Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 34 - Evidence - March 21, 2013
OTTAWA, Thursday, March 21, 2013
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 10:30 a.m. to study prescription pharmaceutical products 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]
This continues our study on off-label use of prescription drugs, the third of a series of four studies that this committee is doing on prescription drugs.
I will ask my colleagues to introduce themselves.
Senator Seidman: Judith Seidman from Montreal, Quebec.
Senator Martin: Good morning. I am Yonah Martin from British Columbia.
Senator Seth: Asha Seth from Toronto, Ontario.
Senator Enverga: Tobias Enverga from Ontario.
Senator Eaton: I am Nicky Eaton from Toronto, Ontario.
Senator Eggleton: Art Eggleton from Toronto, and deputy chair of the committee.
The Chair: I am Kelvin Ogilvie, a senator from Nova Scotia and chair of the committee.
We have two witnesses with us this morning. We are delighted to have you both here. I will introduce you in the order that we have agreed you will present. That means that I will first welcome Maureen Smith, Secretary to the Canadian Organization for Rare Disorders. You have the floor.
[Translation]
Maureen Smith, Secretary, Canadian Organization for Rare Disorders: Hello. My name is Maureen Smith, I am the Secretary for the Canadian Organization for Rare Disorders. I am pleased to represent the organization today and to share with you the challenges of off-label use of pharmaceutical products for Canadians with rare disorders. I myself have had a rare disorder since childhood.
[English]
I will start by giving examples of challenges of off-label use for rare diseases in Canada.
Nicholas and Jonathan are 10-year-olds living in Ontario and diagnosed with Prader-Willi Syndrome, a rare genetic disorder resulting in multiple symptoms but most frequently includes morbid obesity because of insatiable appetite, intellectual disability and short stature due to low levels of growth hormone. Since it is an older drug, there have been no randomized control trials with Prader-Willi Syndrome children, but observational studies have shown that growth hormone therapy can improve stature, coordination and cognitive functioning. Growth hormone therapy is an approved standard of care in the United States and Europe but not in Canada. None of the brand manufacturers or the bio-similar growth hormone therapy will conduct randomized controlled trials just for Canada.
Nicholas' family has private drug coverage and he has been receiving growth hormone therapy since age five. Jonathan has been denied by growth hormone therapy by the Ontario Public Drug Plan. Nicholas is at the fiftieth percentile for physical and cognitive development while Jonathan is closer to tenth percentile. Robin in Alberta gets growth hormone therapy through an off-label drug program, while Sarah in B.C. has been denied access by the public drug plan but receives it through the manufacturer's compassionate access program.
As a second example, severe deficiency of alpha-1 antitrypsin, or AAT, is a rare disorder can lead to pulmonary emphysema and lung failure as well as liver diseases including cirrhosis, hepatitis and cancer. Symptom management includes bronchodilators, steroids, vaccines and oxygen. Infusions with AAT augmentation therapy can slow the progression of the disease for those with lung-involved symptoms. However, there are no long-term studies on efficacy. About three years ago, Ontario decided to deny access to augmentation therapy for newly diagnosed alpha-1 patients in Ontario. The impact on quality of life is profound, with patients no longer able to work or engage in everyday activities.
As a third example, intravenous immune globulin is a plasma-derived product indicated for primary immune deficiency as well as a number of other very rare conditions. Intravenous immune globulin is provided by the Canadian Blood Services or Héma-Québec and may be prescribed by any physician for any condition. In Canada, it is used mostly off-label and is considered "first line" therapy for many diseases that have an immune mediated or unknown pathogenic mechanism, despite the lack of clinical trials.
These examples illustrate the challenges of the off-label use of drugs for rare diseases. While there are no specific studies on off-label use in rare diseases, one Canadian survey in Quebec found that 11 per cent of prescriptions were for off-label use, while estimates are that as many as 80 per cent of prescriptions for rare diseases are off-label. A study conducted by EURORDIS, European Organization for Rare Disorders, suggested that off-label use was the "rule" and not the exception with usage of over 100 off-label medications for 90 rare diseases identified in just 250 responses.
Health Canada provides no regulatory oversight for drugs used off-label. Physicians and patients assume the risk for use. If the drugs are provided through the special access program, there is no monitoring or systematic collection of adverse effects or benefits. Since manufacturers may not market drugs for unapproved indications, physicians are often unaware of appropriate use and this increases the likelihood that patients will be denied a treatment that may be effective or they may be prescribed a drug with no evidence of benefit.
Public drug plans tend to deny reimbursement for off-label drug usage. Individual requests to the exceptional access programs available in many provinces are unsatisfactory. The physician must collect the evidence to justify a request and a provincially appointed expert must review each application. Sometimes the same application is accepted by one expert and denied by another. Where provinces receive a large volume of requests for an off-label use, they may establish guidelines for approval. This reduces the inconsistency, but does not necessarily resolve the amount of paperwork required to repeatedly apply for approval — a process for which the physician receives no compensation.
The proposed Orphan Drug Regulatory Framework announced by the federal health minister last October will provide a process for the review of new drugs but does not address off-label use of old drugs. The regulation should include provisions for adding new indications without requiring randomized control trials. Moreover, the U.S. is considering a provision that will allow manufacturers to market an off-label use pending approval of an off-label application. We recommend that Health Canada consider this as an extension of our Orphan Drug Regulatory Framework.
The U.K. National Institute for Health and Clinical Excellence, NICE, has announced it will provide advice to physicians on the use of unlicensed and off-label drugs for special conditions, including rare diseases. Their goal is to provide patients with better access to these medicines, recognizing that many of these indications may never be licensed but some patients would undoubtedly benefit. We think this is a worthy goal for Health Canada and the Canadian Agency for Drugs and Technologies in Health.
Finally, the next wave of drugs for rare diseases may not be new molecular entities but repurposed old drugs, those on the market and those in manufacturers' drug banks. In Canada, collaborations at the University of Ottawa and Dalhousie, with support from CIHR, Genome Canada and private partners are among those engaged in this research. It stands to reason that an expedited process to review and approve these therapies is needed, as well as an appropriate reimbursement process to bring these medicines to patients as soon as possible.
We look to the federal government and Health Canada to provide the leadership, resources and mechanisms to turn the challenges of off-label drugs for rare diseases into real opportunities to improve the health and quality of life of Canadians.
[Translation]
Thank you, I will be happy to answer your questions in English or in French.
[English]
The Chair: I will now turn to Janet Currie, who is representing the Psychiatric Medication Awareness Group.
Janet Currie, Representative, Psychiatric Medication Awareness Group: Thank you for the invitation to appear before you. I will talk about psychiatric drugs and other forms of off-label prescribing and focus on the risks to consumers and some aspects related to tracking, monitoring and also informed consent.
First I would like to review what off-label prescribing means. Most Canadians would be shocked to learn that a high percentage of the drugs being prescribed by their doctors have not been tested or approved for the use for which they are being prescribed, or have not been tested or approved for the group for which they are being prescribed.
Off-label prescribing is, as you know, illegal in terms of pharmaceutical companies promoting and marketing off- label uses, but there is a loophole as wide as a barn door, as some critics have said, that allows off-label prescribing to still continue and expand because physicians can prescribe any drug they so choose for any reason whatsoever if they feel it has benefits.
There is a bit of a contradiction here. Companies are not allowed to promote or market the drugs but physicians are allowed to prescribe them. That was caused by the thalidomide crisis because thalidomide was prescribed off-label and, as you know, created international tragedy for children born from mothers who had taken it during pregnancy. After that legislation came in saying that companies could no longer market drugs but that physicians could continue to prescribe them.
Off-label prescribing is very common. One of the problems we have is that we do not know enough about it. We do not track it; we do not understand it. However, the studies that have been done indicate that probably at least one in four and maybe one in five of all drugs are prescribed off-label. If you have a father or a mother in a care home, the likelihood that they will get an off-label antipsychotic is very high. We are looking at 30 per cent to 50 per cent of seniors in homes receiving antipsychotic drugs, which are indicated for schizophrenia or psychosis but are being prescribed because the senior is having trouble sleeping at nine o'clock at night. That is a very common use of off-label prescribing.
For psychiatric drugs we are looking at antipsychotics drugs, and 60 per cent of them are prescribed off-label; for antibiotics, 40 per cent are prescribed off-label; ear, nose and throat drugs, 15 per cent to 20 per cent are prescribed off- label; anticonvulsants, 70 per cent.
If you look at specific drugs within those categories you will find sometimes that 90 per cent or 95 per cent of the drugs are prescribed off-label. A drug like Neurontin, which is prescribed for a wide spectrum of pain for which it has not been approved or tested, is prescribed off-label 98 per cent of the time. Another drug, quinine, which is prescribed for leg camping, is prescribed off-label almost 100 per cent of the time. It is actually a malaria drug.
