotic drug.
Those companies also exist in this country. Are you concerned about evidence that they may be selling off-label uses?
Dr. Sareen: Absolutely, it is illegal, and because of time limitations I did not make those comments. However, in the U.S., there have been these fines. If you look at the profits that these companies make from these medications, they are in the billions, so paying a small fine for them does not matter.
I am not clear on how much off-label use marketing occurs in Canada. I know that Canadian organizations and industry regulations have been much stronger than the U.S., but I think that is an important —
Senator Eggleton: That is one reason why you want to have, as you say, unbiased physician education.
Dr. Sareen: That is the key. We have relied too heavily on physicians who have conflicts of interest with drug companies to provide the education to physicians. There is no funding to support both research and appropriate marketing.
I can give you an example of a prostate medication that was discovered to be useful for post-traumatic stress disorder by a guy in San Francisco. This is a medication that has been generic for a long time. They showed that prazosin is a medication that helps with nightmares for PTSD, but the distribution of how that knowledge spread centres around San Francisco. They looked at the VA system, and the spread of use of prazosin for PTSD was geographically around where it was discovered.
The issue of how you get knowledge to practice is the biggest area that we can improve.
Senator Seth: I want to clear up a situation about the practice in Canada because I have been a practising physician for the last 35 years. When filling out the prescription, yes, certainly it is true that we do not write down the age of the patient. However, the prescription is written according to the age of the patient, so if it is a child, of course is written to the age of the patient. I know a lot of pharmacists have to ask the patient's age, especially because it could be an adult or a child. They do not rely on what we have written for the dose, so they make sure the dose is correct for that particular age. If they are doubtful, the prescription is never filled. I know it is very cautiously taken here as well. From what I see in my practice, I have never seen any problem related to age.
Dr. Sareen, how often do you use off-label drugs to treat psychiatric patients, such as antidepressants or antipsychotics?
Dr. Sareen: It is extremely common. As I mentioned, if I have a person sitting before me who has depression, I will more carefully look at their symptom profile, what kind of medical problems they have. I look at the systematic reviews for the best medication for that person rather than focusing on whether I am using on-label or off-label medication.
I treat anxiety disorders. There are five of them, so drug companies will focus on one and get approval for one. However most clinicians say that medication works not only for that anxiety — it is like breast cancer and another cancer — so the same medication should work for the other one.
Off-label use is extremely common because we do not have enough evidence to know which medication will work for the right person. We do not have the biological test; we cannot do screening. We cannot test the brain systems and say there is no epinephrine deficit of this percentage, so we should increase. That is where psychiatry is trying to go, but we are still far away from that.
Senator Enverga: I would like to make a suggestion following up on my earlier question. There is something that we call mind over matter. When we talk about off-label and on-label use, we always think that on-label is better or good and off-label is bad. If you have 90 per cent, that would probably be fine. I am thinking that maybe it is better for the patient not to know it is off-label. Maybe we should name it "okay label" or something like that. Do you not think it would be psychologically helpful for patients to have that?
Dr. Laing: When I talk to patients, I do not tend to use the terms on-label and off-label. I tend to present the data to them in a way they can understand. I may explain that the trials have shown a benefit and this is what it is and these are the side effects. When we talk to patients, we do not use those technical terms as much, but more for them to have an understanding of why we think this will be of benefit to them in this particular setting.
However, you are right. That is where there is perhaps an in-between area that these drugs should fall under. That makes it sound okay.
Senator Enverga: That is right, "okay label."
The Chair: Dr. Sareen, with regard to antipsychotic drugs and youth, do you make the same extensive explanation with parents that a drug that has not been tested in youth —
Dr. Sareen: I think there is a concern about antipsychotic drug use in both children and the elderly. There has been overuse at times. I think it is important, especially with use by the elderly, to carefully discuss the side effects. I think there is a need for education for psychiatrists but also family doctors to ensure that they are aware that atypical antipsychotics have long-term problems and that we need to be careful in prescribing them.
The Chair: Thank you all very much. This has been a very good start to this study. On behalf of my colleagues, I want to thank the three of you individually and collectively for the clarity, thoroughness and frankness of your responses to us today, and for your presentations.
(The committee adjourned.)