Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 21 - Evidence
OTTAWA, Wednesday, October 3, 2012
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 4:13 p.m. as part of its study on prescription pharmaceuticals in Canada. (Subject: Post-approval monitoring)
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
The Chair: I welcome everyone to this meeting of the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie. I am a senator from Nova Scotia and chair of the committee. I ask my colleagues to introduce themselves.
Senator Eggleton: Art Eggleton, deputy chair of the committee, from Toronto.
[Translation]
Senator Chaput: Senator Maria Chaput from Manitoba.
[English]
Senator Callbeck: Catherine Callbeck, from Prince Edward Island.
Senator Enverga: Tobias Enverga, from Ontario.
Senator Seth: Asha Seth, from Toronto.
Senator Seidman: Judith Seidman, from Montreal.
The Chair: I will introduce our guests in a moment. First, I want to remind all that today we are continuing our study on prescription pharmaceuticals in Canada. As per order of reference, our committee was asked to examine this issue in four separate phases. The hearings for phase 1 on clinical trials were completed in the spring. Our objective is to table an interim report this fall. We are now entering phase 2 of the study, in which we will examine the post-approval monitoring process of prescription pharmaceuticals in Canada.
Our witnesses today come from Health Canada and from the Office of the Auditor General of Canada. I am pleased to welcome back to our committee, from Health Canada, Mr. Paul Glover, Assistant Deputy Minister, Health Products and Food Branch; and Dr. Marc Berthiaume, Director, Marketed Health Products Directorate. From the Office of the Auditor General of Canada, we have Mr. Neil Maxwell, Assistant Auditor General; and Ms. Louise Dubé, Principal.
Welcome to all. It is my understanding that Mr. Glover from Health Canada will begin.
Paul Glover, Assistant Deputy Minister, Health Products and Food Branch (HPFB), Health Canada: Thank you very much, Mr. Chair.
Before I begin my remarks, I extend my appreciation to the committee. My remarks are somewhat longer than normal given the complexity of this issue. I hope to be able to provide a fairly comprehensive briefing as you launch this second phase of your study. I will take some time to explain these issues to provide a solid briefing as this moves forward. I appreciate the time allotted to allow me to do that.
[Translation]
I am happy to be here today as the committee starts the second part of its study on prescription pharmaceuticals.
I want to take this opportunity to speak to you about Health Canada's role in post-approval monitoring.
I am joined today by Dr. Marc Berthiaume, Director of the Marketed Pharmaceuticals and Medical Devices Bureau.
As you are aware, the Office of the Auditor General tabled a report in the fall of 2011 which examined Health Canada's key responsibilities for pharmaceutical drugs. Following the report, we appeared before the House of Commons Standing Committee on Public Accounts in March 2012 to provide an update of our detailed action plan to address the Auditor General's recommendations.
While I understand this is not the focus today, I would like to re-affirm to this committee that we take the Auditor General's recommendations very seriously and that we are well on track to meet our action plan timelines.
[English]
I want to underscore at this point that the report of the Auditor General was very poignant and direct, and provided significant recommendations to us. We have tabled a response. We are well under way in terms of responding to each and every one of those recommendations. Certainly, we will be happy to take any questions you may have on our progress. We are meeting all of our time frames or exceeding them with respect to the plan that had been tabled by the department in response to that.
You will recall that when I first appeared before this committee in March, I tabled a presentation that provided an overview of the entire drug regulatory process. I will refer back to that presentation from March 28, which was already tabled, in particular slides 2, 3 and 8. Within the lifecycle approach of regulating drugs, I will focus my comments on the post-approval period, which is this phase of your study. When you hear from witnesses on this topic, you may also hear terms such as "post-market surveillance" or "pharmacovigilance" that describe the monitoring activities that happen after a drug is authorized for sale.
There are four key players responsible for post-monitoring approval. The first player is the pharmaceutical industry, which has the responsibility to monitor the safety of the products that they sell in Canada. Second, health care professionals determine how authorized products are used best and are best placed to identify problems with those products when they prescribe them to their patients. Third, consumers also play a key role in reporting adverse event reactions to their health care professionals so they can report them and us as a department. They can do that as well. Fourth, Health Canada collects and evaluates all of this information from a variety of sources and intervenes when appropriate.
Drugs must meet a high standard for safety, efficacy and quality before Health Canada will authorize them for sale, but our role does not stop there. You have heard in previous testimony about the limitations of clinical trials. In the real world, use of a drug can vary significantly. There will be more diverse populations of patients taking the drug; or they may have more than one medical condition than was there when the clinical trial was being done. Because of this, we must remain vigilant after a new drug goes onto the market.
The collection of adverse reaction reports is an important element of drug monitoring programs around the world. Health Canada has the Canada Vigilance System. Drug manufactures are required by regulation to report all serious adverse reactions. In addition to this mandatory requirement on industry, Health Canada also collects reports from health care professionals and the Canadian public, which is provided to us on a voluntary basis.
To address the problems of under-reporting, about which I am sure you have heard and will continue to hear, we have undertaken outreach activities to increase the quantity and the quality of the information we receive. These efforts have begun to have a significant impact. In 2011, we received approximately 42,000 domestic adverse reaction reports and 450,000 adverse reaction reports that happened outside of Canada. The number of reports that we receive and enter into our databases continues to increase significantly with a 15 to 20 per cent increase per year over each of the last five years.
Health Canada uses adverse reaction data as well as other sources of domestic and foreign information to systematically monitor, analyze and act on safety issues. The sources of information can include post-authorization studies, scientific and medical publications and information from our international partners. From all of these sources of information, potential drug safety issues, or what we call "signals," are detected. Using a risk-based approach, these signals are prioritized and then analyzed to determine whether further action is needed.
There are approximately 16,000 prescription drugs on the market in Canada. Health Canada addresses the most serious concerns first, and the department is always reprioritizing its work based on the level of risk. For example, a safety issue like a sudden death associated with a drug used in children would be prioritized far ahead of any other safety issue. Another example would be muscle damage associated with use of a drug in adults. We look at those factors in prioritizing what we do and how we follow up on these things.
There are other challenges. It is not unexpected, for instance, to find certain symptoms as part of a basic health condition; for example, specific heart-related adverse events in people with heart disease or suicidal thoughts associated with depression. Since these events occur more often in these patient populations than others, it is challenging and requires stronger evidence to conclude that the adverse reaction is linked to the drug and not just the underlying disease. Notwithstanding these concerns, patient safety is our priority.
It is important that we are timely in our work. Health Canada was the first drug regulator in the world to adopt performance standards for the completion of safety assessments. During the past four years, Health Canada has increased the number of safety assessments that we work on. We have put in place consistent processes and scientific methods to support our work to further increase our efficiency and timeliness, including increasing work to share data and analyze with our foreign regulatory partners. Last year we identified 50 safety signals for drugs and completed 91 per cent of our assessments within our performance targets.
There are mechanisms in place for industry to systematically monitor the safety and use of their products. When industry submits a new drug application, they may also submit what we call a risk management plan. The industry identifies how it will monitor for and act upon new safety information discovered once the drug is on the market and being used in the real world. Those uses may include being used by more people and in more diverse populations than those in which the drug was studied in the clinical trial. For example, industry may propose to conduct post-market observational studies in order to better characterize the potential risk between the drug and the adverse reaction. They may also identify any potential off-label uses for their products.