All well and good you might say, but what if these drugs are not effective? The problem is that most of them are not. The studies that have been done, such as the Canadian study that Ms. Smith referred to, found that across the board 80 per cent of the drugs prescribed off-label have no evidence base. If you look at drugs in particular, you will find that 82 per cent of the antipsychotics have no evidence base. For antibiotics, 95 per cent of those prescribed off-label have no evidence base. It is the same for the other classes of drugs.
We are prescribing drugs off-label that have not been tested and approved and are exposing people to harm and have no benefit. I would say that is a very serious problem.
Why do we have off-label drugs? From the company's point of view, it is a very profitable business. Companies can escape the regulatory process by not having to go through the clinical trial process, which is costly and time consuming. They do not have to seek authorization for the drugs. They can simply promote to doctors and physicians and patient groups.
I said at the beginning that it is illegal to promote drugs off-label, for prescribing drugs to anyone, but that has not stopped the companies from doing it.
I have a study here by Bloomberg Markets, which is certainly not a progressive group. The name of the special investigation is "Big Pharma's Crime Spree." If you look at the penalties that have been levied on drug companies since 1985 for illegally promoting off-label drugs, you will see that the penalties have not stopped them from carrying out this practice. That is also a concern.
I believe in my paper I said that between 2004 and 2008 one of the major drug companies was levied penalties of $2.75 billion. That represented 1 per cent of their profits during that time period. The penalties are not working and off-label drugs are being actively promoted to doctors by means of giving out free samples; face-to-face conversations; educational seminars; and also to patient groups and disease groups. The drug companies actively encourage patient groups to ask for, to demand, off-label drugs.
What do we do about this because this is causing harm? One of my greatest concerns is the degree to which off-label prescribing of psychiatric drugs is happening in terms of young people. This has increased absolutely exponentially over the last 10 years. We are finding in Canada that the off-label prescribing of antipsychotics, which are very potent drugs, which are blockbuster drugs and one of the biggest sellers of pharmaceuticals, as well as antidepressants and anticonvulsants, none of which have been tested on young people, are being given to children as young as age 3, 4 and 5. This is a national scandal and I am afraid of the kind of future we are reaping for these children who have been exposed to these drugs.
The other group I mentioned was the frail elderly, who are being overprescribed off-label drugs, as well as all the harms that accrue to people who are receiving drugs that may be harmful and are receiving no benefit.
I concur with many of Ms. Smith's recommendations, but one of the key recommendations that I am bringing this morning is that there should be an informed consent process if people are being prescribed an off-label drug. That is, a patient should be informed that the drug is off-label, it has not been tested or approved and the doctor should explain the potential benefits and why he or she has reached this conclusion. To do that properly, the physician himself or herself must understand they are prescribing off-label. Many times physicians themselves do not know they are prescribing off-label. There needs to be sources of information through the product monograph provided through Health Canada where physicians can get this information. We need to do better tracking and monitoring of off-label prescribing.
There is one study that has been conducted in Canada, which is the one that Ms. Smith referred to in Quebec City that looked at off-label prescribing. We need to facilitate studies where we can link up diagnoses with treatment, with indications and also effectiveness. This can be done through some kind of electronic matching of records. Why are we not tracking a process that is going on so extensively? I believe this is a very serious concern.
I think also that companies that are profiting from off-label should be required to go through some kind of formal authorization and testing process. They should be required by Health Canada to seek proper approval for the drugs.
Those are my main recommendations, but I would say that the most important thing here is patient consent. We ask for patient consent when we undergo any kind of surgical procedure and I think it certainly would apply in cases where people may be exposed to harm without their knowledge and without their consent.
The Chair: Thank you very much. I will now open the floor up to my colleagues for questions.
Senator Eggleton: Ms. Currie, picking up on what you talked about, I read a report in the Huffington Post written by Dr. Peter Breggin, who calls himself a reformed psychiatrist. The title of the piece is "Drug Companies Drive the Psychiatric Drugging of Children." This is a United States-oriented document. There is some alarming information in it. It talks about some companies being fined. GlaxoSmithKline agreed to $3 million in criminal and civil fines; Johnson&Johnson was similarly fined $2.2 billion. These are no small fines, but they are probably a drop in the bucket when it comes to the amount of money they make.
According to the Department of Justice in the United States, they have a total of $8.9 billion in criminal and civil fines against GlaxoSmithKline, Pfizer, Eli Lilly, and Johnson&Johnson related to promoting the off-label use of drugs. The article primarily talks about psychiatric cases, antipsychotic drugs, et cetera. They are also concerned about people suffering from ADHD who at young ages are being prescribed drugs. It appears that there have been a lot more studies resulting in much more information coming out of the United States than we have in Canada. You pointed out that you know of only one study here.
You suggested some of the ways to deal with this: informed consent by the prescribing physician, and the patient will have to know; better tracking and more studies here; and requiring the manufacturer to seek proper approval, which is a tough one. I do not sense they are too interested in doing that. The result of that might be that they will withdraw further from the market of that drug for that purpose; but I do not know.
Tell me how some of these other things might work like, such as better tracking or how we might have better cooperation from the manufacturers.
Ms. Currie: Tracking studies depend on having and linking the data between the prescribing of a drug, the diagnosis and the indicators so that we have a better sense of how much off-label prescribing is being done and in what areas it is being done. For example, the Canadian study talks about 11 per cent of all drugs being prescribed off-label, whereas the U.S. study, which is older, talks about 21 per cent. The U.S. study is much closer to the truth because the Canadian study did not deal with children who were being prescribed off-label, and that is having a big effect.
We need to facilitate studies by creating conditions so that these records can be linked, which is not that hard to do. It is a case of having the will and the push by organizations like DSEN or CIHR to demand some of this data. We need to know what is going on. This would inform all of us of the critical nature of this. If you ask people about off-label prescribing, most will say, "What is it?" The level of consumer understanding of this is almost nil.
In terms of compliance by drug companies, I agree that it is problematic for them. After all, this is something that has dropped in their laps, and they do not want to go after authorization and go through those proper procedures. There should be some kind of system where that is required. It is a problem when drugs go off-patent because they are generic and who will shepherd that process? The U.S. is looking at this now. There has been a very weak effort at compliance. If you look at the rising rates of penalties against drug companies, you will see that shareholders do not mind them a bit. In fact, share prices go up.
I will say something kind of scandalous. A colleague said to me the other day, "It is only when drug company manufacturer executives come out of their buildings accompanied by the police that some people might pay attention to this." They are in non-compliance. This is an illegal practice. It is a dangerous practice. People have died because of it. The fines are not doing much good. I am not the only one who says that. The Bloomberg report says that the penalties have to be ramped up; and I think they will be. We see the ineffectiveness of monetary penalties, which are seen as simply the cost of doing business. If you can make $36 billion on a drug being prescribed off-label, why would you care about a penalty of $1 billion? It seems like a lot of money. We hear about $400 million or $600 million, and it seems like a lot of money, but do not forget that psychiatric drugs are always the first or second most prescribed and most profitable drugs. That is why it is important to talk about them. You have to make the penalties count before there will be compliance.
Senator Eggleton: Companies that have paid $8.9 billion in criminal and civil fines are the cream of the crop of companies. This is in the United States, but do we know of any fines that have been levied in Canada? Have there ever been any prosecutions here?
Ms. Currie: No, I have never heard of any.
Senator Eggleton: Yet, these are the same companies that market the same drugs here.
Ms. Currie: Absolutely.
Another drug that is not psychiatric is domperidone. It was used as an anti-nausea drug. This drug was banned in the United States because it causes cardiac arrest — death; and cardiac rhythm problems with people who have long QT syndrome, which Terence Young's daughter died of. Most people do not know they have this. It is a very serious drug and is banned in the United States. In Canada, it is being prescribed off-label to breast-feeding mothers. This drug passes through the mother to the baby. It is banned because of its serious side effects and it passes to the baby. We do not even know if this will cause heart problems for the baby. Because off-label does not exist, we are not doing studies on it. What is the effect of domperidone on women? What are the risks? Is it explained to a new mother that she is taking a drug that is actually banned in the United States? Is it explained to her that she is taking a drug that has never been tested in terms of its safety for the purpose she is using and that it may be transmitted to her child?
One of the big problems is that we have turned a blind eye to off-label prescribing. This is a good example of where we need the information on how much it is being prescribed, at what dose, and whether people are being informed. To my knowledge, this reflects a big difference between Canada and the United States. The fact that we have not been assertive with drug companies is a concern. We are not seeing that in Canada.
