Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 32 - Evidence - February 28, 2013
OTTAWA, Thursday, February 28, 2013
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 10:38 a.m. to study prescription pharmaceuticals in Canada (subject: Off-label use).
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
The Chair: Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie, and I am a senator from Nova Scotia. I will invite my colleagues to introduce themselves.
Senator Seidman: I am Judith Seidman, from Montreal, Quebec.
[Translation]
Senator Verner: Josée Verner, from Quebec.
[English]
Senator Eaton: Nicky Eaton, Ontario.
Senator Enverga: Tobias Enverga, Ontario.
Senator Dyck: Lillian Dyck, Saskatchewan.
Senator Eggleton: Art Eggleton, Toronto, and deputy chair of the committee.
The Chair: Thank you, colleagues.
Welcome to our witnesses today. I am very pleased that you were able to make it here. We are certainly looking forward to your presentations and your responses to our questions. I will introduce you as I invite you to speak. By order established through the logic of the witnesses, I am going to start first with Dr. Anne Rowan-Legg, who is a member of the Community Paediatrics Committee of the Canadian Paediatric Society. Please make your presentation.
Dr. Anne Rowan-Legg, Community Paediatrics Committee, Canadian Paediatric Society: Thank you, and good morning. I am a general pediatrician at the Children's' Hospital of Eastern Ontario and an assistant professor of pediatrics at the University of Ottawa. I am here today as a representative of the Canadian Paediatric Society, and I am a member of the Community Paediatric Committee of the CPS.
Thank you for giving the CPS an opportunity to address you today on the issue of off-label medication prescribing in the pediatric population in Canada. Contrary to common belief, Canadian children use prescription medications often. A large 2003 study showed that the average child in Canada was prescribed four medications a year, and pediatric medication use has most certainly increased both in extent and scope over the past decade since that study.
Off-label prescribing is the practice of prescribing medications for indications or, particularly relevant in pediatrics, in age groups that have not received regulatory approval by Health Canada. It has been shown that over 75 per cent of pediatric medication use is off-label. The topic of prescription pharmaceuticals is of particular importance to children and youth and the physicians who care for them, not only because it is so common but also because so many of the medications that we prescribe have never been clinically tested in children and youth.
Health professionals often have no specific product information for patients under the age of 18 regarding the product's effectiveness for a specific condition, the appropriate dosing and potential side effects and safety risks, especially those unique risks related to long-term child development. Hence, off-label pediatric drug use has been based primarily on extrapolation of data from adult studies.
While there are so many pediatric examples of effective medical therapies for conditions without official indication approval, off-label drug use can also have serious consequences for children. The history of pediatric pharmacology unfortunately has several examples of drugs used off-label for children that have had devastating consequences before serious adverse events were known.
As physicians caring for children, we continue to operate in that risky prescribing environment. Although the situation is starting to improve with more recently approved drugs, particularly for those more likely to be used in the pediatric population, such as those for asthma, infection and behavioural issues, there is still insufficient information on many of the common medications prescribed and used on a daily basis by Canadian children.
You may ask why it is that products are being used off-label in children and youth. The simple answer is that, as pediatricians, we have no choice. If a teenager has clinically significant hypertension, or high blood pressure, the physician has two options. One is to deny the necessary treatment, and the other is to prescribe an off-label medication never clinically tested in children and youth. The same can be said of medications to treat high cholesterol, depression, anxiety and other chronic pediatric diseases. Children and youth are increasingly being diagnosed with diseases previously unseen in the pediatric population, an unfortunate consequence of the rising rate of obesity and mental health conditions calling into consideration an even greater necessity for off-label prescribing.
Allow me to give you an example from my own practice. Gastroesophageal reflux, or heartburn, in infants is very commonly treated with a family of medications called proton-pump inhibitors that have been traditionally used for adult heartburn. For these newborns, the dosing is speculative. There are limited published studies supporting their efficacy, and we know little of their side effects in this young age group. None of these medications has been approved for children under one year of age. Still, it is very common pediatric practice to use them. In this scenario, I find it especially difficult to adequately and candidly counsel parents regarding these medications, given the paucity of information available, and I can imagine that parents must have a challenging time making an informed decision whether to treat their infant.
For the practising physician, another unfortunate consequence of off-label prescribing of pediatric medication is that the formularies of approved medications for publicly funded provincial or federal programs, whose candidacy for inclusion depend on review of medication safety and efficacy, may not actually reflect contemporary prescribing practices and suffer from limited evidence-based support.
The CPS very much appreciates the efforts made by Health Canada to initiate improvement in the system regarding pediatric prescription pharmaceuticals, particularly in the establishment of the Office of Paediatric Initiatives and the Paediatric Expert Advisory Committee.
We also believe that more can be done. The following recommendations were approved by the Canadian Paediatric Society's board of directors in November 2011 and are published in the CPS journal, Paediatrics & Child Health, from that same month. I will read the recommendations verbatim:
Health Canada, the Canadian Institutes of Health Research (CIHR), and industry should develop a national research network focused on the unique therapeutic needs of infants, children and youth, to improve the environment and infrastructure for drug research for children in Canada. . . .
The CIHR, Health Canada and Canadian academic child health centres should work to enhance human capacity in drug investigation in children . . .
The CIHR, Health Canada and Canadian academic child health centres should support drug studies in children, notably for drugs and diseases where optimal therapy is poorly defined.
The CIHR and the National Council on Ethics in Human Research should work with organizations, such as the Canadian Paediatric Society, to define and address the evolving ethical challenges of drug research in children, with a view toward how the issues are addressed both nationally and internationally.
The CIHR, Health Canada and Canadian academic child health centres should support innovation in drug research in children . . .
The federal government must demonstrate its commitment to optimal treatments for Canadian children by providing robust, dedicated and sustained support for training in drug research in this group. . . . Finally,
— and most pertinent to this discussion —
the federal government must continue to evaluate and establish incentives that will best encourage industry to submit paediatric data when presenting information to Health Canada.
Thank you for your time today. I appreciate the opportunity to speak with you.
The Chair: Thank you very much.
Dr. Jennifer Blake, Chief Executive Officer, The Society of Obstetricians and Gynaecologists of Canada: Good morning. I am an obstetrician, a gynecologist and the chief executive officer of The Society of Obstetricians and Gynaecologists of Canada. I assumed this post in January of this year, so this is my first opportunity to come to Parliament Hill in this capacity. Prior to this, I was the Chief of Obstetrics and Gynaecology at Sunnybrook Health Sciences Centre in Toronto and I was a professor and the associate chair in the University of Toronto Department of Obstetrics and Gynaecology and had a practice in obstetrics and gynecology. In all of these roles, the issues that you are debating were very relevant and important on a daily basis.