A risk management plan can also be requested by Health Canada after the drug is on the market. This is done when a safety issue has been identified. The regulated industry has a primary role in monitoring the safety of the drugs they sell, and we continue to work with them.
In some cases, especially when there is no alternate available treatment, Health Canada will provide earlier market access to potentially lifesaving drugs based on promising clinical trial results. This is called a notice of compliance with conditions. These conditions typically include increased monitoring and reporting of the drug, a requirement to provide educational material for health care practitioners and patients, restrictions on advertising and labelling, and a commitment to carry out additional post-approval clinical studies to confirm the clinical benefits of the product. This unusual step is important for getting patients access to the necessary medications that they need; again, when there are not other therapies available for them.
All drugs have benefits and they have risks. No drug is 100 per cent safe. Through our monitoring, sometimes new safety information is identified and communicated to health care providers and Canadians. This information is then considered by the doctors when determining how best to treat a patient. We do this through the issuance of risk communications. Risk communications and updated warnings or instructions on the drug label are an ongoing part of our work.
We may also issue advisories or other public notices before completing a full safety assessment so that Canadians and health care professionals may receive timely information on potential health and safety risks and take appropriate action, if necessary, while we are completing our detailed analysis. Further information may then be communicated as it becomes available and once the full safety assessment has been completed.
Last year we issued 154 risk communications. However, it is worth noting that, unlike certain other jurisdictions, Health Canada does not currently have the authority to require industry to change the label of a drug once it is on the market. Therefore, we must rely on industry's cooperation and, in rare circumstances, Health Canada can require a company to stop the sale of its drug entirely if it does not agree to change the label.
As I am sure you heard in previous parts of your study, off-label use of drugs is quite common and it is a practice of medicine for a doctor to determine what the most appropriate treatment for a patient is. Health Canada's mandate does not include oversight of these individual patient-related medical decisions, which may include using a marketed drug to treat a condition or in a population for which it was not specifically authorized by Health Canada. Should a potential risk associated with an off-label use be identified, Health Canada will take steps to investigate the risk and take appropriate risk-management actions if needed, but this is really a practice of medicine and professional judgment issue.
Health Canada's issues are often compared to those of Europe or the United States. In some cases, Health Canada issues warnings ahead of these jurisdictions, as we did for the drugs Aclasta, Avandia and Yasmin. It is important to realize that different drugs are sold in different countries. There can be differences in what the drug has been approved to treat, the formulation or doses available, the type of patients who have used the drug, and the safety profile of the locally available alternatives. Medical practice also differs between countries. Therefore, sharing of information with our international partners is a critical part of our work. However, the scientific analysis must support the best approach for Canadians.
The market for pharmaceutical sales in Canada is approximately 2.6 per cent of the global market. Our information sharing with international partners allows us to take advantage of our knowledge gain when products are used in greater numbers for people in other countries.
In summary, we are relatively small compared to the global marketplace, and it is very important for us to cooperate internationally. We can potentially identify a safety issue earlier than it becomes apparent in Canada by working with international partners.
The regulatory submissions from industry, such as risk management plans or periodic safety update reports, use internationally harmonized formats that both facilitate our discussions with international regulators and reduce the burden for industry.
The science and practice of pharmacovigilance is evolving. Following the Thalidomide tragedy in the 1960s, regulatory systems around the world focused on increased requirements for drug submissions. A higher bar of evidence for safety was put in place in order to obtain market entry. Drugs sold in Canada continue to meet a high standard for safety, efficacy and quality, but we know that all drugs have both benefits and risks.
Our value added for Canadians going forward will not be to stifle innovation and limit access. It will be evolving the requirements for how drugs are monitored once introduced into the marketplace and increasing the precision and nimbleness of our tools to rapidly identify and address new safety issues while maintaining the benefits for Canadians. In keeping with this global evolution and pharmacovigilance activities, Health Canada is in the process of implementing electronic reporting of adverse reaction reports.
The first phase of this initiative will implement reporting by industry, and the efficiency gains will be welcomed by industry and our staff. They will allow us to increasingly shift our efforts from a very slow manual process of data entry to manipulating the data in an electronic format and look for those safety issues which are so much more important and value added.
When I last spoke to the committee, I talked about the global problem of underreporting adverse events. As one strategy to address this, we are also exploring the potential to leverage adverse drug reactions information from electronic health records and electronic medical records. Certainly there will be technology and privacy challenges to this approach, which we are thinking through, but because health care providers are best positioned to provide this critical information, an integrated health system approach will be very important.
There is a challenge to find the balance between high demand for access to innovative medications and a tolerance for risk of those medications. One of our primary roles is to put information about the benefits and the risks of drugs into the hands of health care professionals and their patients so they may make informed medical decisions.
Health Canada makes our domestic adverse reaction database holdings publicly available, with all personal information removed to protect privacy. We actively share new safety information with Canadians through our website, email, RSS feeds and via our stakeholder partners. Through partnerships and social marketing, we continue to push for increased awareness on the importance of adverse event reporting and reactions to ensure that Health Canada is regarded as a credible and unbiased source for new safety information. I believe our strategy is working. Last year there were more than 1 million visitors to our MedEffect Canada web pages and over 21,000 Canadians signed up for direct updates on safety information provided through email.
The regulatory industry in Europe and the United States is now subject to new requirements for the ongoing monitoring of marketed drugs. The European Medicines Agency is in the process of 16 pharmacovigilance guidelines based on their new regulations. Similarly, the U.S. Food and Drug Administration Amendments Acthas also advanced pharmacovigilance requirements.
Bearing in mind that Canada is a smaller market and we do not match the U.S. Food and Drug Administration or the European Medicines Agency, we will still benefit from the implementation of these requirements and determine which are appropriate for implementation in Canada. A key priority for the Health Products and Food Branch is regulatory modernization, and the review of our regulatory tool kit for post-market approval monitoring will be part of our process as we move forward. In an environment that is mindful of the burden of regulation on industry, you will want to keep pace with international requirements for monitoring drugs because Canadians deserve a world class system for post-approval drug monitoring.
[Translation]
In closing, I would like to say that the post-approval monitoring program which we have in place today has evolved significantly over the past 10 years, since the creation of the Marketed Health Products Directorate.
Furthermore, 2015 will be the 50th anniversary of adverse reaction monitoring in Canada. We have a vision for the ongoing evolution of this program to best serve the needs of Canadians.
[English]
This concludes my remarks and I welcome questions from members of the committee.
The Chair: Thank you very much, Mr. Glover.
[Translation]
Mr. Neil Maxwell, Assistant Auditor General, Office of the Auditor General of Canada: Thank you for this opportunity to present the results of our audit on regulating pharmaceutical drugs at Health Canada. With me is Louise Dubé, the Principal responsible for audits in the health sector. The audit, tabled a year ago, covered a number of aspects of pharmaceutical drug regulation. Among other things, we found that the department had not adequately fulfilled most of its key responsibilities related to post-market activities. In particular, we noted concerns related to the timelines of the Department's response to potential safety issues.
There are about 13,000 drugs on the Canadian market, many of which are critical to high-quality health care. The department is responsible for ensuring that the benefits of using a drug outweigh the risks.
It fulfils this responsibility by gathering and assessing safety information from a variety of sources and by implementing measures to reduce the safety risks associated with marketed drugs. Sources of information include domestic reports of adverse drug reactions submitted by the pharmaceutical industry, health professionals and consumers; foreign reports of adverse drug reactions submitted by the pharmaceutical industry; and scientific literature, as well as actions taken by other regulators.