Senator Eggleton: Let me turn for a quick question to Ms. Smith on the Orphan Drug Framework, which the minister announced last fall at about the time that this committee was recommending it, I might add.
Ms. Smith: Great; thank you. I am happy to hear that.
Senator Eggleton: Whether it does all that we want it to do is another thing. You talked in your presentation about new indications without requiring randomized control trials. If not randomized control trials, then what would there be? You then said that the U.S. is considering a provision that will allow manufacturers to market an off-label use pending approval of an off-label application. I do not know whether that will apply here if they do not want to make an application. Would you expand on those two comments?
Ms. Smith: The problem with rare diseases is that often we cannot get a manufacturer to do a randomized controlled trial. The first example I gave was Prader-Willi syndrome. We cannot get the drug approved for them off-label because there is no one who will do a randomized, controlled trial. We would like to have in our regulatory framework a provision whereby new indications do not require a randomized controlled trial.
We will not serve the needs of patients with rare diseases if we do not have that kind of provision in the regulatory framework. They will not have access to off-label drugs, unfortunately, which are saving the lives of some people with rare conditions who cannot get any relief from any other kind of drug and they need new therapies.
Senator Eggleton: If you are adding a new indication, what kind of process does Health Canada take it through?
Ms. Smith: That is it. We do not have a process. That is why we are worried.
I want to take up what Ms. Currie was saying about informed consent. In the rare disease community, patients are very informed. When you have a rare disease, you have to work very closely with a doctor. In my personal case, it was four years before I was diagnosed. You have to become a mini-advocate if you are going to get anywhere. Informed consent for rare disease people and working with the doctors is very important in the rare disease community; and that is exactly what she was saying. We may not be aware of what is off-label, and we do not have information on how it is being used; and that puts the physician and the patient at a very big risk. Patient advocacy in rare diseases is essential for survival for these people.
Senator Munson: I might have an outrageous thought about the scary dollar figures you give us and the picture of drug company executives being led out of their offices by the police. Would you favour this government legislating off- label use as perhaps illegal?
Ms. Currie: There is a restricted benefit for certain off-label prescribing, and it may be in diseases where there are serious health consequences and where there is no effective treatment. However, that is not what most off-label prescribing addresses. Most off-label prescribing addresses the broad range of diseases where there is no evidence base of the success. To close the door on off-label prescribing — to slam the door on that completely — would be a mistake. However, I still think that with these provisos it needs to be regulated; that companies should seek approval for off- label uses; that there should be informed consent; and that we need to know the true extent of it. Think this would go a long way to creating a more controlled environment.
There is a process for approving new indications of drugs. Drug companies can apply to Health Canada to approve new indications. This is sometimes a lengthy process, but we also have provisions for drug companies to do new testing of drugs for new indications. Unfortunately, drug companies do not always follow through with those commitments. When they go back to Health Canada with a request to add a new indication to the product label, such as the drug can be prescribed for an additional purpose, Health Canada will not release the information that tells the public whether that indication has been approved or not approved. Therefore, we do not know that history. There is a process in place, but I do not think we are using it in a robust way. Off-label prescribing may have a place.
In the early days of AIDS, there were concerns because people were saying their lives were at stake and they had nothing to lose. We were making certain presumptions about drugs and accepting the treatment until it became more rational. Many people suffered serious side effects, such as heart attacks and cancers from those drugs. I would say that even in those cases, caution needs to be exercised. Off-label prescribing is really like the Wild West because it is the most uncontrolled environment. We are saying, "Let us start with understanding and controlling it to some degree because right now it is uncontrolled."
I want to comment about Canada again. Most of the information we have about promotion of off-label and marketing comes from the United States from whistle-blower testimony. As you know, in the United States whistle- blowers are protected and can get part of the monetary settlement with the drug companies. Most of the information we have about promotion comes from whistle-blowers. It is all underground, so that is in part why we are not dealing with it. It is almost like an underground economy and could be described as that.
Senator Munson: You mentioned the one and only study, which was in Quebec City. Was that last year? I would like to know who sponsored it, what the results were and whether it got much play anywhere, particularly in the pharmaceutical industry and for those who were taking these off-label drugs. What was the final analysis?
Ms. Currie: It was sponsored by McGill University, and I have a copy of it here. It was in 2012 in Quebec City and the study was published in the Archives of Internal Medicine.
The Chair: If I may interrupt, we have had that evidence.
Ms. Currie: Perfect.
Senator Munson: I am sorry, but I was not here then.
The Chair: I want to raise one important issue. You have twice said that there was no evidence base. In fact, I think they say that there is no strong scientific evidence.
Ms. Currie: Yes, that is right.
The Chair: In the article, they describe what they mean by "strong scientific evidence," and in fairness for the record, you would agree.
Ms. Currie: Yes, without a strong evidence base. The criteria that they use are good. They use a number of indicators. It would be hard for them to say "no evidence base." It is a very limited evidence base in terms of what the drug has been approved and tested for. That is a fair statement.
The Chair: I was referring to what the article says.
Ms. Currie: That is a fair statement.
The Chair: Not going into your interpretation, I am saying that you are giving evidence here, just to put it into context. Thank you.
Senator Munson: As Senator Eggleton said, in October 2012 the government announced this Orphan Drug Regulatory Framework for regulations to improve access to new medicines for rare and neglected diseases. Ms. Smith, can you talk a bit about the Orphan Drug Act and how that works in the United States? Would an act along that line be beneficial to Canadians?
Ms. Smith: Right. The Orphan Drug Act came to be about 30 years ago in the United States. I believe it was in 1982, but I do not have the exact year. The European Union added theirs about 10 to 15 years ago. Canada is the only developed country that does not have an orphan drug act or a definition for "rare diseases." You said that you recommended a framework, so I will not go over all the statistics because you probably know all of them on that.
The Orphan Drug Act provides incentives for developing drugs for rare diseases. It provides a different path for the approval of rare disease drugs. It takes into consideration all of the special needs of drugs that are to be developed for rare diseases. You may not be able to do a clinical trial with two million people if you have a condition such as mine, which affects five people in a million. Given that, Canada has access to only 50 per cent of the drugs that they have approved in the United States and in Europe. Canada, because we do not have a policy, does not encourage companies to come here to do research and develop drugs. We do not have any incentives and make it very difficult for drugs to come through the system.
Senator Munson: How would this kind of act in Canada work with our study?
Ms. Smith: Given that we are last to the table with our Orphan Drug Framework, we can take all of the best practices that have been incorporated over the last 30 years and incorporate them into our framework and off-label use. Regulations about off-label use could be part of that framework. As I said, we have no information on the safety, risks and benefits. It is time, now that we are developing this policy, to include off-label use in our rare disease policies so we can get monitoring of adverse effects and all of the concerns that Ms. Currie has raised.
For rare diseases, we tend to look everywhere. With the nature of our illnesses, we look to Europe and the United States and all the different models. We are looking at what is happening, for example, in Britain, where they have said that they will provide information for physicians and patients. They are going to do this. They call it a common sense approach. It is ridiculous that we do not know how these drugs are being used. If we look at what is happening internationally in the FDA and everything else, we are hoping that with the framework we will incorporate off-label use because in rare diseases it is not rare. It is not the exception. It seems to be almost the rule.
Senator Eaton: I have to say that I walk today because I used an off-label drug, so I see the good points to it. Should it be something as simple as asking doctors? For instance, when the doctor prescribed this off-label drug to me on the recommendation of my neighbour, should he have been obliged to report that to the drug company, saying "I have prescribed this to Mrs. X for X reasons," and then perhaps as a follow-up two weeks later write that it is working well or it is not working well? Could we start by doing something like that, which would provide the drug companies with some idea how this thing is being prescribed and what its uses are?
Ms. Currie: I do not think there is any system right now for drug companies to deal with that data, but if it was on your medical record that this was prescribed, that it was off-label and that it was prescribed for this indication, then we would have a way of tracking the degree to which off-label is being prescribed. The system of reporting adverse drug reactions is a totally different system. In other words, yes, in that case reporting an adverse drug reaction to Health Canada or to the company would be recorded.
Now, the question is how do we link all that data?
Senator Eaton: However, when doctors prescribe an off-label drug, should we recommend that they have to report it to the drug company? For example, "I prescribed Janet Currie today with X for X?"
Ms. Currie: First of all, most doctors do not know they are prescribing an off-label drug, so you would have to build the capacity of doctors to understand that, which is a very big job.
I actually do not know if the doctors would do that. There is no process in place and I am not sure what benefit it would produce.
Senator Eaton: It might start creating a data field where X is being prescribed for X and it is working. It might give them some idea of the other uses of the drug, especially when dealing with rare diseases.