I have had the chance to read through the transcripts of the earlier sessions of this committee on the topic of prescription pharmaceuticals and this particular issue of off-label. I am aware that you have heard from some leading authorities. I do not want to go back over ploughed ground, but I do want to speak to some practical and policy issues that come from this.
I would like to make three observations at the outset and then end with a suggestion.
The observations are, first, that it is important, as you have concluded, to include special groups — women, pregnant women, nursing women — in clinical research on prescription medications. However, the correct method for including these groups is not necessarily the randomized control trial that we would typically do for a drug entry. The method needs to be appropriate for the particular question that you have.
Second, the testing of generic medication should also address the unique needs of women.
Third, and very relevant for today's discussion, the labelled use of medication does not necessarily reflect the evidence, but it may be determined by business and practical considerations that have nothing to do with the science. The practice of good medicine, of necessity, regularly employs off-label prescribing.
I will start with the last statement and give two examples. There is an IUD that was approved in Canada in 2001 for contraception. We already knew from the scientific literature that was coming to us from Europe that this device would reduce menstrual blood loss and that it was credited with reducing the rate of hysterectomy in countries where it was available. The same has proved true in Canada, but it was nine years after its release before we had the labelled indication for abnormal uterine bleeding. During that time, I have to say personally that 95 per cent of the time that I was using it, it was indeed for abnormal uterine bleeding, where it was very effective.
Alternatively, I can remind you of the medication raloxifene, which is indicated for osteoporosis in Canada, but in the United States is also indicated for reducing the risk of breast cancer. Good research evidence shows that raloxifene reduces the risk of estrogen receptor positive breast cancer, which is the most common form of breast cancer, by 84 per cent. It is a substantial reduction. However, because this is not an indication that was ever sought in Canada, it does not appear on the label and is only known to those who have read this particular research literature. Most doctors and patients are unaware of the benefit, and the company is prohibited from even distributing the relevant research papers that may be published in The New England Journal of Medicine. I accept that there are differences between Canada and the United States, but I do not believe that this difference extends to our breasts.
With respect to generic medications, you have heard in prior testimony that they are expected to be bio-equivalent. That is important, but in this case, it is actually important that they be physiologically equivalent. We know that the absorption and metabolism of a drug is affected by the way in which it is compounded, and that in turn affects the drug levels in the body.
Therefore, how do we know that a different formulation of a birth control pill has the same contraceptive effect if we have never measured it; and how do we know a drug has the same peek absorption in pregnancy or persistence in the body if it has never been tested in those populations? This can affect the therapeutic effect of the drug in a woman, for example, with an anti-epileptic drug, or it can affect the potential for persistence and accumulation in the fetus.
We need sound and relevant information on changes in drug behaviour and pregnancy that may be as much affected by formulation as the active compound. This really does apply to generic as well as to non-generic medications.
As to the issue of special populations, there is no disagreement that there are important physiological differences that affect how women will respond to medications, particularly for pregnant and breastfeeding women. It is not reasonable to simply avoid prescribing in pregnancy. I will quote Françoise Baylis, who has appeared before this committee: "Pregnant women get sick, and sick women get pregnant." The age at which women are having families is getting significantly older. I would like to add that this is not, by and large, by a woman's free choice; it is a societal problem. However, older women do have more health issues and do require treatment in pregnancy.
Women are concerned about the risks of taking medication in pregnancy, especially when they have written material that warns them about unknown risks during pregnancy. The natural reaction may be to think that they should not take anything — it is safer than taking off-label — but we know this is untrue. Untreated depression has serious consequences to both mother and child, as does untreated epilepsy, et cetera.
It would be a mistake to believe that the solution is to require that pregnant women be included in clinical trials. That may be the solution for some medications, perhaps those used only in pregnancy, such as the antinauseants. However, the issues in pregnancy are complex, and they are different in each stage. In the early weeks of pregnancy, we are most concerned about the risk of birth defects. Thalidomide is a classic example for this. In the later stages of pregnancy, we are concerned about how the medications may affect the mother and her safety issues during delivery, or how they might be passed through to the fetus and affect the newborn child.
Randomized control trials may not be feasible or provide appropriate research evidence. I know it is often held up as the best evidence, so let me explain. Many of the medications we use have a limited application; we would never be able to assemble enough women to mount a clinical trial. RCTs typically last a matter of weeks, maybe months, but some of the unexpected effects of a medication may not be evident until years later and can be either a benefit or a risk.
I will give a few examples. Diethylstilbestrol, or DES, caused problems for women whose mothers had been given the drug during pregnancy. It was given in the hopes of preventing a miscarriage, but it led to a myriad of problems — vaginal cancers, uterine malformations and infertility — that became apparent only decades later.
Some long-term impacts of medications have been beneficial. Folic acid given in pregnancy has reduced the risk of certain cancers in children long after they were born. A clinical trial may therefore be appropriate, but a registry may be a more appropriate method for drugs needed in pregnancy.
I hope this committee will consider implementing a registry. It would have the support of professional organizations such as the SOGC, as well as women. No one would be more motivated to participate in a registry and no one would be more reassured to know that she was being carefully watched than a pregnant woman. As it is, prescribing in pregnancy is, for the most part, off-label. If we continue to rely on RCTs, it will remain so. There are many sources of evidence that can be used to assure ourselves of safety and to guide practice.
I am grateful to have had the chance to share some of these observations and would be happy to answer your questions.
The Chair: Thank you very much. I will now turn to Dr. Allen Huang.
Dr. Allen Huang, Member, Canadian Geriatrics Society: Good morning. Thank you for the invitation. I am a geriatric medicine specialist and the incoming Chief of Geriatric Medicine at the Ottawa Hospital and the University of Ottawa. I am new in town; I came from Montreal and the McGill system six months ago.
Thank you for the opportunity to talk to you about the issue of off-label drug use in the last under-represented population, the elderly. We tend to call this group now "older adults" because we are not sure where we define the threshold for being "elderly."