The department uses this information to determine whether further action is needed to protect the public, including: conducting a full assessment of potential safety issues, recommending that manufacturers revise product labels and working with manufacturers to implement these revisions, and communicating new safety information to health care professionals and the public.
In 2010, Health Canada received approximately 330,000 foreign reports of adverse drug reactions. Health Canada did not have mechanisms to receive these reports electronically in a database to help identify potential safety issues. Although the department could consult the reports when necessary, it did not regularly analyze them to detect emerging safety issues. Canada's relatively small population compared with many other countries reduces the likelihood of serious, rare adverse drug reactions being identified in this country; therefore, the capacity to receive, search and analyze foreign reports electronically would contribute to more comprehensive safety monitoring.
Health Canada used information obtained through its monitoring activities to assess whether there may be a safety issue with a specific drug. In 2009 and 2010, Health Canada completed 99 assessments of potential safety issues, 54 of which resulted in recommendations about updating the labelling for specific drugs or classes of drugs or issuing risk communications.
[English]
We found that Health Canada was slow to address potential safety issues. The department took at least one year to complete over half of the 54 assessments, which were all assessed as medium or low priority. In some cases it took significantly longer. These timelines are well beyond performance targets the department established for completing safety assessments.
We also found problems with internal communication in the department. For example, labelling recommendations were not directly communicated to the departmental officials responsible for working with the pharmaceutical industry to update labels for generic drugs. This led to cases of undue delay, as we noted in the report. Once the department decides to implement a recommendation to update a drug's label with new safety information, its officials are responsible for starting the process by notifying the manufacturer of the requested update. We found it took Health Canada between 3 and almost 20 months to issue notifications. Of the 54 safety assessments we examined, Health Canada recommended that 24 risk communications be issued to inform the public of new safety information. Close to half of those communications were not issued by the department until six months after the assessment had been completed. In three cases, we found the department took more than one year to issue the recommended risk communications.
Overall, we found that for half of the 24 recommended risk communications we examined, the department took more than two years to go through the complete process; that is, assess a potential safety issue, update the drug's label where necessary, and issue the risk communication.
Mr. Chair, pharmaceutical drugs play an important role in Canada's health care system and economy. Canadians who purchase and consume pharmaceuticals authorized for sale in Canada rely on the government and industry to monitor the safety of these products. Health Canada has a responsibility to help protect the public against undue health and safety risks from the use of pharmaceutical drugs. The committee may wish to ask Health Canada about the progress made since last fall, when we tabled our audit in Parliament, in meeting the commitments made in its action plan in response to our recommendations.
Mr. Chair, that concludes my opening statement. We would be very pleased to answer the committee's questions.
The Chair: I thank both of our principal witnesses.
Senator Eggleton: I will follow up on Mr. Maxwell's invitation to ask Health Canada about the progress that it has made.
You say, Mr. Glover, that you take this all very seriously. Well, prove it. Demonstrate to me what you are doing, because some of these things that they have suggested are deficiencies are rather alarming, and this was a year ago. I would like to know what you are doing about them specifically.
Mr. Glover: Thank you very much, Mr. Chair, for the senator's question.
I could speak at length about the report and its recommendations. The Auditor General was very comprehensive in its review and tabled a long list of recommendations. For the sake of clarity, we have already appeared before the Public Accounts Committee. We have a management response. I would be happy to table that full response with the committee so that you have a full and detailed accounting of what we are doing, along with any public progress reports that we have done.
Senator Eggleton: That would be good. Maybe you could give us some examples and then file a full report with us.
Mr. Glover: Absolutely. We will do that.
The first thing is processes. There was talk in there about breakdowns internally. Those have been corrected so that there is no falling between the cracks. If the safety signal is identified, it is passed on to the appropriate people so the label can be updated. If it is found in the brand and equally applies to the generic, those things now happen as a matter of course. Some of the things that they found that were not happening now have been corrected and are happening as a matter of policy, and procedures have been put in place to protect and correct from those problems.
As I said in my remarks, we were dealing with huge amounts of paper. We have invested in technology so that we are no longer doing huge amounts of data entry. We are actually sorting through, looking at those signals.
I know this is a little repetitive and perhaps frustrating for the committee to hear, but in April we updated our fees that we charge industry for this work. It is not just for the approval of a drug but also for a licence to continue to sell a drug, and that funds some of the post-market surveillance activities. Those fees had not been updated in over 14 years. Those have now been updated. They include an ongoing escalator so we are never in that position again.
We have new staff in place. We set performance targets in response to the Auditor General's observations. We are the only country in the world that has performance targets for signal assessment. We are, by and large — I will fully admit not 100 per cent of the time, but approximately 91 per cent of the time — now meeting our performance standards in that area. That is something we were not doing when the Auditor General was in.
More substantively, and frankly alarming when you look at the original report, was the lack of transparency. We are taking steps to be far more transparent in what we do and how we do it. The inspections that we do of clinical trial sites, inspections generally, putting summary basis of decisions for why we approve or do not approve a drug, have all begun to be published on our website so Canadians can have access to that.
We are well on our way to making available a list of all clinical trials that have been approved in Canada, something that was a critical gap. Canadians did not know if Health Canada had approved or not approved a clinical trial. We hope to have a full list of all the sites up and maintained very shortly as we move through that.
There were concerns about conflict of interest. While we were following the Government of Canada's general policy, it did also say that the department should assess if there were additional risks given the line of business that we were in and take steps to deal with that. We have done that. We agree that our reviewers are susceptible to different risks than regular public servants when they are making significant decisions to approve or not approve a drug that can be worth billions of dollars, so we have a process with all of our employees that they proactively have to declare if they have a conflict or interest. That has been implemented. We have 100 per cent compliance within every employee in the organization on that process effective within weeks after the report was tabled.
We have had a consultant come in to review if that was sufficient. We believe it is, and we will continue to monitor that as we move forward.
I am sure there are other things outlined in the report that we will table with you.
Senator Eggleton: I wonder if Mr. Maxwell has any particular concerns about areas that you have not touched on yet that are outstanding.
Mr. Maxwell: Thank you, Mr. Chair. I will start with the auditor's caveat, which is, we have not been in to audit since we finished that audit. That said, we have been monitoring what is going on in the action plan. Our sense is that the department is quite serious about this. It has certainly moved in a lot of areas. I do not think, in answer to the question, there is any particular gap that I would point you to. By and large, they seem to be on track with their action.
Senator Eggleton: Let me ask Mr. Glover about the resources he has. Two of your other divisions that we have talked about before, Therapeutic Products Directorate and the Biologics and Genetic Therapies Directorate, have a budget I understand of about $74.6 million and have 830 full-time equivalents. The Marketed Health Products Directorate, which is our concern here, by and large, has $23.6 million and 214 full-time equivalents. It sounds like you are really understaffed or under-resourced here. Can you comment on that?
Mr. Glover: Thank you very much for the question. As a bureaucrat, it is kind of hard to say that more resources would not be helpful, but we deal with the appropriations made by Parliament, assign them accordingly, and do the best job within which the wisdom of the Parliament has decided to appropriate.
Senator Eggleton: Can you meet the auditor's requests, then, within the resources that you have?