Ms. Currie: I do not know if that is the best way of doing it. I still think that a more systematic approach to effectiveness might be the way. That is more of an anecdotal report. I am not saying it is a bad thing, but I think a more systematic approach to looking at efficacy of drug would be my recommendation. Through a proper clinical trial or some kind of modification of a clinical trial process where you are actually comparing it with a placebo or other treatments, tracking people and monitoring is the best approach.
Physicians do not report adverse drug reactions very highly and I am not sure whether they would be willing to do that, considering the level of reporting that they now do for adverse drug reactions. I am concerned that if we have that kind of data it should be managed by Health Canada, which does not have a stake or vested interest in whether the drug is successful.
Senator Eaton: However, the drug companies do.
Ms. Currie: That is the problem, because you want more of an objective body that would determine is this effective, is it safe. The drug companies themselves have a conflict of interest because they are selling the drug. It is a difficult —
Senator Eaton: Not if they could use the drug for more than one use. I guess that is what I am getting at. There does not seem to be enough pooling of information about how drug X might only help you and I, but if nobody reports that I gave it to you and to me and that it has worked, then how do they ever find out? It continues to be off-label.
The Chair: You are right, that is the issue and I think Ms. Currie has given a very positive direction to it. If it goes to the individual drug company there will be no dissemination of the information; it is not required. What we are exploring here is the body. I think she is quite correct, and you are correct, in terms of what is needed. However, I think she is making the very important point that it needs to go into a central system. The question that we have been asking at every one of our meeting is: What is a central collection way to do it?
Senator Eaton: I guess I disagree with you.
The Chair: The drug company will not use it in the way you are suggesting.
Senator Eaton: I think the drug companies have an incentive to market a drug to a wider audience.
Ms. Smith: Can I chime in on that one?
The Chair: Certainly.
Ms. Smith: I agree with Ms. Currie that we want a third party to do it, like they are doing in the U.K. NICE has set up a system where they are going to collect data and they will disseminate that to physicians and patients. It is very important that patients will be aware of that for the negative side — the adverse effects. When I look at the rare disease community for the positive benefits, if this drug is saving lives of people and no one is aware of it, that is a horrible thing. We are looking to either CADTH or Health Canada for that to be part of their mandate to get that information and make it available to patients.
The Chair: An additional issue is that a significant amount of the off-label is dealing with drugs that are off-patent, so there is absolutely zero incentive to a company to do the work required to get approval for the additional indication in those cases.
The question you raise is the essence of what we are dealing with here today. The question is how to get that information collected and in a body that will actually benefit from everything from the research community to the patients. That question is the key one, and I think your answers have been very helpful.
Senator Martin: Ms. Currie, you say that in essence the prescribing of off-label drugs is an underground economy. We met with the industry yesterday and we have heard from health professionals. We are hearing from you, the advocacy groups. Of course, there is the responsibility of the patients themselves to be informed, and often it is the patient who is the most informed. However, we have also heard that in order to address the problem of widespread off- label drug usage, the experts need to be well informed and have this information in their hands at the time of prescribing the drug.
I do not want to point the finger at my colleague that the physicians, the health professionals who are doing the prescribing and asking patients to report on adverse effects, is one perspective, but they are the ones suffering, and they are not medically trained to necessarily decipher or analyze that information. I want to squarely put the light on the physicians or the prescribers themselves and find out from your perspective, as advocates, what we can do to encourage or obligate the professionals to do their job even better than they are doing. They are doing their jobs, but as a former teacher, I would not ask my students to report on something when, as a professional, I would be the one responsible to ultimately look at the full scope of their education.
In terms of health care, I feel that in collecting data — and the fact that it is illegal for companies to promote and yet doctors prescribe them — they may not even be informed or be aware that it is an off-label use.
The question is how do we inform them? We have heard some of the solutions. However, I feel that responsibility should not be squarely on the physicians themselves but those doing the prescribing. How do they become more well- informed? What systems do we have to encourage greater professional development, for instance? If they are the ones responsible for prescribing, are they not also responsible for a lot of the post-care, the follow-up as well? I am looking at this metaphor of the underground economy, and the people doing the prescribing to me are very important in the solution for this growing issue.
Ms. Currie: I am very glad you raised that point, because I think you are absolutely right, and it is a complex issue. You mentioned whether off-label prescribing should be banned. Where I think we should ban, or exercise more control, is marketing to physicians. This is where a lot of physicians receive their information about drugs and where off-label use is promoted. One aspect of educating physicians is removing drug company influence from marketing off- label prescribing. You really have to start there.
You have to develop and implement more academic detailing programs, which I am sure you have discussed in this committee, where the people who are providing information to doctors are doing it on the basis of a strong evidence base and are doing it without conflict of interest. I agree with you that doctors need to be held responsible for off-label prescribing. Some of the studies I have read from the States say that doctors themselves should be prosecuted if they are high prescribers of off-label drugs that have no strong evidence base. I do not think we have reached that point, but one of the drug companies' strategies is to go into medical record systems and find out the doctors that do prescribe and are high prescribers of off-label drugs. They target promotion to those doctors. Some of those doctors, I think, need to be held accountable through some kind of legislation, through their medical associations, because the drug companies are certainly targeting them.
Finally, I think we need to have a system where doctors become educated and educate themselves about whether a drug is being prescribed off-label and the potential risks and harms of doing that. It is very difficult or doctors do not seem to know that. If you are prescribed a drug, you can go on the Internet and find the drug monograph that provides all the indication, all the contraindications and all the risks. This is sometimes complicated for doctors to do, especially if they are receiving most of their information from drug detailers. There needs to be a simpler way for doctors to become informed and take responsibility for that prescribing habit. I am feeling that if a consent process was in place, this would result in two things: Patients would become more informed, which is part of what you are talking about; and doctors would have to become more informed. It kills two birds with one stone. It is one thing that we could do.
I have had minor surgical procedures; I am sure most of us have, or major ones. We always sign that consent form. Why is it different in this case? The harms can be equally as bad. I think if we started doing that, doctors would take more responsibility. I would say that high prescribing of off-label needs to be dealt with in a more assertive way.
Senator Martin: For this informed consent process, has a body or a working group has put forward a template or a process that potentially could be applied?
Ms. Currie: I included in my report some documentation from an ethics study in the United States that talked about the questions that would be involved in an informed consent process. Who would manage it? I think there would have to be some kind of collaboration between the provincial health authorities and Health Canada and physicians groups. Hopefully even the pharmaceutical companies would be onside with it. We do implement informed consent when there are surgical procedures. If you are going to a day clinic or to a hospital, you will have that form handed to you on a clipboard. Even though it seems like a daunting process, I think with collaboration and with the will to do so, we definitely could do it. I actually think the Canadian public, if they realized the extent of this, the potential harms and the lack of a strong evidence base for most of the drugs, would be all for it.
It is not just disease potential or risks. If you think that 40 per cent of antibiotics are prescribed off-label, which I think that is conservative, and over 90 per cent have no strong evidence base — and I appreciate you pointing out my wording — these are antibiotics that are being prescribed that have no strong evidence base for reasons for which they are not tested and yet are contributing to antibiotic resistance in our society. We are facing a very serious problem with antibiotic resistance so that when we take antibiotics we will not respond to them. Inappropriate off-label prescribing is contributing to this problem. I think there are many other costs of off-label prescribing that we could discuss.
Senator Martin: I agree.
Ms. Smith, you said in your presentation that there is a manufacturer's compassionate access program.
Ms. Smith: Right. Most manufacturers have some kind of compassionate program. I gave the example to show the disparity across the country.
For the same condition, Prader-Willi Syndrome, four children have different stories. Some get the drug, which is puts them in the fiftieth percentile for cognitive functioning and stature; some do not get the drug. They get it through different means. It is like a patchwork. That is one of the things that we hope the regulatory drug framework will address, namely that your postal code should not dictate which drugs you have access to. When it is off-label, it causes more problems because off-label drugs are harder to get paid for by the provincial drug plans.
Could I just talk about what you said about the physicians' education?
Senator Martin: Yes.
Ms. Smith: That is a great question for rare diseases. I am sure you all have in your circle of families and friends people with rare diseases who took 10 or 15 years to get diagnosed and went to many doctors. Physician education is one of the most important things that we do in the rare disease community, and physician education about off-label drugs is a huge problem. Often people are not getting the treatment that they could possibly get, or they are getting the wrong treatment. Developing expert assessments that we could give to the doctors is important. As you said, if there are no incentives, doctors will not report back on the effects of the drug; there are too many other things to do and there are no formal programs to report to. It is all observational data.