I totally agree with the comments that you have heard from my colleagues regarding the younger population. The geriatric group is certainly under-represented in the usual randomized control trials due to several reasons. One, they like to have an age cut-off, for whatever reason, whether good or bad. Two, many older patients have multiple co-morbidities that they want to tease out of the study because it will interfere with the results. Three, older patients have altered pharmacokinetics and pharmacodynamics. That complicates the standard study for a clinical trial determining what the effectiveness or effects of a particular drug are.
It creates a bias in our system to say the evidence is based on normal adults of a particular range, of which you have heard exclusion at the younger age and also at the older age. Likewise, you have heard that off-label use of medication is practiced commonly by clinicians because there are no other choices or no better alternatives. Therefore we have to continue to treat our patients and relieve distress and symptoms, even though the evidence may not have resulted in an indication being put on the box.
I think there are problems in the process of prescription writing in Canada that have partly contributed to this issue coming forth. Right now across Canada, when a clinician writes a prescription, you do not have to put down what indication you are writing that prescription for. Likewise, the pharmacist who is trying to fill that prescription cannot discern the indication even if they ask the patient what they are taking the medication for. Some medications with a single indication are easy to discern. If you are being prescribed insulin, people can figure out that you are diabetic. If you are getting an antibiotic, you have an infection somewhere.
However, for some medications — and I will give you the example of a neurologic or a neuropathic pain syndrome, be it from a post-herpetic neuralgia or diabetic neuropathy — there is not one best medication. The medications that are used can be used for different purposes, and if the physician or the prescriber does not indicate exactly what he or she is trying to treat, the pharmacist cannot know, the patient is not sure, and you have the situation of off-label prescribing.
The flip side to that is that, with all the prescription of medication that is potentially off-label, there are adverse events that occur. However, those adverse events may be less common, or even rare, so that each individual prescriber or a pharmacy dispensing these medications may only see the rare event and not get a signal from it and see that there may be something happening. It is difficult to gather together all that side-effect stuff to say there is a problem or not a problem.
In thinking about the issue of off-label medication, especially in the older adult population, I have come up with a few potential approaches that will help the management in older patients. First, on research trials, you have heard that the randomized control trial may not be the end-all and be-all for these patients. However, if we take our European colleagues' example, we see that they have created what is known as the PREDICT Consortium, which stands for participation of the elderly in clinical trials. This will better match our association of older patients with multiple co- morbidities and multiple medications being eligible to enter these trials to try to tease out the effects and effectiveness of new drugs on the market.
Another potential solution is to encourage the documentation of indication during prescription writing, in whichever way or form. Again, there have been proposals that electronic health records and prescribing are methods that can enable this easily. The formulary is electronic. When you prescribe electronically, you can have a drop down menu of the indications you can pick from. Lo and behold, most physicians will do that easily. If it is not on the indication list, they will put down whatever they think they are trying to treat. The electronic lists include both on-label and off-label, so you can get a sense of how these drugs are truly being used in real life.
Another tool that could help is the development of better post-market surveillance. Once a drug is approved, it goes into usage by everybody in the community. They may or may not be using it precisely in the way that it was designed for approval in the clinical trial.
One of the last points that I would like to bring up to the committee is to encourage electronic data sharing, which is an evolution of the idea of the registry. A registry can be local to a city, regional to a jurisdiction or national. With health care, we have to think global. If we are having uncommon or rare events, it would be much better if we had a global experience to share this data electronically in a standardized fashion and get more signal out of what is happening worldwide in order to make better decisions based on true data.
The Chair: Thank you. I remind senators that we are dealing in this phase specifically with off-label issues related to pharmaceuticals.
Senator Eggleton: To yesterday's panel, I quoted a couple of comments that were in Maclean's last May in an article, Off-label drugs are off the charts in Canada. Dr. Tewodros Eguale of McGill University said that of the drugs prescribed off-label, 79 per cent lacked scientific evidence. I repeat: 79 per cent lacked scientific evidence. Dr. Joel Lexchin, a professor of health policy at York University, said that most of the off-label prescribing in Canada does not have a scientific basis. That sounds alarming. Do you agree with those comments? How can we strengthen the system as quickly as possible? There are many structural things that you have recommended we could do, but surely we need to increase the evidence-based level for making these decisions by prescribers as soon as we possibly can do it.
I also wonder about the need to disclose to patients medications that are being prescribed off-label. Should we do that? Should physicians describe the potential pitfalls? Should there be informed consent with respect to off-label? We are putting a great deal of reliance on the doctors. While we have a great deal of trust and confidence in them, it is kind of alarming when you read statistics like the two professors talked about and the need for an increased evidence-based level. I ask this as a general question to all the witnesses.
Dr. Huang: I know Dr. Eguale quite well and the study that was quoted in Maclean's. It was interesting to find out what the true level of off-label prescribing is in Canada. We have had some figures from the United States and only some guesses in Canada. That was the first time we looked at real electronic prescribing records and the reasons that they were prescribing a particular drug. Again, when a clinician is met with a situation where they are trying to alleviate a symptom or distress from something, they have no other choice but to turn to whatever drug they think is appropriate. They are really doing a one-on-one clinical trial with the patient. In the best circumstance, they would need to follow that patient and ask whether they are reacting favourably or unfavourably to the off-label use.
It was surprising to see how high the percentage was, but it was an off-label drug for neuropathic pain or a sleep disorder. For example, trazodone, which is a mild anti-depressant, was being used as a sedative to help older patients sleep. It is nowhere on the indication, but it is used commonly clinically. We have to try to manage that gap somehow and ensure that even though it is effective and safe, we can continue that in the absence of true scientific evidence.
Dr. Rowan-Legg: To build on Dr. Huang's point, we have all commented that in the various populations we deal with, there is a lack of scientific study. Many disorders like sleeping disorders in the elderly or in the example that I gave with reflux being a very common problem in children, we end up being taught and teaching others. We become comfortable using these medications despite scientific evidence, which is an issue, because they are so commonly used. That leads to the question of how to organize this volume of information. There is a lot of clinical work going on and a lot of individual trials, which you alluded to. How do we harness that information and organize it into publishable data, because it is certainly going on?
Dr. Blake: I had also read the article in Maclean's and there were several points. It is always easy to make a headline that sounds alarming, but there is usually a more mundane story behind it. In some of what was said, he was referring to specific classes of medications and to the fact that many of them were older medications where, exactly as Dr. Rowan-Legg has said, there is a much broader base of experience. It comes back down to what you are calling best evidence. You may call a double-blind randomized control trial best evidence and everything else lesser. There is good reason to think that other kinds of evidence are also important in therapeutic decisions, such as post-market surveillance or large cohort studies. When this is all teased apart, there is much that is less alarming than the headline would give you to believe.