Mr. Glover: We believe that we are now able to meet and are allocating resources appropriately to meet the performance standards that we have set. It is also important to note that if the Marketed Health Products Directorate sees a signal, they will work with the review community that first approved the drug to see how this factors into the approval. It does not entirely rest with them and their shoulders to do some of this follow-up. They will work with the approval divisions. That was the breakdown that the Auditor General found where the communication was not good, or it would go to the person who approved the brand and not the generic. There is a link back. This is an intelligence unit that finds the signals and then works with the review divisions to ask if the label is sufficient. Is the monograph — does it contain enough information that a physician can prescribe this safely? They work with those other two directorates you mentioned to ensure that the signal is properly investigated and the safety of that drug continues to be appropriately dealt with.
Senator Eggleton: Let me ask you about risk mitigation strategy. You pointed out in your opening remarks that you do not have authority to order a product recall, which I think would surprise the public, or to enforce its requests for manufacturing labelling changes, or additional studies into product safety or effectiveness. You do not have the authority, but you do have other means of applying pressure here and making sure that if a product needs to be pulled off the market it can get pulled off. You have authority to cancel the approval. You have other authorities here. Sure, it would be good if you had these authorities, but surely you have other means of dealing with these?
Mr. Glover: The short answer is that the senator is absolutely 100 per cent correct. Other international regulators have these authorities. We wanted to be clear and transparent with the committee as you conduct this study that when you do that comparison there are authorities that this country does not have that others do.
That being said, we have a fair amount of persuasion available to us. Frankly, the strategy I employ is that, if a drug company does not agree with our assessment of these things, we will let it go for a very brief period of time to have a scientific exchange. We do not want to be arrogant about these things. We want to hear from the company; but after a reasonable period of time based on our concern, if the company does not agree, we simply say, "Well, it is very unfortunate. Tomorrow we will be issuing a press release expressing our disappointment that company 'X' does not agree with Health Canada. We are advising all Canadians and physicians to stop using this product because of the following concerns." It is surprising how quickly they suddenly comply.
Senator Eggleton: Oh, I bet that is true.
Mr. Glover: I think that tells us that their reputation — their brand — matters to them. It is how we exert influence over these things. In some ways, you could make an argument that actually having a regulatory authority could draw these things out and create avenues for legal challenges of them and that influence is oftentimes more efficient and more effective. It requires a certain confidence in the science and the ability to move forward, but, thankfully, we have some of the best-trained and most capable people in the world doing that science for us.
The Chair: Thank you very much. That was a very important exchange.
Senator Eaton: Senator Eggleton asked most of my questions, luckily, so I will be very quick.
What you are saying is that you would not like to have the ability for mandatory recall, say, for labelling? You would not like to be able to force manufacturers to re-label at any point? You want to use the persuasive method first?
Mr. Glover: I appreciate very much, Mr. Chair, the honourable senator's question. I think consistency of regulatory frameworks is important, so it provides me with a chance to clarify.
If we had the authority, I think we would use it very diligently and only as a matter of last resort. I think that a persuasive approach — a dialogue with the company — would be preferred before resorting to an attempt to invoke a legislative or regulative power. That being said, for consistency, there would be times when that incentive might help some of those negotiations, but it would not be something with which we would be looking to start a conversation with a company. It would be used as a matter of last resort.
Senator Eaton: I think that the U.S. has mandatory recall.
Do you ever initiate post-clinical follow-ups with the same people who have, say, tested the drug once it has been out in the real world?
Mr. Glover: I will defer to my colleague, Dr. Marc Berthiaume.
Dr. Marc Berthiaume, Director, Marketed Health Products Directorate (HPFB), Health Canada: I am sorry; I missed part of the question. Would you mind repeating it?
Senator Eaton: Do you ever initiate post-clinical follow-ups on, say, rather high-risk drugs on the same people that you used to test the drug in your clinical trials once the drug has been out in the real world?
Dr. Berthiaume: There are some approved drugs for which there will be a follow-up of the clinical trials on the same people that have been in the clinical trials for the approval. However, I would say that most often, once a drug is on the market, if there are follow-up studies, they will be on a broader range of people. This is called real world effectiveness. The people will sometimes have more conditions or use more medications, which gets closer to giving a good understanding of the safety profile of the drug in its real use.
The Chair: Doctor, there is another aspect to the senator's question, which would be that a number of the people who direct these clinical trials do continue to be involved in the application and advice on these drugs within the country. Could I extend her question to that aspect? Do you follow up with any of the directors of specific clinical trial sites who might continue to be engaged with the medical symptom with regard to the follow-up on the drug once it is approved?
Dr. Berthiaume: Thank you for your question. When we follow up, we keep in touch with the people leading the clinical trials, as long as the clinical trial is ongoing. If there is a clinical trial that continues after the drug is on the market, then there will still be discussions, with the clinical trial people at Health Canada, of the safety profile and of the findings of these clinical trials.
Mr. Glover: If I may add to my colleague's response, Mr. Chair, the Auditor General pointed out in their study that this area, from an inspection point of view, was a weakness that we have moved to correct. We did not have clear procedures to identify which clinical sites should be investigated and how to prioritize those. We now have those. We have trained staff, so there is, in fact, inspection of the clinical trial sites. There are recordkeeping requirements. There are safety issues there. We do not inspect all clinical trial sites. There are literally thousands of them. However, we do know where they are, and we do inspect. We do have a process for prioritizing which ones should be inspected, and that would include any trial that is operational.
Senator Eaton: Thank you very much.
Getting back to mandatory requirements, you do not have mandatory reporting from the pharmaceutical industry? It is voluntary right now?
Mr. Glover: What we do have is a mandatory requirement from industry to report to us.
Senator Eaton: It is mandatory.
Mr. Glover: They have a number of ways to do that. There are periodic safety update reports that they can do. There is certainly an expectation that any serious adverse events are reported to us on a very timely basis, and then there are lots of other reports that would be considered less serious that they can do in an annual report to us as that moves forward. There are a number of mechanisms.
The real challenge in this is whether we know, whether the companies know and whether adverse events are being reported at the rate that is truly helpful. The companies are required to report to us not only those adverse events that have occurred in Canada but also any adverse event anywhere around the globe. That is why we differentiate between the number that we have seen in Canada and what the company reports to us in other jurisdictions.
Senator Eaton: When you are talking about the globe, I notice that you have mutual recognition agreements with the European Union, Switzerland, Australia, Norway, Iceland and Liechtenstein. How about the U.S.? The U.S. is not listed here.
Mr. Glover: That is correct. There are two parties that are required to sign those things and two parties who need to agree.
Senator Eaton: So far we do not agree?
Mr. Glover: I think we are anxious.
Senator Eaton: It is an ongoing thing?
Mr. Glover: Perhaps I am being a little too coded here.
The Chair: I do not think we need to explore this further. We understand the implication here.
Mr. Glover: If I may, Mr. Chair, I think there is a relevant point that I would appreciate the committee's indulgence on. A mutual recognition agreement, or MRA, actually implies that both countries literally accept the decision of the other country. It is not just that we will use their report. An MRA says that if that country has made that decision, we do not even look at that report. We do not decide if we were going to make a decision on our own; we accept their decision. When it comes to the U.S., they, I think, have not signed any of the type of agreement that you are talking about.
Senator Eaton: With any other country?
Mr. Glover: With any country. We do share information with them, but to go that extra step is not something that they have done with any country because it is two-way. It is not just sharing information and having somebody accept your decision; you also accept their decision.
The Chair: Thank you, Mr. Glover. That was a very good clarification. I was a little concerned that we might be going down a slightly different track that perhaps would not have been constructive, but your response was extremely constructive.