We strongly would like to see some kind of formal monitoring by a third-party group, such as Health Canada. That would give us access to what is out there, to what is being used off-label and to what are the results. Many rare diseases are life-threatening and this could save someone's life. Physician education is a big issue for us.
The Chair: Before I move on, Ms. Currie, with regard to your comment about the antibiotics, our next phase is about unintended consequences, which this particular example you gave of the antibiotics falls into clearly. We will be looking at those issues as a clear focus of the next phase of our study.
Senator Seidman: Ms. Smith, you made several important points in your presentation to us. Senator Eggleton asked you about one of them and I would like to explore it a little more. It has to do with the Orphan Drug Regulatory Framework announced last October. You said that it provides for a review of new drugs but does not address off-label use of old drugs. You make a very important point in talking about the rare diseases and how they are treated. First, you said that 80 per cent of the prescriptions for rare diseases are off-label. In order to treat rare diseases, clearly we need to use off-label forms of treatment. You make that point well. You also say that very often it is the use of old drugs, not new drugs. How do we approach this if the current system, this Orphan Drug Regulatory Framework, is only addressing new drugs, not old drugs? Old drugs are important; they are used often.
One of the suggestions that has been made here — and I would like to know what you think about it — is a progressive licensing that allows for labelling changes throughout the product lifecycle based on emerging evidence. Could you please give me some of your ideas on that as an approach?
Ms. Smith: The FDA is looking at that now with their reform of the off-label use of drugs. The policy they are looking at would give manufacturers the right to share evidence on off-label use. They will allow manufacturers to apply for approval of off-label use through a new drug application, while allowing them to market the off-label use. That is the reform they are looking at in the United States. That is a progressive step forward in that framework.
For our regulatory framework, we do not have anything yet. We only have promises that we will get it. In the promise is a new system to look at clinical trials for the approval of rare disease. There is never any mention of off- label. That is why we are saying if we could tack that on to the regulatory framework, given that so many of our drugs are used off-label, that it would help all Canadians with rare diseases.
Senator Seidman: Potentially that is the Orphan Drug Regulatory Framework already in existence?
Ms. Smith: No, we do not have it yet.
Senator Seidman: Sorry, it was announced; excuse me.
Ms. Smith: That is right. They are working on it as we speak.
Senator Seidman: Supposedly it could address off-label use.
Ms. Smith: It could.
Senator Seidman: Would be the case for not only new drugs but old drugs as well, for example?
Ms. Smith: Yes. We are suggesting that because we are last to the table with the framework that we should be including this because this is up and coming and what other countries are doing, and internationally it is a huge issue. Because of the changes in rare disease drugs, with all the genetic advancement, looking back at old drugs and repurposing them, it seems if we are to do a framework now we should get it correct right off the bat and be leaders in this area rather than lag behind. Canada has the potential to do really well and to do the right thing and to lead. I know that the people at Health Canada working on this policy are working internationally all the time. They are constantly looking to see what other countries are doing.
For us, it is very important that off-label use is included in the framework, and progressive licensing is definitely something we would support.
Ms. Currie: May I comment a bit about progressive licensing because certainly Health Canada has the stated objective of introducing progressive licensing? I was involved in the modernization of the regulations hearing which dealt with that.
It is not specifically oriented to off-label, but the theory is that pre-approval could be given on the basis of the pharmaceutical company committing to doing safety studies. I think a similar regime could be put in place whereby the company seeks approval for major changes to the product label. For example, it has prescribed a drug off-label or there are many prescriptions in that area and they want to have it as an approved indicator. They could also get some kind of approval on the basis of committing to doing safety studies.
The problem, even in progressive licensing if you look at the FDA, is the compliance with safety studies is not high. Health Canada does not have either the will or the mandate to insist, as of yet, on companies complying with safety studies. In other words, the approval would be given for a drug that is not necessarily off-label and the company is supposed to commit to doing a safety study within a period of time; they do not do it or they do not do it adequately. If you are to have a successful progressive licensing system, whether or not or for off-label use, you do need a robust compliance mechanism to ensure that the company lives up to its commitment. Otherwise they will not do the study and we will be no further ahead.
Senator Seidman: Because it is based on emerging evidence, what would you consider? Ms. Smith, you talked about not requiring randomized trials, for example. Especially if it is old drugs, it may be that randomized control trials will not be done for all kinds of reasons we could easily think about. What kind of evidence would be acceptable?
Ms. Smith: If you look at the Prader-Willi Syndrome, synthetic growth hormone has been on the market not so long but growth hormone has been on the market since the 1960s. It has been proven to work; there is no doubt about that. For Prader-Willi Syndrome where they have the short stature, there are not enough patients. Because it has been approved in the U.S. and in Europe, no one will come here and run a randomized clinical trial. They just will not do it, so our patients are not getting it. Some are getting it; some are not getting it. It is inconsistent. That is very common with rare diseases.
What do they use? They use observational data. The people who have gotten it, we know that Jonathan is in the fiftieth percentile for height and cognitive functioning while the child not getting it is in the tenth percentile. They get that data because doctors are collaborating. That goes back to physician education. Some doctors are collaborating, but maybe there is a strong patient advocacy group for Prader-Willi and they are getting all their data together and are forcing the doctors to talk to each other and gather all that information, but that is hit or miss. Maybe you have another disease where they do not have a patient advocacy group, and so how will they get that information? It is observational.
Senator Seth: I know that 90 per cent of rare disease patients are being treated off-label. In your experience, you have stated that when rare diseases are treated patients are well informed. I understand that. Is that correct?
Ms. Smith: Most, not all, but I would say it is more common.
Senator Seth: In practice, if a physician writes a prescription for off-label medication, they have to discuss it first with the patient and then write in their file to tell the patient they are writing and that the patient is giving permission to prescribe the drug to them, because physicians can never give a prescription unless they get that permission from the patient.
Ms. Smith: However, there is no official consent form.
Senator Seth: Yes, but we protect. I am coming to that. We are regulated through the college. We have continuing education medical seminars and a certain number of hours to finish before we can be allowed in hospitals or open a private practice. Every five years our practices are audited as to whether or not we are capable. That is what we do for off-label prescriptions. If any new medication or disease comes to our attention, we have seminars. Often we have to go through them because as a physician our education never finishes. We continue to learn because every day something changes and we are well informed.
I think a consent form, as you suggested, would be a great idea. If there is a regulatory framework, it will improve our efficiency. Yes, there will be more paperwork, but never mind, we care about the patient. As you can see statistically, our health system is the best system in the world. There is nothing we are not doing well.
I know we are sitting here to improve our system and make it better. That is why we are sitting here, and I certainly agree with that. However, to say our patients are dying or there is negligence, then we could not practice. We are very careful. Health professionals are careful in this country and they need to be well informed and have knowledge before we can go further.
The Chair: We can discuss this in committee later. Senator Seth, do you have a question for our witnesses?
Senator Seth: I had to say that because people get the wrong information.
The Chair: Do you have a question for the witnesses?
Senator Seth: Yes, I have more questions.
This is well informed, because not everyone knows that.
The Chair: Do you have a question for the witness, please?
Senator Seth: Thank you.
Psychotic drugs are often linked to the increase of tendencies in young adults and children. Would you say this is somehow linked to the off-label prescription of these drugs?
Ms. Currie: Was your question about psychiatric drugs?
Senator Seth: Yes.
Ms. Currie: Yes, I would say so. The overprescribing of antipsychotics, antidepressants, mood stabilizers and anti- seizure drugs has a strong profile of adverse drug reactions. They cause akathisia and agitated depression.
Senator Munson: What is akathisia?
Ms. Currie: It is a physical sensation in the body of having a motor running inside. It is extreme agitation. It often leads to suicidal ideation or suicidal attempts.
The overprescribing of ADHD drugs, amphetamines and a potent mix of psychiatric drugs has caused a profile of drug reactions that has contributed to high levels of anxiety and psychotic episodes. There are many factors, so I do not want to simplify the prescribing of potent drugs and often multiple drugs. Research has been conducted at the University of British Columbia where they have seen over the last ten years a ten-fold increase and younger and younger children with the profile of side effects. Certainly, this is a contributing factor to a range of the psychiatric problems that young people experience.
If you look at data on children in care, you will find that it is often our most vulnerable children who are getting most of the drugs. B.C. did a study on children in care, in group homes and in foster care. Children who have had a rough ride are among the most likely to be prescribed these drugs. It can be a vicious circle.
Senator Seth: Prescribing drugs for patients with rare diseases often is difficult and must be done with great care. What guidance does your organization provide to members with regard to off-label drugs?