Senator Eggleton: I have two specific questions based on your presentations. Dr. Blake mentioned a registry. How might that operate? Who might operate it? We have a split jurisdiction situation. For drug approvals and monitoring, we have Health Canada's role and the role of the CIHR and its subcommittee, the Drug Safety and Effectiveness Network, DSEN. Also, medical practice comes under the jurisdiction of the provinces, as does repayment for many of these drugs.
I am wondering where this registry fits in with all of that, who might operate it and how it might operate.
Dr. Rowan-Legg, you give seven things that you think we should be looking to implement. The final one deals with incentives to industry. What kind of incentives to industry? Industry does not seem to be too interested in doing a lot of extra research with respect to where some of these prescriptions are going in their off-label adaption.
Dr. Blake: The best way to implement a registry and who should operate it are questions that, as clinicians or professional societies, we cannot advise on. The suggestion that it could be done electronically makes good sense. Linking patient data to indications would raise privacy considerations. I suspect that most people would feel confident if this were handled by a regulatory body and not by the pharmaceutical industry itself. I think there is a sense that there is a potential for conflict of interest if industry were to be running a registry.
For pregnancy you would also want to know the stage and the number of weeks during which a medication was given, that is, what the patient's exposure was. You would need a fairly detailed collection of data to go into a registry.
Dr. Huang's suggestion that we look at this as a global issue makes very good sense. We can collect data much more rapidly if we cooperate across borders, and the issues are the same for all of our patients.
Dr. Rowan-Legg: Thank you for the question on incentives for the industry. The act of labelling, or in fact going back to a regulatory body and getting a secondary indication for approval, takes a lot of time because one has to accumulate and synthesize all that data and potentially do the trials. It is also a financial hit for a company.
I would like to make two main points. First, for a regulatory agency like Health Canada, the up-front necessity of providing some pediatric information in order to get approval for a new medication does exist in other countries for these respective populations. Second, as an example, in the United States, as an industry incentive, if someone does provide some data on pediatric populations, patents can be extended by six months. That is the current status in the U.S., but that would be another potential incentive to offer.
Dr. Blake: I read about the six-month incentive. The incentive might vary. I cannot imagine that there are enough pregnant women to make it a financially viable investment for a company, unless it was a primary indication in pregnancy. It may be that some consideration to incentives would be discussed with companies to sort out what would be a reasonable offset.
Senator Eaton: I want to talk about all your different populations. It is even more complicated than pregnant women, babies and older people, is it not? Surely weight, age, metabolism, multiple drugs in the system and gender come into it.
Where do you and the pharmacists meet on the idea of a global or even a national registry? Are they able to help you with off-label drugs? It is a guessing game; it is really a brew? How exact is the science when you prescribe off-label medications?
Dr. Blake: When prescribing off-label you are driven primarily by the patient before you, and then your knowledge of what is available to you for her particular therapeutic condition. As to whether pharmacists can help us, pharmacists are limited in this because they have the on-label information and not necessarily the off-label information. It can be confusing for patients. I will go back to the example of the woman with heavy menstrual flow who was prescribed an IUD to reduce flow. If she is in her forties, the pharmacist may wonder why she is getting a birth control device when she clearly does not need birth control at this point.
In the United States, a young woman who has had her ovaries removed because of cervical cancer can be given hormone replacement with testosterone. In Canada, we do not have any for women. If we are giving her testosterone, it is prescribed for a male, and the pharmacist will wonder whether her doctor does not realize that she is woman. We do, but we are not working from the same song sheet.
In an ideal world, we would also have education around off-label indications that are legitimate and based on good scientific evidence. Currently the labelling is not based on science wholly; it is also based on financial and patent and commercial considerations that have nothing to do with a physician.
Senator Eaton: It is you, the doctor, who judges the patient?
Dr. Blake: Yes. You have alluded to something very interesting, which is the whole era of personalized medicine. I think you have heard about that in the past. It is a bit of a Holy Grail for us in medicine to think that we might be able to have medications that could be targeted to the individual and their particular condition, but I do not think we are close to that yet.
Senator Eaton: When you talk about trials that reflect more of your populations, do you have any ideas about how these trials should be set up, how Health Canada should encourage these trials to be done?
Dr. Rowan-Legg: That is another very good question. From the pediatric perspective again, most studies in the pediatric world are funded by academic centres and the CIHR and there is not a lot of funding from industry.
Senator Eaton: Pharma does not do the whole gamut of ages?
Dr. Rowan-Legg: Not as much. Again, speaking only to pediatrics, most of it is initiated at institutions. There is some networking in Canadian institutions and pediatric hospitals for research, but the question was how Health Canada can facilitate these trials.
Senator Eaton: By a more diverse population.
Dr. Rowan-Legg: It is a very good question. The funding and the networking of these, the locations where the trials are happening, which are the academic centres, in Canada, primarily, would be hugely important. Up until now it has been driven largely by those institutions that have created research alliances, but Health Canada could facilitate that from a structural and financing perspective.
Dr. Huang: I would like to see much more international global collaboration. Speaking about the older adult population with multiple co-morbidities and multiple medications, if you are going to do the trial properly, you are going to need a huge cohort. Older patients are very similar whether they are in Western Europe, Eastern Europe, Asia or Canada.
Why not try to leverage that global population by creating creative partnerships, et cetera, so that we are able to share that data and study this cohort globally rather than locally, because we only have 33 million people? If we could expand that number to 500 million, then we would have access to phenomena that would occur much more frequently and we would have answers faster.
Senator Dyck: Thank you for your presentations this morning. They were very clear.
I was going to ask you, Dr. Blake, about the registry, but you already answered that with Senator Eggleton's question.
You also, in response to Senator Eaton, talked about how pharmacists do not have the same type of information that the prescribing doctor would have and that perhaps education was one way to bridge that gap in knowledge. Is there any other way of bridging that in terms of information that goes on the prescription so that there is more of an alert in giving the reason you are prescribing testosterone, for example, is for a specific condition or a different condition from normal?
Dr. Blake: That is a very important question and it might be addressed by the issue of, if we were to be indicating our indication, why are we using this. We also have to be mindful of patients' privacy when we do that. There are medications where patients would be quite comfortable and others where they might not be as comfortable with having that written down somewhere, and so I think that is not an easy fix.