Senator Callbeck: The adverse reaction reporting, comes, as I understand it, from three places: the consumers, the professionals and the industry, right?
Mr. Glover: Yes.
Senator Callbeck: For the industry, it is mandatory. For the other two, it is not; it is on a voluntary basis.
I see where there have been tremendous increases — you say 15 to 20 per cent — over the last five years. I think, in the last year in fact, it increased something like 35 per cent. Of the reports you get, what percentage would be from consumers, what percentage from professionals and what percentage from the industry?
Dr. Berthiaume: The breakdown by reporting type of the reports we receive overall is 24 per cent from physicians; 13 per cent from pharmacists; 16 per cent from health care professionals, not otherwise specified; 17 per cent from nurses; and 27 per cent from consumers.
Senator Callbeck: Is industry 30 per cent?
Dr. Berthiaume: No, this is by reporter type. If a physician reports to the industry and the industry reports to us, it will be a physician report. We receive reports from both industry and directly from the Canadian public. If the Canadian public reports to industry, then industry reports to us.
Senator Callbeck: What percentage are you getting from the pharmaceutical industry?
Dr. Berthiaume: From the pharmaceutical industry, it is 82 per cent of all the requests we are receiving.
Senator Callbeck: Has that increased much or has it stayed about the same?
Dr. Berthiaume: The percentage of reports from the Canadian public is slowly increasing. It used to be more from industry and less from the public. We now accept reports from the Canadian public, and they are at 18 per cent and growing.
Senator Callbeck: The percentage from the pharmaceutical industry is growing. Is the 82 per cent growing?
Dr. Berthiaume: The overall number is growing.
Senator Callbeck: Yes, but what about the breakdown?
Dr. Berthiaume: It is decreasing because the portion from the public is increasing.
Senator Callbeck: Has it increased a lot in the last five years?
Dr. Berthiaume: I do not have a lot of information about the evolution of the trend, but it has gone from a small number of reports to 18 per cent of 42,000 reports, which is significant. That is the number of reports we are getting from the Canadian public.
Senator Callbeck: You mentioned that to address the problem of underfunding, you have taken outreach activities. What are those activities?
Dr. Berthiaume: We have had a publicity campaign to encourage the Canadian public to report. There was information in the media. There was a learning module for health care professionals to explain how to report and the process of reporting. We have engaged with a community of pediatricians from across Canada since 2004 to have them report adverse events, when they see them, directly to us. We have taken a number of steps to increase our outreach and have more reports. The numbers we are getting now are testimony to that.
Mr. Glover: If I may, building upon that, there is a general phenomenon. Certainly, I support what my colleague has said; he is absolutely correct. However, another phenomenon is happening concurrently: Canadians generally are more involved in their health care. That has driven us to change the way we behave. It drove some of the Auditor General's observations, to be frank. Canadians, not all but a large number of them, want more information about the drugs being prescribed to them. They have questions of their physicians. The MedEffect Canada website has the Canadian Adverse Reaction Newsletter that not only feeds information to Canadians about the potential risks of drugs but also encourages them to talk to their physicians and encourages physicians to report adverse effects. It has created a channel for them to report adverse events to us. As more Canadians become involved in their health care systems, we will see more Canadians continue to report adverse events to us as well as to their physicians. I suspect that all boats will rise with this trend.
Senator Callbeck: I certainly agree with you that Canadians are more interested in learning about drugs.
Going back to mandatory reporting, industry is the only one that has mandatory reporting. Is it the same in other countries? Professionals do not have to report and is on a volunteer basis.
Dr. Berthiaume: To my knowledge, four other countries have mandatory reporting for health care professionals: France, Sweden, Spain and Norway. Basically, these countries submit their reports to the World Health Organization. In terms of reporting per capita, we are doing better than these other countries. Even if reporting were not mandatory in Canada, in terms of the number of adverse events reports we are getting, we are doing well. In fact, we are sixth in the world in terms of adverse events reports that we receive from the different sources of information.
Mr. Glover: That is the physician's response. As the head of this organization, let me be blunt. If the committee were to consider that, I would be apoplectic about how to enforce it. How do you go into a doctor's office and ask if they reported and police their behavior? What would we do if they did not report?
As Dr. Berthiaume said, other countries have this and are doing no better than we are. As a regulator, our responsibility is not only to have those authorities but also to enforce them. The issue of the practice of medicine, patient confidentiality and finding our way through that would be an incredibly complex area to place the regulator in all of this as it moves forward. I appreciate the interest in this issue, but it is a case of being careful about what we wish for on some of these points.
Senator Callbeck: You talked about issuing risk communications and updating the warnings or instructions on drug labels. Who receives the risk communication that you issue? In my province of Prince Edward Island, who receives those messages?
Mr. Glover: I will have Dr. Berthiaume elaborate, but the short answer is that we target the communications. Some communications will be targeted to the health care community because the drug is used only in a hospital setting, for example by cardiology. We target the professional level with specific technical advice for the health community. In other instances, we do a broad public communiqué that is picked up by the media, reported in newspapers, placed on our website and put in the MedEffect newsletter. Depending on how a particular drug is used and the level of risk, we try to target both the messaging and the audience to greatest effect.
Dr. Berthiaume: In a typical letter to provide safety information, if the drug is issued in collaboration with the manufacturer, we would ask the manufacturer to mail it to all physicians in all provinces. We would ask the manufacturer to post it on their website, and we would post it on our website. As well, we would send it to the MedEffect newsletter that Mr. Glover mentioned. It is an outreach strategy such that any member of the Canadian public can register on the website and they would receive all of our postings each time we issue a risk communication. All types of risk communications are included.
Senator Cordy: Mr. Glover, you are absolutely right in saying that Canadians know far more than they knew years ago. When many people go to the doctor about a health concern, they go armed with amazing amounts of information.
I was glad to hear you raise the issue of lack of transparency because we on the committee have heard that people are very concerned about the lack of transparency. I do a lot of work with MS patients, and they are concerned about the lack of transparency for drugs. As you say, there is always the risk benefit when you look at a drug. Every drug has risks, and we hope that all would have benefits to the patient.
You talked about whether a drug has been approved or disapproved. When a drug is not approved, would we know why that is so? If clinical trials for a certain drug were to stop, would the public be aware of why it was stopped? Drugs come under review. MS patients were concerned when Gylenia was under review because no one knew why it was under review. People were still taking the drug and wondering if they should be taking it. Have those doors been opened in terms of transparency? Will that information be available to all Canadians?
Mr. Glover: I will try to work backwards through the questions.
Without a doubt, we are moving to make more and more information on all of our activities available to the general public. Why we approve a drug or do not approve a drug is called a summary basis of decision. We started it with our positive decisions, so people know why we have approved a drug. We will look to expanding that to those that we do not approve, giving the rationale for not approving it. We have not yet done that, but we have every intention to do so, as you will see in the response we have tabled. We are moving to open the doors that you talked about that are currently closed.
The same applies to clinical trials that we have approved so that Canadians will know which sites have been approved by Health Canada, and we will maintain that as we move forward.
I in no way want to mislead the committee by indicating that we have completed all of these activities and that the system is as transparent as Canadians and Parliament would like it to be, but the department has committed to make it that transparent and steps are well under way to do that.
There are challenges with confidential business information and personal information that need to be considered as we move forward. That is by no means an excuse not to take these important steps, but it does at times complicate matters in terms of needing to respect the privacy of patients, particularly in small locales and those sorts of things.