Ms. Currie: Ms. Smith and I agree that we would like to see a stronger evidence base. We would like to see better tracking and more research to find out what exactly is happening. We feel that all patients, whether rare disease, deserve to know that a drug is being prescribed off-label. They need to know what evidence base exists and that drug companies need to do proper testing.
I disagree with Ms. Smith in that I do not think observational data are sufficient. However, I understand why people would make that choice if they feel they have no other option. Ms. Smith is the best person to discuss rare diseases, but I want to stress most strongly that most off-label prescribing is not done for rare diseases. Rare diseases are rare. Most off-label prescribing is done for the whole range of other kinds of diseases. This is almost a special case and has to be considered so.
Ms. Smith: That is why we would like to have a regulatory framework. I have to go back to that. We are so excited about it. We have waited 30 years for this, and off-label use could be included in the regulatory framework. As Ms. Currie said, in rare diseases it is very common and often it is the last course of action because nothing else is available. There is no other treatment, and patients want to live. They want to have a quality of life and will assume bigger risks quite often when the stakes are higher.
I hear everything that she is saying. My mother had dementia, was in a home and was prescribed antipsychotics; so I understand where the psychiatric community is coming from. Rare diseases have special needs and we need special policies that will not deny Canadians a treatment that could save their lives because other drugs are used off-label in the wrong way.
Senator Cordy: You both have been excellent witnesses; thank you very much.
Ms. Currie, in your summary of main points you said that in 80 per cent of the cases there is no strong evidence base for drugs prescribed off-label, and psychiatric drugs are routinely prescribed off-label. You said that in over 90 per cent of cases, they have no proven benefits. That is startling. With any drug, whether helpful on-label or off-label, there are risks and benefits. If it has no benefit and we know it also has risks, we are providing a risk to the patient and an economic cost to the system, to be crass about it. You talked also about children in care, where the off-label usage is extremely high. We seem to be focusing on the most vulnerable people in our population. You both talked about the need for an evidence base. There clearly seem to be cases where what we are doing to the most vulnerable is almost criminal. Could you expand on that?
Ms. Currie: If you think of young people being major recipients of off-label prescribing promoted by drug companies as a matter of fact, then yes, you could consider them to be most vulnerable, as well as the frail elderly or the elderly with dementia or living in care homes. We are seeing huge rates of off-label prescribing and yes, we are exposing people to risk with drugs that have not been tested and approved and where there is no strong evidence base. We are exposing people to harm; and that is very serious.
I also want to say that we are actually exposing the public to costs. Zyprexa is a good example because it was actively promoted by the drug companies for use by Medicaid in the United States. Medicaid bought more antipsychotics than any other drug, and that is not a small prescribed group. It is huge in Canada as well. This was lobbied for by the drug companies. Medicaid entered into bargains with the drug companies to prescribe Zyprexa, Seroquel and Risperdal quite a lot. They then found that one of the side effects of antipsychotics is weight gain and irreversible diabetes. They also cause strokes and fatalities among dementia patients. The initial problem was diabetes. I have talked to people in B.C. who run programs for youth. Vulnerable kids with troubles were given anti-psychotics. The workers at the group home had no experience with drugs and noticed that all the kids were developing diabetes; and they started to keep track of it on their own. They found that 10 per cent of their caseload of kids was being diagnosed with irreversible diabetes. The United States participated in the lawsuits against the drug companies and Medicaid. They said, "You illegally promoted this drug and did not talk about the side effects. Now we have people in our system that have diabetes and will require a lifetime of care." That is why they took these companies to court.
We are not only creating risks for patients but also costs for ourselves.
I want to say to Ms. Smith, who is in a very tough spot, that drug companies exploit the desperation of people with rare diseases. I think they actually exploit the desperation of people for whom there is no treatment and will actively market to disease groups so that the patients can be on the front line for demanding certain drugs. I am sure Ms. Smith feels the same way. Even a person with a rare disease who feels that they do not have alternatives has the right to assess a drug and its safety implications and to know that sometimes the safety implications may not be apparent. I have talked to AIDS patients who have said, "Yes, I accepted early treatment because I felt I did not have a choice. In retrospect, I wish I had not done that because I had a heart attack or cancer. I wish I had waited." Ms. Smith's clientele are people who need to assess risks. Sometimes risks are not apparent right away. They may take a decade to turn up or in some cases it may take the next generation. It is a big problem, but I am concerned. Sometimes I feel that drug companies exploit the hopelessness and desperation of people who do not feel they have an alternative.
Ms. Smith: I would disagree with that. I think that you see people in the media who are asking for medication and are actively seeking treatment, but without drug companies making the drugs that save lives I know I would not be sitting here personally. I take life sustaining medication. I would not be here.
I just did a huge promotional video for Rx&D to promote medical research in Canada. It was a bunch of TV commercials and print ads. I am basically telling my story, which is quite complex; I will not get into it. It is about how drugs have given me the life I have now. About 15 years ago I was using a walker and lay in bed. I have heard from some people that, "The drug companies are using you." I do not feel that because if I do not get out there and promote research and development, it will not happen. They need to see some of the good stories, too, not just the tragedies or people being led away to jail. There are a lot of good things happening, too. I do not share that opinion, but I do share the vulnerability of people with rare disorders and the fact that they are entitled to information and should be able to make a judgment based on good evidence. We need to provide that to them because it is very important.
Senator Cordy: Most people believe — and I among them — that when you are prescribed a drug, it is being prescribed for exactly what you have. Fortunately I have not had that many prescriptions, but I have never asked a doctor if it was off-label. I have never asked a pharmacist if it was off-label. I am not sure the pharmacist would know unless I explained what was wrong with me.
I think your answers have certainly described the conundrum that we are in as a committee. My question is: What should the role of Health Canada be? What could we do? We talk about informed patient consent and then we discovered that the doctors do not always do know. You referenced Terence Young's case. If you read that book, it is heart-wrenching. However, it is also unbelievable that that situation could happen here in Canada and neither they nor the doctor would be aware that the information was available in the United States and it was not available to the family in this case.
Where should we start? What should this committee recommend that Health Canada do? What should the role be? You both talked about the collection of data and the need for informed consent, which would require the data and the information that we do not have. We do not even know how many drugs are prescribed off-label. We do not know the risks and benefits. We hear in psychiatric drugs that in 90 per cent of the cases there is no benefit, but we know that there would be risks. Do we need clinical trials for these off-label uses? Where should we start? What should we recommend as a committee?
Ms. Currie: I made a series of recommendations.
Senator Cordy: Yes you did. They were excellent.
Ms. Currie: I think Health Canada must have a more robust role in all these areas.
Our funding agencies, such as CIHR, and our drug safety agencies such as DSEN and Health Canada need to take a stronger role in monitoring the use of off-label supporting research. I am not saying that we can undertake a massive review, but even replicating small studies such as the one done in Quebec — including children, which his study did not — would be helpful in understanding the degree to which off-label prescribing is done.
We know from research that physicians do not always know what off-label prescribing is or whether they are doing it. Working with physician groups and exposing them to the extent and risks of off-label, providing easy to access information on the product monograph so they could identify off-label prescribing, supporting or facilitating a process for off-label prescribing is probably where I would start.
In terms of helping Canadians become more informed, it is also a question of literacy around prescription drugs. We are really building an understanding of a culture of safety here. We have it for the nuclear industry and the aviation industry; we do not have it for prescription drugs yet, but we are trying to build that. I think that Health Canada, in its regulatory modernization capacity, has to develop more robust standards for companies seeking to add indications to its product label through testing, retesting and authorization. The bones of the structure are there, but there must be more rigorous enforcement of compliance of drug companies doing the safety studies. That is not happening right now.
If I had one recommendation, it is that Health Canada has to take a more proactive role in tracking, monitoring, understanding, communication and enforcing compliance around off-label. I think that I would like to actually see some evidence in Canada of holding physicians and drug companies to account for off-label prescribing where there are risks.
One of the things that I think this committee is doing is shining a spotlight on off-label prescribing. This will have an enormous impact because we are really starting at a low level of knowledge around the practice, so I think that is a big contribution as well.
Ms. Smith: I agree with almost everything that Ms. Currie has said about what Health Canada needs to do. For CORD, we would like to see an understanding of the special needs of the rare disease community with regard to off- label use of drugs, an understanding that it is not the exception; it is often the rule. It is the last treatment possible. There is nothing else like it; there is no drug for scleroderma. It is all off-label. If they do not use off-label drugs, they get nothing. We would like that understanding built into the Orphan Drug Regulatory Framework. Just as we are showing that clinical trials ought to be looked at differently for rare disease drugs, we like to see them look at off-label use of drugs in the same way, considering this population as special. Given the numbers we have on the amount of off- label use that there is and to monitor it, I absolutely agree that patients need to know it is off-label. We need the data collected and we need it monitored. That is where the rest of the world is going now and we should be on that, too.