I do think that to have awareness of the common other indications that are supported by good research, for which a particular medication might be used, would be a useful addendum to the information that is generally available on a prescription drug.
Senator Dyck: Dr. Rowan-Legg, you talked a lot about the different conditions within pediatrics and you had some really good recommendations. Could you give us an indication of the magnitude of the use of off-label drugs within the pediatric population and whether the use in behavioural areas is growing rapidly and whether there are any concerns about the use of such drugs considering that the brain is developing and that there may be additional medical problems here that have to be tracked?
Dr. Rowan-Legg: That is a very good question, and particularly pertinent because there is a group of medications that are some of the more frequent medications prescribed for behavioural issues in children and they are in the family of the antipsychotic medications. More specifically, they are the second generation antipsychotics and these are used off-label for the indications that we use them for in pediatrics. They are widely used.
Your question brings up a good point that was part of one of the recommendations, which is that we need to focus as pediatricians and clinical pharmacologists on how to design trials specifically and do this research, whether or not they are randomized controlled trials, and whether we have a population that has unique end points that need to be measured because they are developing. In the newborn it would be the developing brain and developing throughout all of childhood. We need to define those end points better and make them more useful for people. That is a good point.
Senator Dyck: Dr. Huang, you were talking about the elderly and gave a good example of the use of electronic tracking with drop-down boxes for indications for drug use in the elderly. Is there any kind of non-regulated system in use now that physicians can use?
Dr. Huang: I was involved in an ongoing research trial called MOXXI, the medical office of the 21st century. This is an electronic prescribing solution that we invented and put into a clinical trial. It allows primary care physicians to electronically prescribe drugs, and it uses a database that is maintained by a private company in the province of Quebec that has every drug in the formulary, both the Canadian and the Quebec formularies, and every on-label and off-label indication for each one of those drugs. In fact in this research trial environment we were able to capture the data that Dr. Eguale had actually published to show this is what people are using in real life in using our system.
The answer is that it exists, and the electronic database is available and used across Canada in pharmacies. To respond to a previous question of how pharmacists can help, this electronic data is available and it shows both on-label and off-label, but it is not across all pharmacies; it is certain brands. Again, it exists. The information is there; we just have to share it.
Senator Dyck: In the elderly of course you were talking about the problems of co-morbidity and so on. Are there any major conditions or major drugs or major individual drugs or types of drugs that are the most commonly used off- label in the elderly?
Dr. Huang: The classes that I would target as a geriatrician are anything that will affect someone's thinking and increase falls risk, so that would be motor control and blood pressure. We have a similar situation with the atypical antipsychotics being used off-label, and are they contributing to falls risk or delirium. It would be anything that would impact on someone's mobility, independence and thinking.
[Translation]
Senator Verner: I am going to speak to you in French. Dr. Blake, in your presentation you mentioned differences between Canada and the United States, as regards Raloxifene, in particular. Why do you think this product was approved in the United States to fight breast cancer, but not here in Canada? I understand about the incentive measures, but why was this done in the United States and not here?
Dr. Blake: I am going to reply in English.
[English]
I only know what I was told. We did have long discussions with the company that held the patent at the time that this was going on. The issue was one that, had they filed for that, because the molecule had been registered long before the clinical trials on the osteoporosis use, it had been registered potentially for this use, and so it would have had patent implications at that time. These are business considerations and, as I say, I was informed of this and there may have been other reasons that we did not know, but as clinicians it was very disappointing to us to know that this indication was not going to be made widely known to Canadians, and of course once it lost patent protection there is no incentive for anyone to add an indication to the label. That is where it sits.
[Translation]
Senator Verner: This leads me to direct the following question to our three witnesses: do you think that Canada is behind the United States and the European Union when it comes to the off-label use of authorized medications?
[English]
Dr. Blake: I do not know who I would say is the practice leader right now. We have a system that is struggling, but I suspect every system is struggling. I do not know; I could ask my colleagues, but we tend to think that the Scandinavians have good systems for many of their processes, and good databases and registries, but I do not know who is the practice leader.
Dr. Huang: From the perspective of the older adult, the jurisdictions in North America, Europe and the Pacific Rim have problems in different areas. We are all at about the same level. Perhaps the Scandinavians may be more of a leader, but they are not that far ahead.
Senator Seidman: Thank you very much for your expert presentations. When we look at important population subgroups like the ones you are speaking about today — children, pregnant women and the elderly — there can be no doubt in our minds of the importance of safe and expert prescription of medications off-label. In fact, as Dr. Rowan-Legg said, as much as 75 per cent of prescriptions for children are off-label. Dr. Huang, you mentioned that with the elderly very often it is so complicated because of interactions among the many medications they are taking.
Our interest must be in how we can maximize the certainty of safety, expert prescription and sharing of information. Keeping those three things in mind, I would like to explore with you, always remembering our federal jurisdiction, because this is complicated by jurisdictional issues, what your best recommendation might be, ensuring safety, expert prescription and sharing of information. I could pick on individual things you have said. You have already been asked about them.
Dr. Blake, you were asked about your registry, which has interesting potential.
Dr. Rowan-Legg, you talked about incentives. You might have something else as your second-best offer here.
Dr. Huang, you talked about data sharing so much, and that came up yesterday in our hearings again, this idea of how to share the information post hospital in the community. There are many aspects to this. You also mentioned electronic records. I have put some things in your mind and you might have something else to say about this.
Dr. Rowan-Legg: Thank you for that good question. I will address each of those separately. With regard to the safety, again I will come back to pediatrics in particular. Adverse events and side effects are important with any medication, but in pediatrics the outcomes become very important. They are different from other populations, and we need to be thinking about how we design trials and what the outcomes would be. Those demand time, longitudinal time.
I think the adverse drug event reporting becomes important from a safety point of view, especially when we are using such high numbers of off-label medications, and there might not be the studies to back them up. I will put, as an example, because I am not sure that people would necessarily be aware that in pediatrics there is a program called the Canadian Paediatric Surveillance Program, which is an active surveillance program that polls 2,500 pediatricians across Canada. By "active surveillance" I mean they send an email every month, or a letter, to request adverse drug reporting, in an attempt to compile some information. That was an initiative of the Canadian Paediatric Society. Those would be my main things from a safety perspective.