As we move to make more information available, there are some things we have to take into account to protect privacy and to protect confidential business information. We do not want to drive innovation out of this country. We do not want drug companies to withhold products Canadians need, should the pendulum swing too far. It is very important to find the appropriate balance to give Canadians and the health system the information we need while still creating a climate which, recognizing that we are a very small per cent of the global market, provides an incentive for the companies to bring product here.
I receive much correspondence from people saying that a certain drug is available in Europe or in the United States and asking why they cannot get it here. That decision is often times not mine as the regulator. Rather, the company has said that they are not interested in bringing it to Canada as the market is not big enough, or they are focusing on other markets before coming to Canada. There is that delicate balance.
I will ask Dr. Berthiaume to respond to the question on clinical trials.
Dr. Berthiaume: This is not entirely my area of expertise. We encourage people who submit clinical trials to register. There are two international websites where they can be registered. People who submit clinical trial applications are strongly recommended to register them, and that will eventually include information about the outcome of the trial.
Senator Cordy: We are doing post-approvals, so I am asking about when a drug is under review after it has been approved. If a drug is under review, Canadians do not get the information about why it is under review. That again relates to risk benefit that patients should look at. Will that information be available to Canadians?
Mr. Glover: That is a very delicate question and all I can say is that we continue to consider that. We have moved to announce that we are initiating safety reviews. We need to have further consultations with the medical community about what to do.
One thing we are concerned about is creating unnecessary concern when we have not completed a safety assessment. We want to signal to patients taking this drug and to practitioners prescribing it to be careful, to read the label and use it appropriately as there may be problems. Given that we have not conducted a full review of what the potential problems may be, we do not want the health system to overreact in the event that, upon completion of our assessment, we find that it was not the problem we thought it was. We are struggling to find that balance.
Dr. Berthiaume: This is key. There is a balance between transparency and providing relevant information. It is a dilemma in public health whenever there is an emerging safety concern. You need to know what the concern is and what to relay as information, especially on drug safety matters, because of the phenomenon that Mr. Glover mentioned; that is, that adverse events may be due to external factors rather than the drug. We need to ensure that safety concerns that we see are actually related to the drug. This is why there is sometimes a delay between what we call a potential signal and regulatory action on the signal. This is not typical to Canada; this is how it is done everywhere in the world.
Senator Cordy: Mr. Maxwell, in point 10 of your presentation you speak about the 54 safety assessments. Health Canada recommended that 24 be issued to inform the public of new safety information. Half took up to six months and three took up to a year. I would think that those communications would have to be dealt with in a very timely manner. Have you been monitoring how quickly Health Canada has moved on this?
Mr. Maxwell: No, we tabled the audit in Parliament about a year ago. We finished the actual work 16 or 17 months ago. No, we have not been in to get an update on how they have improved on those time standards.
Dr. Berthiaume: The committee should rest assured that whenever there is an urgent safety issue, we communicate urgently on it. Some changes, such as labelling, are not in the warning section but rather to provide complementary information. Sometimes we wait until the label changes are implemented before we issue the risk communication. The fact that there is some discussion and there are sometimes a number of drugs involved in updating the label process means that the issuance of risk communication can be delayed. We never delay a risk communication when the issue is urgent or if there is new information that needs to be provided to Canadians. In those cases we issue a risk communication right away and complement it with additional information later.
Mr. Maxwell: On the question of timeliness, when we did the audit there were time standards in place for only certain parts of the process. There was not a time standard that dictated how quickly a risk communication would come out. The time standards that were in place were largely about the duration of time necessary to do the safety assessment.
Senator Martin: This is a very complex and interesting area. I have had some personal experience with family members and friends who may not have been sufficiently informed in order to ask the questions they should have, or the information was not available.
With regard to the communication of information, you have talked about targeted communication as well as general communiqué. In the case of a mental health patient, would case managers, counsellors and doctors who prescribed medication all have access to the safety information of drugs? They are all dealing with the patient at different times. In one case that I witnessed, there was a lack of information at the front end. The doctor prescribed a drug that had all sorts of risks associated with it. There was an advertisement on TV that listed all the risks, but the information was not necessarily available to the patient. With the communication you are speaking of, would all of the health professionals and partners have access to such information?
Mr. Glover: The answer is yes and no, and I will elaborate. If this is for an indication that was part of the original submission — i.e., there was a clinical trial upon which the submission and approval of the drug was based — that information would be in the product monograph or label. That is available on our website. Those are published and any health practitioner would be able to use that. The short answer is that our websites are not targeted to physicians; they are open to anybody. Broadly, we try to make the information available.
However, the issue of off-label use comes into play where it becomes a professional judgment and practice of medicine issue. It then becomes difficult to communicate anything about the product other than what is in the monograph. If, in the professional opinion of the treating team of health care practitioners, they decided to use the drug for a use that was not approved, there is nothing other than their professional judgment driving it. Frankly, a lot of off-label use happens and it becomes a challenge. We will update and provide safety information on off-label use if they have information that is brought to our attention.
The other reality that is important for everyone to be aware of is that when we go to the pharmacy and get a prescription, we get a little bottle and stickers with warnings. The health care practitioners deal with the monograph. That is our assessment of that drug and it can be 80 or 100 pages of warnings to be careful with that population or with this subclinical. This is not an easy, light read. When you think about the number of drugs that are involved and the size of that advice to a health practitioner, they are big, complicated documents. This is in no way critical.
The volume of information people have to move through is tremendous. As the drugs get more complicated and become more targeted for certain sub-parts of a population with certain sub-conditions, the complexity will increase. That is a long winded answer to a short question, but we work to make as much information available as we can.
Senator Martin: Your role in providing information is being done, and the onus on the professionals to sort through the volume would be their responsibility as well?
Dr. Berthiaume: This is what is known about the product. When there is an emerging safety issue there will be risk and public communications. We will issue a technical document to health care professionals, but there will be communication in simpler language that is available to the public so it becomes more broadly understandable. If people want more information they can refer to the technical document for health care professionals. We try to think about the public in our outreach strategy.
Senator Martin: Mr. Glover made a comment in his presentation about increasing the precision and nimbleness of our tools. One of the ways that you are improving the overall monitoring is to look at the tools you have and improve the precision and nimbleness. Are there other tools out there that would be very useful for Health Canada or do we have the tools that are necessary and it is about making it more precise and nimble? Would you expand on those comments?
Mr. Glover: The short and frank answer is no, we do not have the tools yet. We were dealing with paper-based systems, and that is not a good way to mine data to look for these signals. The first step has been to move to automate, have companies submit electronically and allow Canadians to submit electronically through the web so we are not hunting through stacks of paper. We are moving to automate, which is an important step.
The second step is international collaboration. If you asked any regulator, we all feel we do not have all the tools we need yet. This continues to evolve and we are all looking through the same data for the same signals. We are comparing what tools we have and what we are developing. We work closely with the European Medicines Agency. They have pharmacovigilance committees that we observe to get early signal detection. We work with other jurisdictions about tools they are developing and automation to find and sort through the signals. We constantly train our professionals, keep them nimble, encourage them to work for us and also to practice medicine a couple of days a week to stay sharp on the issues and be current.
The tools are evolving. We are building the tools and working closely with international partners so we can benefit from their work as well.
Senator Seidman: My question involves this line of reasoning. It is the absence of an electronic system to record adverse events. I was going to pick up on what Mr. Glover was saying about our "value added" for Canadians going forward. We will be evolving in the requirements for how drugs are monitored in the marketplace and, as Senator Martin mentioned, increasing the nimbleness of our tools.