Senator Enverga: Thank you for your presentations. This is a follow-up question from those of Senator Cordy and Senator Seth. It is in regard to the psychiatric medication, stimulants, antipsychotics and painkillers.
How can you relate this to drug abuse? About 81 per cent of off-label prescription drugs are for unapproved uses or dosages. How do you relate this to drug abuse? Do you not think the reason it is increasing for those kinds of drugs is that it is drug abuse?
Ms. Currie: Whenever you have overprescribing of drugs that are addictive in nature — which are all the psychiatric drugs and painkillers — you will have an upsurge in illegal drug use. I tend to think they are quite separate. You are talking about people that are getting a drug prescribed by a doctor; they are not illegal street drug users. However, whenever you dump a huge amount of prescriptions on the market — and we are talking about millions — you will have more street use.
Particularly for kids who are taking ADHD drugs, there is now concern that, as they grow older, they are used to a stimulant effect and this might transfer to the use of drugs like cannabis. I have certainly seen that, but I do think the worlds are quite separate, although they interrelate.
Does that answer your question? I am not sure if it does.
Senator Enverga: Yes. My concern is that, with these off-label drugs, we are sort of legalizing drug abuse among people.
Ms. Currie: I do not think the people using the drug would consider it drug abuse. These are legally prescribed drugs. I actually do think it is drug abuse, but I think it is an abusive system because it is not monitored, controlled and regulated.
Another thing that concerns me is that off-label prescribing is basically saying to the drug companies, "You can bypass regulations." I think that is a very dangerous precedent when you state to a huge institution, "Do not worry about the regulations because you can bypass them and profit from them." I think that is a very dangerous precedent for a government and society to support.
Senator Enverga: Is there a way to prevent or to at least minimize this kind of addiction?
Ms. Currie: Again, I think it is partly consent. It comes back to physician awareness and to patient awareness. Most patients do not realize that psychiatric drugs cause tolerance and that they will become tolerant or addicted and will have to withdraw from the drugs. That is a very complicated issue. Most patients are not informed of that, and many doctors do not understand that.
I go back to this question of drug literacy. There is so much we do not know about drugs. I have a friend who is a pharmacist in a hospital. Her grandfather was a pharmacist and her father was a pharmacist. Her grandfather said, "It was written in Latin. No consumer would ask a question about it. It was like a foreign language." Her father did not understand the idea that consumers can come in and ask questions about prescription drugs. We are gradually becoming more informed as a society. Even for the concept of adverse drug reactions, people ask me what that means all the time. Off-label is really a concept that people do not understand, so I think it is a question of basic information.
Senator Enverga: If there are medicines that could be addictive, should they be labelled as such?
Ms. Currie: Yes, and that brings up the question of how much information patients get about a drug when they get their prescription filled. As you know, Health Canada has never passed any law that requires certain information to be given to the consumer. That is certainly something that Health Canada should be doing. When you get that little insert in your box of pills, the drugstore has decided to give you that information, and you are only getting 10 per cent of the side effects in that.
Just as a tip, if you are, or a family member or friend is being prescribed a drug, you can Google the product monograph for that drug. Use the word "product monograph" for Clonazepam, and you will get the company's information about that drug: what it has been approved for, what it should be used for, what the side effects would be, what the possible risks are. It is a pretty good source of information. If you have been prescribed a drug for migraine headaches and you look into the drug and the drug is being used for eczema, then you have an off-label drug. You should be saying, "Is there any evidence that this works?" because it is quite disturbing to see that a drug like Neurontin, which is quite widely prescribed, is 98 per cent prescribed off-label and that 99 per cent of it has no strong evidence base.
Senator Enverga: Thank you.
The Chair: I want to come back to a number of these things. We have had a pretty dismal portrayal of off-label use here today. A very significant amount of prescriptions are off-label, as you both have indicated. I would like to take two examples.
Ms. Smith, you identified the human growth hormone. In actual fact, there are enormous positive benefits of many off-label uses of existing pharmaceuticals. You indicated that it has been used for dwarfism and related issues since the 1960s. Here is a drug that in the 1960s and up to the mid-1980s could only be obtained by extraction from the pituitary gland of human cadavers. It was used to treat a very serious issue, which is dwarfism. Many of you might not know that dwarfism causes very serious problems, including the malformation of limbs and organs, life expectancy of approximately 40 and so on. Yet, if treated with human growth hormone starting roughly six months after birth — it might be different now; I am going back in my knowledge base to when I was aware of this — a child can have a reasonable expectation for a normal life expectancy. In the mid-1980s, we were able to engineer bacteria to produce human growth hormone in the lab and then to scale it up, to produce it free of all of the contaminants that were coming along with the extraction from human cadavers and to make it widely available to people. Here is an example of the enormous benefit of a drug that is essentially used off-label in this regard. However, there are clearly jurisdictions, as Ms. Smith pointed out, that are not making this available in their areas. This is one example of the kind of issue we face in this area.
I want to give you another example. You referred, Ms. Currie, to HIV and some of the sad situations that occurred in the use of drugs. HIV first emerged on a large scale in the early 1980s as well. I should point out that HIV does not kill anyone. It makes you susceptible to opportunistic infections, and other things actually kill you. One of those other things was cytomegalovirus, a virus that exists widely in the population and in hospitals. It is a member of the herpes virus family, and when an individual's immune system is weakened, it emerges and can kill you. If it does not kill you, it can cause a very horrible disease. The drug I invented, Ganciclovir, was the only one in the world that would treat cytomegalovirus, and because of the emerging issue of HIV and the horrible problems of death among the HIV patients in the 1980s, the FDA fast-tracked that drug.
This comes, Ms. Smith, to another issue you identified — humanitarian use of drugs. Essentially, fast-tracking is a humanitarian, deliberate decision to treat a life-threatening or very serious issue with a drug that has not completed all of the clinical trials. It does not have, Ms. Currie, the evidence that you are seeking. In this particular case, it immediately eliminated cytomegalovirus as a problem for HIV patients, and it has been used around the world and now saved probably millions of lives.
The second thing was that transplant patients by the 1980s were not dying from mismatched organs. That had been all worked out before, but cytomegalovirus would emerge because you have to suppress the immune system when you do a transplant. You deliberately suppress the immune system, and you make the individual susceptible to opportunistic infections. Cytomegalovirus would emerge, and patients would sometimes die. It is now used prophylactically to prevent that. I want to use these two examples — human growth hormone and my own experience with a drug — to indicate that while all of the things you indicated, particularly in the psychotic area and other areas, are enormously important and we need to find ways of minimizing the issues that arise there, it is not a totally negative story. In the rare disease area, it is a very important story.
Very clearly the issue here is, on the one hand, the adequate informing of patients and, second, the collection of information that leads to reasonable prescription of off-label uses. In actual fact, when a clinical trial is done, it is done under very controlled conditions. However, once it is approved, it is released into the general population of which there are subsets and sub-subsets in the real experience. Therefore, the real-world prescribing of a legitimate pharmaceutical is an enormous clinical trial for which we are not capturing the information.
I want to put to you some possibilities and see how you might react. I think Ms. Currie already mentioned that patients can go onto the Internet and find a great deal of information on drugs. We know that a lot of that information is getting out there for a number of reasons, including that there are people with certain diseases of which we heard the oncologist talk about. Oncologists are dealing a lot of the time with rare or very small population groups of specific rare cancers. They have a tremendous network of sharing experience and the off-label use of drugs. The Crohn's disease folks, we have heard, have a network that they developed spontaneously through social media in order to connect. Therefore, we know that it is possible to disseminate in today's world information. I recognize that there is an issue of evaluating the information, so take it as understood that I understand the limits here and the concerns that one would have in just the random use of the information you collect in this way.
Let us come now to the prescribing. Today, in 2013, we have electronic capabilities that are phenomenal in terms of the use of information. Why would it not be possible to collect in a database the information we know about a drug and its off-label use? The prescribing physician, when they prescribe that drug, would have access to pull-down pages and would have to add supplementary information, like what the drug is being prescribed for and the category of person to whom it is being prescribed. Those two pieces of information, in addition to the name of the drug, would give the database the instant capability of returning an off-label use, as well as other indications, contraindications, et cetera. We know that that could be expanded and that the database could be extremely useful. Let us not go down that road into all the complexities; let us just take that as an example. If that information is on a prescription that the physician sends electronically to the pharmacist, the pharmacist would get it and see that it is was an off-label use, the indication, the category of patient and so on.