With regard to expert prescription, the issue becomes that the expert is the individual writing that prescription. In all of these groups there are specialists writing prescriptions, there are family doctors writing prescriptions, and there are nurse practitioners. There is a huge population that one has to reach with this information, and people have varying degrees of ability. Part of being a practising clinician is being able to synthesize the information that is out there and being able to write a prescription based on the best available evidence. I guess I am saying that the expert prescription depends on the information out there and the given individual's ability to put that information together.
The sharing of information is important. I will give an example, and Dr. Blake alluded to this. Often in the Compendium of Pharmaceuticals in Canada, the book that people will often use for doses and indications, for pregnant women and for children there is a line at the bottom that says it has not been approved for children and pregnant women. That is not extremely helpful for the practising clinician: fear mongering, but not practical.
I guess I would speak to having the information that may exist in other jurisdictions, in the United States or Europe, and to have that information available to Canadian regulatory agencies. There is some information often, but it has not been taken into account; it is just said it is not approved.
Dr. Blake: The answers to these questions are complex, and I do not think any of us will be able to give you a simple solution to a complex problem.
However, to add a few more complexities, we may not know that a patient has had an adverse response to a medication. The chances are good that a patient will simply, if something disagrees, stop taking the medication, whether or not the problem is related to the medication. There is no causality that we can presume; it is only by putting the pieces together that we may deduce that. A patient may be unhappy with the medication and never come back, so again we do not know what happened with that particular patient or their medication.
An active surveillance system, I think, really does need to include the patients and engage them in putting information out and to give them an opportunity to recall.
Having said that, you could then get into all kinds of complexities: You may prescribe a medication, the patient may go and pick something up at the health food store that changes the way the medication is metabolized in her body, to Senator Eaton's point, and you get a completely different reaction. You do not know that she has taken that other substance, and she does not know it has a potential of interacting.
Any kind of active surveillance has to take into account a myriad of other potential confounding factors.
Dr. Huang: You asked the question where this could possibly reside, the expertise, the safety and the sharing of information. My suggestion is there must be a neutral body, it must be national and must be trustworthy.
As an aside, of the various interactions I have had, the Canadian Patient Safety Institute meets part of that. They are not a very big operation and it may not be the mandate for them, but they do have patient safety in their mandate. They do pull in expertise. They do not have the information-sharing capacity, but again that is sort of an example of something that is Canadian and trustworthy.
Senator Seidman: To follow up a little with Dr. Huang, I am interested, because you linked sharing of information and electronic records when you spoke. If you could elaborate just a bit more on that aspect, how you would see that happening, who would be responsible for maintenance of that kind of thing on any kind of scale? You talked global, we talk national and regional. How do you see that happening?
Dr. Huang: Every province is trying to move ahead in electronic medical records in some way, shape or form. Electronic prescribing would be part of that structure and system. The provinces could create some sort of secure, non-identifiable data-sharing capacity to look at drug use and sequelae from drug use and drug interactions, et cetera, whichever technical model you use, either a push or a pull or a query that respects jurisdictional boundaries but allows the information to be transferred.
Another research trial I am involved in is looking at international pharmaco-surveillance where we are exploring each jurisdiction doing its own analysis but sharing the analysis results between jurisdictions. No data is transferred, just the analysis is transferred. There are many ways that can be explored to make that happen within our existing systems.
Senator Seidman: Thank you. That is a good start.
Senator Seth: Thank you very much for your presentations. They were wonderful.
We know and see how much off-label drugs are used in all subgroups, such as pregnant women, the elderly and children. We are all aware that there is much debate or controversy about the use of antidepressants in pregnant women, as we know these drugs are not approved for use during pregnancy. My question is this: Keeping in mind the safety and side effects of off-label use, what is your organization's position on the use of anti-depressant off-label drugs during pregnancy?
Dr. Blake: We believe that women should be treated during pregnancy. Depression is a serious medical condition. We do provide guidelines where we go through the evidence, but absolutely women should be given the treatment that they require.
Senator Seth: Do you explain this to the patient and not just prescribe? Some women like to know the side effects to their child and might refuse to take the drug.
Dr. Blake: Of course, in any prescription, as you would know, there is always a discussion of the risks and benefits and the limits of our knowledge.
Senator Seth: There is no controversy here? We can use it, depending on the type? It may be mild.
Dr. Blake: Absolutely. I do not think for this particular hearing we want to get too deeply into the specifics of how one would manage a particular condition in pregnancy, but that is the sort of work the society does. It helps guide clinicians in going through the literature and understanding the limits of the literature we have.
Senator Seth: Thank you.
Senator Martin: Thank you for your presentations. All three of you represent very vulnerable subgroups. I want to focus on the elderly and geriatrics.
As a pregnant woman, I could have refused certain medication, and I had the choice, in my opinion, to at times make that decision as an adult who could refuse the drug. With children, the parents are involved, so there is that oversight. Adults are in the mix or in the conversation that is taking place. With the elderly, that is not always the case. My mother has recently gone into a long-term care facility.
My question is to Dr. Huang. What suggestions would you have with respect to strategies that could be implemented for providing prescribers with the needed information at the time of prescribing that drug? In asking the question, I want to share my observation that the prescriber is least present in the situation in a long-term care facility, for instance, whether it is a physician or a nurse practitioner even. The people who are most present and in the largest numbers would be the care workers, and also family members if there are family members involved.
My mother has recently gone into a long-term care facility. In the case of my mother, she was first admitted and prescribed a sedative to help her settle at night. I was there the first night and could tell the dose was too strong. She almost fell over and could have broken something. She has osteoporosis. I immediately asked for a lower dose, and in fact it was removed entirely. I wonder what would have happened if I had not been present.
It is so important at the time of prescribing that the needed information is fully gathered. Would you comment on the role of the care workers that are present in the lives of the elderly in these settings? They are taking notes and entering data all the time. How is that data taken into consideration when drugs are prescribed? I am really curious about your strategy for that. I do not want to say they are more vulnerable, but unless family members are there to advocate, the elderly could be subject to certain drugs that may not be suitable for them, and maybe they cannot speak for themselves.
Dr. Huang: Senator, you are absolutely right that care of older adults is complex because, as they became cognitively impaired, they lose that capacity to decide the best for themselves. There may also be an attitudinal shift where older adults tend to implicitly and explicitly trust a physician and say, "Do what is best for me," whereas the older adult's offspring are asking, "Are you balancing risks and benefits appropriately?"