Could you tell us more about the implementation of the electronic reporting? I know the Auditor General's report signalled this and mentioned something about the fact that there was a pilot ongoing and that you would be beginning in the 2011-12 fiscal year. What has your experience been with this? I believe this is where industry must report and you are trying to electronically enter that report.
I would also like to ask you about the other piece you mentioned in terms of nimbleness and tools, which has to do with the health care providers and an electronic system of reporting. You mentioned electronic health records and electronic medical records, which seems to be a superb way to identify adverse reactions depending on health care providers.
Could you please help us with those two aspects? What might bring our adverse reporting into the 21st century?
Dr. Berthiaume: The first question was about e-reporting. It is quite a major undertaking to convert from paper-based to computer-based. As you mentioned, we are in the pilot phase. A limited number of manufacturers will start to submit their adverse event reports to Health Canada in November. There will be a phased approach and the full implementation is targeted for the end of 2014.
It is a long process, but it is important to mention that there are tremendous information technology challenges, compatibility of electronic systems and confidentiality issues involved. The electronic reporting will be starting for manufacturers in November and the full system will be operational by the end of 2014, including electronic reporting from other sources such as health care professionals or the Canadian public.
Mr. Glover: I will add to that. The other issue is not just going forward. We have rooms filled with boxes and boxes of these adverse events. We have begun the process of digitizing all of that. We want to ensure that as the new data comes in, we can match that up with historical signals that have been on file for some drugs. When you think about the life of the drug and how long it is on the market, it is not just when you are looking for adverse events here and there and connecting the dots. We are doing that work.
With respect to the electronic health record, we are optimistic and hopeful. It is a lengthy process in which we work with federal partners on the creation of the record and the adoption in all jurisdictions. We are at the table. We are making them aware that this is an excellent vehicle to improve our ability to collect this, to reduce the burden on the physician, who is probably noting this stuff in the chart anyway. We think they are receptive to this issue. We do not see this as huge opposition. It is more the adoption and uptake of the EHR that is the rate-limiting step there, not what we are trying to integrate into it as that moves forward. People have been mostly positive about what we are trying to do and willing to accommodate us as we move forward. Again, not that that will not be without its challenges for privacy-confidentiality reasons, but we feel those can be overcome.
Senator Seidman: If I might just ask about two very specific aspects of electronic recording and what progress you are making on those, one has to do with foreign reports, which I understand have been entered manually as well, and whether they will be added to the system. The other has to do with what Mr. Glover mentioned several times in his presentation, and that is vulnerable populations, subgroups — women, children — and whether there will be some means to specifically monitor the adverse drug reactions in those population subgroups.
Mr. Glover: You can tell from body language that my colleague would like to help me out with that answer, but I will get the ball rolling.
Absolutely, all adverse events; in fact, industry is most excited about the international format because of the volume. Again, if you go back to 450,000, they are not really thrilled about having to fax those things to us either. They are as anxious as we are to get into the 21st century, so that will not be a problem at all. They are quite eager to do that, and as we have said, there are international formats for doing this. We will adopt that international format so that we can work with partners on it. This will be something industry will be used to doing in other jurisdictions as we move forward.
As we move to have these more robust tools to mine the data, the populations we are looking at can be broke down anyways and it can be very detailed scientifically. It can be people with a particular condition. It can be people of a particular age.
Some of the warnings we do are incredibly detailed, such as, "We have seen bleedings in this population with these sub-conditions." We really have to be able to parse that data any way necessary to find the safety concerns.
The short answer is that we will have no choice — and it will go far beyond whether they are a vulnerable population, male, female, of a particular age — but to connect the dots on where the adverse events are being found and produce the safety warning.
Dr. Berthiaume: It is also important to mention that there are other tools than the adverse events report that we use to monitor drugs once they are on the market. For example, we can ask for a post-market study within a specific sub-population. The database will allow searches in certain age groups or certain types of diagnosis or sometimes even with another drug you can identify certain sub-populations and then do research. The system will have that capacity.
Senator Seidman: My concern is that, as we discovered in the clinical trial study, women and children, specifically, and pregnant women are not generally included in clinical trials. The idea would be whether we have some system where we absolutely can flag these adverse reactions in these subgroups and that they would not slip into oblivion somewhere. I would like to be assured, and I know that this is also marked in the Auditor General's report very clearly where we would have a system to monitor adverse drug reaction data for vulnerable populations to systemically — and I think that is the word they use, "systemically" — monitor adverse reactions that are rare, serious and often linked to marketed drugs and data for vulnerable populations.
Is there some assurance that there is a systematic approach to this?
Dr. Berthiaume: There is a systematic approach for the pediatric population, and whether it is on-label or off-label use it is relatively easy to monitor. For pregnancy, it is more difficult because not all pregnancies are declared within the system. There is currently some will from some manufacturers to conduct certain types of indication studies in the pregnant population, so I think there is more awareness of these sub-populations, more will on the side of manufacturers to try to provide more safety information around the use of their drug within these populations.
Europe, in fact, is strongly encouraging manufacturers to conduct studies, for example, in the pediatric population. We will benefit from the results of all of these studies whenever we review these drug applications or whenever we review these risk management plans when the drug has been marketed. More and more information will be available for these populations and probably others also in the future.
[Translation]
Senator Chaput: My question is addressed to Mr. Glover. On page 8 of the presentation you made before our committee on March 28, you indicated that Health Canada documents approximately 22,000 medications on the Canadian market.
Now according to the Auditor General's report, 80 per cent of health products used by Canadians are manufactured abroad.
You mentioned that Canada has signed mutual recognition agreements with 26 partners in various countries.
Do all pharmaceutical products that are manufactured abroad and imported into Canada come from a country with which Canada has signed a mutual recognition agreement?
Mr. Glover: No, but that is not the main issue. The most important thing, in my opinion, is that every product that enters the Canadian market be subject to review.
Senator Chaput: By Health Canada?
Mr. Glover: Yes.
Senator Chaput: Even if the country does not have an agreement?
Mr. Glover: Precisely.
[English]
The issue is, all the drugs entering this country, coming from a country where we have mutual recognition, do we exclude those? The answer is no. In fact, you will find that a lot of the source ingredients, active pharmaceutical ingredients, the APIs that start the building blocks of a lot of the drugs are coming from countries like India and China, which used to be manufactured in places like Germany. We do not have agreements with those new countries yet, the developing economies. We go in and inspect those. Our partners go in and inspect those, so we use that. Whether we have an agreement with the country or not, the drug must be subject to a full review either by us and our partners or by us alone so that we are confident, before allowing any product on to the market, that it has been evaluated regardless of where all the aspects of that can come from.
The global supply chain is huge here. You can have gels manufactured in China. You can have the active pharmaceutical ingredient coming from India. You can have the pressing of the pill done in Brazil. All of these products are moving, and we understand all of that. We look at all of the different parts of the supply chain, and our safety assessment deals with all the different complexities of that system.
[Translation]
Senator Chaput: So you have the authority to do so, even without an agreement with the country in question?
Mr. Glover: Undoubtedly.
Senator Chaput: Very well. Approximately what percentage of these medications comes from a country that does not have an agreement with Canada? And how many of the 22,000 medications do?
Mr. Glover: I do not have the numbers with me to answer your question at this time, but I could provide them to the committee. But generally speaking, I believe that most of these medications contain one aspect or another that comes from a country with which we have not signed an agreement.