Consider this system now in this example. I am not trying to be absolute here; I am just trying to get your reaction to a possible framework. Within this situation, we have the possibility of covering a number of the things that you have identified, such as properly informing the patient. You can even attach it. Once any one of these other things comes up with an asterisk, you have to get informed consent, as a possibility, in the physician's office. That is all the way through to the possibility of following up with the patient in terms of asking how they used it and what their results were.
In leaving that, I want to remind you that one of the adverse or unintended consequences of the way we prescribe drugs is that those very pamphlets you are talking about, Ms. Currie, that go into that box can scare patients. I know when I look at it, I would be scared if I did not know a lot more about this than most people; I would be scared to death to take some of the things, because even the literature on Aspirin will tell you that you could die under certain circumstances. We know that many patients do not take their prescriptions because they have been scared off from those sorts of things. We see a lot of issues related to this.
Do you see what I have just described as a way of moving forward an approach that meets some of your key objectives?
Ms. Currie: This kind of database, stemming from the physicians' diagnosis and prescribing, was exactly what the Quebec study did. This was the kind of record keeping that they looked at, and they were able to do that because they had that capacity.
What it did not do was give immediate feedback to the doctor that a drug is prescribed off-label, which I think could be a useful way of informing doctors.
I am a little skeptical about the wholesale applicability of this system, since we have been struggling for decades with electronic records and there are concerns about electronic records — doing it in a holistic kind of way. However, I think certainly this kind of initiative could be piloted. We do not actually need to do it on a huge basis to get a real sense of what is happening out there, but incorporating those kinds of methodologies would be helpful.
I like the idea of the feedback to the doctor because that would certainly deal with that.
The Chair: Or with Health Canada, even.
Ms. Currie: It still does not deal with the fact that many drugs are being prescribed off-label without a strong evidence base and which can carry risk of harm. I am concerned about how we crack that nut, because even if a doctor receives information that a drug is off-label, he may go ahead with it. I would almost like to have the harms listed right there: "Do you know you are prescribing a drug that is not recommended for patients with dementia?" You could really develop that model further.
The other issue that does not address my concern is the degree to which the pharmaceutical companies are actually promoting off-label. I think that this is a very assertive system. I think it is actively promoted, and I think we need to "cut the water off at the source," too. We need to do all those things.
I do not want to give the impression that I think information will solve everything; I think there are a number of factors that need to be dealt with, as well.
The Chair: Thank you.
Ms. Smith?
Ms. Smith: It is very interesting that you use the human growth hormone as an example. You have sitting before you the first girl in Canada to be treated with human growth hormone for dwarfism. As you can see, I am not a dwarf. I started in the 1960s on the first pilot program in Montreal, and it was very successful.
However, I went through a 20-year period of absolutely horrible health. I was on the human growth hormone; it ended when I was 18. Because of the shortage, no research was done on adults, so they just left us high and dry with all of our other medications. None of my endocrine system works at all. I replaced absolutely everything.
For 20 years I wrote letters, called people and tried to get clinical trials organized, and no one would do a clinical trial on adult use. When I got to the point where I knew I was dying — that I would not survive past my forties — finally I found a doctor in Toronto. I am back on human growth hormone, though it is not covered by Ontario. I am very fortunate to have private coverage.
When you talk about Prader-Willi Syndrome, I have a lot of affinity for those children because I know that it works, and we know that it works. What is happening that some are getting it and some are not getting it? If your system, which you were proposing would have more data monitoring and more information, worked properly, it would then be difficult for the provinces to refuse a treatment that is not that expensive; it is not a drug that is in the hundreds of thousands of dollars. That would move a child from the tenth percentile of cognitive functioning to the fiftieth percentile.
For CORD, the importance is getting the information out there through a third party, such as Health Canada or CADTH, but then moving from there to saying, "Here is all the information. This drug works. Let us get it to the people who need it" or "This does not work; let us get it away from the people that it is harming." It is just very important to us that the information is out there, and that will encourage funding. It is nice to have the drug, but if you cannot get it, then it is difficult. I would not want to be in the position of those parents.
I live in fear that my insurance company will cut the drug off because that drug has made me throw away a walker and I am now preparing for a 10K run. I would have never thought 30 years ago that I would be in this shape in my 50s. It is due to the right drug prescribed to the right person — still struggling to get it covered — but the right drug to the right person. I am not using an off-label. It is not exactly what I am saying here, but anyone with Prader-Willi Syndrome would be using it off-label. They simply do not have enough data from studies to warrant that.
The Chair: In the interest of full disclosure, Ms. Smith, we have never met before and I was not aware of your condition.
Ms. Smith: Really?
The Chair: I was not aware that that was your situation, but I am enormously familiar with human growth hormone, the genetic engineering that produced it and all of the impact. My point in bringing these examples up is that when we find a solution, we have to be careful because we are aware that we have with us somebody for whom that kind of use has saved a life; and we know that that is part of this equation.
We have to find a way of moving forward that ensures that we provide adequate protection.
Ms. Smith: Right, and I hear everything that Ms. Currie is saying. I find it is extremely important, as a Canadian hearing this. I also speak for my community where I know that it often is the last course of treatment, and we want information on it and access to it. It is a matter of life and death for many of our people.
The Chair: I want to come back to Ms. Smith further on the rare disease issue. When we think of orphan diseases or rare diseases, many of us tend to think that there are not as many as there are headaches or other kinds of things. However, as you started to point out, it is often perhaps 1 in 10 million, not just 1 in 5 million. Indeed, we have circumstances in Canada today for which there are between 2 and 30 individuals over a range of, say, some 12 or 15 exceedingly rare disorders. Putting that in perspective, these are often disorders that the world is not even aware of, let alone pharmaceutical companies in terms of telling them they have to investigate and find drugs to treat them.
Often, it is in the medical arena and the research hospitals where a great deal of time is spent trying to figure out what is wrong with an individual patient and why they are showing such symptoms. Indeed, that is where CIHR comes into play. When a physician, based on the literature and related issues, has a brainwave and decides to try a drug in a clearly off-label issue, it may have a benefit to the people involved, which sometimes may be just one or two in a country like Canada. This whole issue that we are dealing with covers an enormous range of health issues, individuals and approaches. We have to be very careful when we make statements that seem to cover the entire aspect.
In your experience, Ms. Smith, do you see the role of that kind of experimentation as part of the CIHR support of medical research in that way?
Ms. Smith: Definitely.
The Chair: I gather that is part of what you were saying you were arguing for in terms of research into these issues.
Ms. Smith: There are 2.8 million Canadians with over 7,000 rare diseases, which is 1 in 12. As we always say in rare diseases, we are alone but together we are a big force. There are more than 7,000. The CIHR is moving forward with all kinds of research into rare diseases. As well, Genome Canada is pairing with Dalhousie University. There are many studies. The field is really moving, and off-label use is moving along with it. We need the provisions to help us to continue to repurpose old drugs and apply them to people with rare diseases. That is why the regulatory framework is so important. If we get it right at the outset and include that, we would truly be helping many Canadians.
The Chair: Ms. Currie, I cut you off.
Ms. Currie: Your points are very well taken, but I want to stress that that is not the norm for off-label prescribing. I agree that you need to find a way through those.
I also want to say that I am struck by the fact that drug manufacturing and drug testing are economic activities. Rare diseases and the diseases that do not generate a lot of profit will be given short-shrift in terms of the research. It is tragic to put people with rare diseases in a situation where the research is not being done, the monitoring of adverse drug reactions is not being done in such a robust way, and the drugs have not gone through a clinical trial because it is just too expensive and the drug companies do not want to do it. That is a tragic statement about our society; but I am not sure there is much we can do about it. Whether there can be a role for a regulator or university academic institutions, it sounds like you have had somewhat of that role as to whether diseases, where it is not profitable for drug companies to run clinical trials, can have some kind of role.
I have a friend who has just been diagnosed with ALS. Such a small number of people have that disease. It has such a short lifespan that the drug companies have shown very little interest in researching remedies for it. Most of the responsibility falls on the people who have the disease to assess whether the drug is safe. What is the information? Should they take it? It puts people with rare disorders in a very difficult situation, and I wish there was a solution to it.
The Chair: I should qualify that the issue of cytomegalovirus was only one of the issues that HIV patients face. I was dealing with that specific. The other range of issues you have commented on correctly, and so on.
You have brought these very important issues into a focus today. You have left us with recommendations. We have had a very full discussion with ideas coming out. As you leave here, if examples occur to you, for example the Mayo Clinic database as a kind of concept, or ideas spring to mind, please follow up with the clerk of the committee to give us the further benefit of anything. Sometimes a witness may walk away and say, "I wish I had remembered that particular example."
Ms. Currie: Yes.
The Chair: On behalf of the committee, thank you so much for being here.
(The committee adjourned.)