The best answer is that when you present the prescriber with all the information possible, that prescriber will make a good choice. It is in the absence of that information, easily obtainable, that they make their best choice and it may not be as good as it could be. Observations from anybody and everybody, including family members, allied health, nursing, if it has gotten to the point of the prescriber making the decision, they will make the best choice. How do we do that? Right now it is a hybrid of paper and electronics. Eventually, if we move to an electronic system, they will get the information at the time they are about prescribe, with adequate warnings, and they will do the right thing.
Senator Martin: You are saying one of the keys is the electronic information, but what about the information or the data being entered every day by the care workers? How is that information made available or accessed by prescribers?
Dr. Huang: That will be a system decision to say observations should be sharable by everybody. It can be a care worker in a nursing home. If they are entering information, why is it not shareable by the prescriber? It should not be isolated.
Senator Martin: Is it up to the prescriber to check on some of this data? Is there any onus on the doctor or the prescriber to do that? We know it is important to have the necessary information. I am just saying I think that information is critical. Is it being shared with the prescribers, and is it important to do this? If so, how do we ensure that is done? From my observation, I would feel that would be critical information.
Dr. Huang: That issue is complicated because, again, it involves people and processes. The design of a particular aspect of the health care system has to take all that into account, including a prescriber's workflow, to make sure that the information arrives at the time that is best for him or her to make the best decision. It is complex, but it can be done.
Senator Martin: I do not know if any of the others have a comment on the sharing of information and how critical that would be and how it is done?
Dr. Blake: It is an important issue in the hospital environment in general and wherever there are inter-professional teams. There has been a lot of work looking at how to put together medical records that are easily digested and that have information. It used to be the doctor's notes were one place, the nurses' notes another and the social worker's yet another. Increasingly, you see that it is an integrated health record so that, as part of your monitoring of your patient's well-being, you would read through those notes.
There is also an important phenomenon of the reporting that the nurses will make verbal reports on how the patient was through the night and any issues that they encountered. That conversation between health professionals is really critical. It is not just the formal but also the informal conversations and interactions that give us a much richer understanding of how the patient is doing. It is a combination of what is in the electronic record and the observations. Of course, there are also the observations of the patients themselves on how they are managing.
Dr. Rowan-Legg: I certainly agree with both my colleagues. I would just add that that needs to be the prescribing doctor's responsibility in the sense of soliciting that information. I would say it is hard to ask people to volunteer information when they are not sure what they might be looking for.
To bring it back to the off-label medication use, we need to use all of the information that we do know about things in order to make the best decision possible when writing a prescription or directing care in any sort of way. A lot of that has to come from the primary care provider because we need to extract the information that we need to know about the side effects that are known.
Senator Enverga: My main concern is about the explanation by Dr. Blake that there are some business restrictions. If we found that a medicine good for osteoporosis helped breast cancer patients, what could government do about the labelling process? Is there a way to assist in the labelling process? Perhaps if it is widely known and widely used and there is a recommendation that this medicine is also good for breast cancer, is there a way that government can help industry so that we can label it correctly and everyone will be able to know and fix this labelling issue?
Dr. Blake: I am probably the wrong person to ask because I am not from industry. I could well imagine that if you had that same conversation with representatives from industry, they might suggest that if it did not impact on their patent or might even give them additional patent protection to bring a new submission forward. I suspect there would be ways. To be clear, it is not that it treats breast cancer but that it reduces the risk. Women on this medication had 84 per cent less likelihood of developing a breast cancer than women who were on the placebos. That was the specific research finding, which was borne out in many studies, not just one. Legitimate questions to ask are these: What are the barriers to additional indications? How can we reduce them?
Senator Enverga: Do you agree that we should have a committee to look into this — maybe a group to determine that a label is good for this and for that? Why do we not do it right away?
Dr. Blake: There may well be ways of collecting to the extent that there is information on off-label use available. That might direct a conversation to say: Why not get this as an indication? Certainly, it would be helpful for us if medications were supported with on-label indication; and when the patient goes to the pharmacist, they are given the information sheet. They can recognize that their condition is listed as a condition. They feel much more comfortable and confident taking that medication, rather than feel like they are out on a limb.
Anything we can do to mirror the on-label indication to the actual indication would be helpful.
Senator Enverga: For our next meeting, maybe we should invite someone from the industry.
The Chair: We have a whole work plan, senator. We will get to those. The issue is complex, as the witnesses are communicating,
Senator Eggleton: First, on the issue of adverse reaction reporting, should there be special protocol mechanisms or rules for the reporting of adverse reactions with respect to off-label use? Second, should we have a mechanism for monitoring the impacts or effectiveness of off-label use? I do not think we have that. Should we have some way of determining the effectiveness of off-label use?
Dr. Huang: Adverse reactions apply to on- and off-label use of all drugs and the current system does a relatively poor job of that. As Dr. Blake mentioned before, whatever drug you prescribe to the patient, if after they take first dose or the second dose they do not feel quite right, they will go to emergency or call the physician that prescribed the drug or simply not take the medication and never return.
We do not have a good mechanism for picking up adverse reactions to anything that we prescribe, and we need to improve that in some way or fashion.
The Chair: The whole next phase of the study deals with unintended consequences, which is a nice term for "adverse reactions." I would ask the witnesses to deal with the collection of data regarding off-label use and confine their comments to off-label use specifically. We will get into the issue of unintended consequences as a full study.
Dr. Rowan-Legg: I would mention the program that exists for pediatrics. I would say that as a practising clinician, I know there is a voluntary reporting system at Health Canada. I do not know whether they collect information on adverse drug reactions related to off-label medications. I submit to the Canadian Paediatric Surveillance Program. Dr. Huang mentioned that there is not a lot of reporting done voluntarily on adverse drug reactions. Speaking as the average practising clinician, I do not know if I could even report an adverse drug reaction to an off-label drug to Health Canada. If I were not in pediatrics, that would be the go-to site to report drug events.
Senator Eggleton: Are there any comments on monitoring the effectiveness? Are there any special protocols for off- labels? I believe you are saying that on adverse reactions, general reporting and off-label are the same. There is no particular protocol you would recommend for off-label.
Dr. Blake: I am not quite sure what you are getting at with monitoring the effectiveness of an off-label indication. Both will often be well supported by evidence. Any collection of evidence for efficacy would need to be in a systematic way. What you are talking about is post-marketing surveillance, which can be done. Some European countries have launched very effective post-marketing active surveillance programs. It is possible, but it is not simple.
Senator Seidman: Dr. Rowan-Legg, my question is for clarification of something you said in your presentation. You said that for the practising physician another unfortunate consequence of off-label prescribing of pediatric medications is that the formularies of approved medications for publicly funded provincial-federal programs may not reflect contemporary prescribing practices and suffer from limited evidence-based support. Could you elaborate on that so we are clear, for the record? I think it is important.
Dr. Rowan-Legg: Thank you for picking that up. To be clear, in each province and territory there is a compendium of approved medications that are publicly funded. When we are using drugs off-label, and I can use that same example I used in my talk about the drugs for heartburn, that would not necessarily be considered an approved medication. It would not make the form, even though it is in common use. There is some evidence to substantiate its use in pediatrics. I could not offer that. It would not be covered for a patient who gets their medications from a publicly funded program.
This is particularly pertinent to me because I find it happens most days in the office on medications that we use commonly, because Health Canada, and understandably so, is weighing the safety and efficacy data. If that does not exist in a decent amount, despite our using them commonly, they will not be available to patients who have publicly funded medication programs.
Senator Seidman: That is obviously important, given that 75 per cent of medications prescribed for the pediatric population are off-label. How do you deal with that?
Dr. Rowan-Legg: It is a good question. For some of them, we do have to go to a second-line therapy. As Dr. Huang pointed out, because one often is not asked the particular indication you are using the medication for, you can prescribe a medication that may be included on this list but for a different indication.
Senator Seidman: Okay. That does help, but I have a follow-up to that, which would be my last. This is a serious problem, so what can you recommend from a federal jurisdiction in terms of off-label use that might help solve that, if there is anything that you can think of?
Dr. Rowan-Legg: The crux of the question is that if there does exist information elsewhere that Health Canada can use to make these decisions about approval, that would be a lot of help for the general discussion that we are having now, and particularly for the formulary. That information often does exist in that there are some studies that are supportive in a different jurisdiction that have not necessarily been evaluated but that could be helpful in labelling an approval, and hence including it in a public formulary.
Senator Seidman: Thank you.
Dr. Blake: I think that this is also an issue very much in our field. Let me come back to the example of the IUD we used. A device that might cost a woman $500 up front but that, over the next five years, would substantially eliminate a problem for her, a woman who cannot afford $500 up front — and a lot of women cannot because a lot of women do not have drug benefits and that would represent the rent or the groceries — has the hysterectomy option, which is fully funded. That is not an appropriate trade-off.
I do think that there is another source of evidence base that can be used to help with those. Those are the evidence- based guidelines put out by Canadian societies and that go through a rigorous process where we would discuss those methods. It might be that such evidence could be used in supporting an application to receive funding for an off-label medication.
The Chair: I would like to pull these things together a bit and then perhaps ask you to think about it in the context I will frame it.
The whole issue here really emerges from a very complex, total set of circumstances. If we were to take that approach, we will never get anywhere. The reality is that we have to begin to address these issues in some manner where we can make progress toward an ultimate objective.
You represent three areas that have a very significant involvement with the deliberate off-label use of pharmaceuticals that are approved for a specific indicator. We have off-label use where we have drugs that are approved for a particular indication in the population that was part of the clinical trial, and then their use for children, older adults and pregnant women is an off-label use, because it is not described on the label.
Then there is another general category. You have given examples of it. There is a pharmaceutical that is approved for a specific indicator and then the very alert observers in the medical practice observe that the drug has a benefit in some other area. That is a different type of off-label use — if the physician starts to prescribe it for that indication.
Then we have the issue thrown in on top of this of seeking formal approval for changing the label, which generally can only come from a party that stands to benefit from it financially — in other words, the industry. Society is not generally set up to carry that out, because it requires further deliberate testing beyond the observation of experienced clinicians, and that has to do with our laws around liability and all those kinds of issues.
I will not even get into the knowledge of individual practitioners across the broad spectrum of human health. It all starts with information. Yesterday and today, we have heard from individuals who have expertise in particular areas where there seems to be a fair degree of knowledge transfer within the medical fraternity in those areas — oncologists and pediatricians let us say, and perhaps other areas.
However, from the study we just completed on post-market surveillance, the reality is that fewer than 5 per cent — and 5 per cent may even be an exaggerated number, with it being perhaps as low as 1 per cent or 2 per cent — of adverse reactions are reported and collected in any kind of systematic way.
All this comes back to information. You have all referred to information — the e-collection, the e-world. We all believe that. Every Canadian I am sure thinks that is where we are. Yet, when we look at the deliberate study with regard to the health accord in Canada, we find we are in fact light years from that. One distinguished physician from a highly recognized hospital system in Toronto stated with passion that he is at the point of frustration, where he does not care if he can get the patient's record from Calgary; he wants to be able to get it from down the hall in his own hospital.
All this comes down to your recommending strongly on the use of information, collection and analysis to help us find solutions to this. Yet, we heard that a lot of the problems in the transfer of information are the multitude of operating systems that the physicians, the hospitals and so on have developed over a period of time.
What I would like to ask you to think about as you leave here today is the following: On the one hand, the very clear, strong and articulate suggestions you have made to us mostly hinge on the collection of information. You are the professionals; you operate within those systems and you know the day-to-day issues involved in communicating with your own colleagues. You are closest to the issues that Senator Martin and others have raised with regard to communication among the various people involved in the provision of health and therefore the observation of how people are reacting.
Could I therefore appeal to you on behalf of the committee to think about this from the reality of the environment of practising medicine? If you think of ways — any ideas — of how the system to collect that information could be developed, that would be helpful.
I will just give you a couple of examples. We had in our previous study the indications that when there was a deliberate follow-up with a patient who was prescribed a medication — the prescribing physician would find out how the medication turned out to be used — there was a fairly high return of information that people were willing to get involved in responding in that area. There was a really good example here in Ottawa and one from the east coast of the U.S. There are perhaps ways that could be done.
Again, I want to say to you on behalf of the committee that I believe we have understood your answers to us today very well. You have been very clear and thorough in dealing with a very complex set of issues. To repeat what I am saying to you, through all of this and all our testimony today, this is our third phase of our study: Information collection, analysis and distribution in appropriate ways are the bases for reasonable decision.
Thank you for your appearance today and for your testimony. As you leave, I will ask you to think about it more. If you can come up with anything you think might be of interest, or even anything observed in the literature you deal with, please pass that on to us through the clerk.
Having said that, on behalf of my colleagues, we are adjourned.
(The committee adjourned.)