[English]
Again, just to underscore, given the complexity of the system, the system has really changed. We used to deal with domestic manufacturers making products in this country. The industry is consolidating. Often one or two plants serve the entire market, so it is highly probable that for any drug entering our country, some aspect of it has come from a country where we do not have a mutual recognition. There are thousands of ingredients, molecules that are assembled.
As to an exact percentage, we will follow up with the committee, but not in an attempt to mislead or stall in any way. I would suggest that the vast majority have some aspect that has come from a developing economy or a developed economy for which we do not yet have a mutual recognition agreement.
[Translation]
Senator Chaput: On the medicine bottle, or on the label, it would say "made in Canada"? What would be indicated?
Mr. Glover: I do not think that is indicated.
Senator Chaput: There is absolutely no indication of where it comes from?
Mr. Berthiaume: I believe the bottle indicates where the medication was manufactured. However, the label does not tell you where the various ingredients came from.
[English]
Senator Enverga: Most of my questions were answered already. However, my other question is about the adverse reaction reports. It says that 450,000 adverse reactions were reported from other countries. What other countries are we talking about? Are we talking only about the MRA countries, or are other clinical trials being done in countries other than the MRA ones?
Mr. Glover: The short answer is that the requirements state that if the company is made aware, they must tell us. It is not limited to where we have those mutual recognition agreements. If the company is made aware, regardless of where it occurs in the world, they must tell us. There is no limitation on that. If the company is aware, they have a legal requirement to tell us that there has been an adverse event, and that is not limited to the clinical trial phase. That is after the drug is on the market and has been on the market for many years. Any adverse event that the company is made aware of, regardless of where it occurs, must be brought to our attention as the regulator in Canada.
Dr. Berthiaume: May I just add a little piece of information? For the rest of the world, usually what we want is what we call unexpected serious adverse reactions, the ones that are not on the label, the ones that we do not know. For Canada, what is expected to be reported is all adverse events. As for the rest of the world, if you have penicillin and there is a skin reaction in Ireland, for example, it does need to be reported here because it is on the label. It is well known, so it will not need to be reported by the manufacturer. They can still report it, but it is not what is mandatory to be reported. What is mandatory to be reported in Canada from use in other countries are the reactions that are unexpected. We define as unexpected the ones that are not described in the Canadian product monograph — the Canadian label.
Senator Enverga: Has there been any time when some adverse effect was not reported to us by countries other than MRA ones? Have there been any examples?
Dr. Berthiaume: There are numerous examples. If you think, for example, of an adverse event that would happen to 1 in 1,000 patients or 1 in 10,000 patients, these adverse events will be identified much earlier in countries that have bigger populations. There are a number of adverse events that occur in other countries before they occur in Canada. With our partnership and our collaboration with international regulators, we can leverage that.
Also, there are a number of other means through which we can have access to this information. It will be submitted to us via the manufacturers but also via periodic safety update reports, which is a document that we can ask for from manufacturers. It provides all of their international data, so that is another way that we can have access to the international information. We can also have access to the WHO database, as I mentioned before. Through the WHO database, we will also have access to all of these foreign reports. We have a number of ways to access the adverse event information that occurs outside of Canada. On top of the direct reporting from a manufacturer, we can indirectly access that information through at least three other means.
Senator Enverga: Do we have a standard? Do we know of any standards for clinical trials? Is the same thing done in the MRA countries being done in other countries that are not part of the MRAs?
The Chair: I am going to ask you to defer that question. We will provide the senator with the results of our clinical trial phase. We are now dealing solely with post-approval. He is new to our committee today. We have done a full study on that aspect, so please stick to the post-approval issues.
Senator Enverga: Sorry about that. Those are all of my questions.
The Chair: That is okay. Thank you.
Senator Seth: I think it was really informative today compared to last time. A lot of things change. Thank you very much.
There are a few questions coming to mind. I understand, of course, that safety is the most important part as far as health care in Canada. I am a physician, so when the drugs come onto the market, you are usually given the information by medical reps. That is how we get the first information, with the full details of the pamphlet and all of that. Then we try the medications, and they come, at various times, to follow up for particular drugs. We give them information that we are getting. We try to insert into that what side effects the patients are having.
I thought these things were documented so that they could give them to their manufacturers. This is transparency because we are health care providers. We give them the side effects that are happening. We say, "This is happening with this patient, so we cannot use the drug." We get back further information the second time when they come for review.
It is not true that we have been documenting, and they do not give it to the Health Canada. We do not know that part. However, the physicians are already responsible for documentation.
As for my second question, I will give the example of birth control pills. Yasmin came out, and there was a very low hormonal effect, which you use a lot. It came out that there was a problem with blood clots if it was used. Of course, Canadian health professionals recognized this before it was even released from the USFDA. I wonder why we continued to use it when we knew there were many more side effects aside from the really serious one — the blood clotting compared to other birth control pills. Why did we not stop? At what stage is a drug withdrawn from the market?
Mr. Glover: I will turn to my colleague for some help with some of these answers.
With respect to our level of certainty, part of our inspection process does include reviewing the procedures that are in place so that we can have confidence that, if adverse events are identified, they can be reported. We do make efforts to try to have confidence in the system so that the adverse events can be both identified and reported and that, throughout the clinical trial, there is a process that allows that to happen. That is part of what we look for as we move forward.
It has not come up so far in the discussions, but part of what I suspect you will hear is that, in post-market, there are not only adverse events but also issues of effectiveness that are not necessarily adverse events. We have not spoken about that. For example, Health Canada conducts a review of a drug. We make a decision to approve or not to approve that drug. CADTH, on behalf of the provinces, then says, "Should we recommend to provinces that that drug go on their formulary and be paid for?" This is not asking whether or not the drug is safe; it is asking whether or not it is cost effective. That is also a significant part of the post-market activities that occur within the health system. It is not just Health Canada saying that the drug is safe. It is provinces and territories and others looking for effective, cost effective treatment. They are very heavily involved in that. It is not just, "Are there events?" but also, "Does it work? Is it treating? Is it working as well as they thought? Is it a more effective intervention than some other drugs that are on the market?" I suspect that will be something you will hear about from other players as this moves forward.
With respect to Yasmin and the birth control pill, this is an interesting case study, given that we are often compared and criticized for not moving more quickly than other regulatory agencies. This is a case where in fact the Health Canada label already had the warning and concern on it. We did not need to update our label. We did not need to follow the FDA action of updating the label because it was already included on the label in Canada and was part of something we had already picked up on in our approval of the drug.
With respect to why it was not withdrawn, there were concerns about its safety with respect to more clotting than normal, but there were some populations for whom this drug was more effective. That was included on the label so that a practitioner, if using it wisely, could still reap the benefits of that drug without the risks. In our instance, where there are always benefits and risks, the label says to the health community when and where to use it appropriately so that the benefits outweigh the risk. If they stick with that, we think it can be used appropriately.
However, they can deviate from that as a matter of professional judgment, but that is how we move forward. We will note the risks and encourage health practitioners to read the label and then to prescribe appropriately to the patient.
Dr. Berthiaume: The issue is that a lot of information that we provide on products, once they are marketed, is to help with informed decisions. With antibiotics, for example, some have more risk than others, but they also have additional benefits. For a regulatory agency to decide to pull a product from the market, it has to be a clear shift in the balance of the risk versus the benefits.
A bit more risk, when it is clearly labelled and the information is available to both the prescriber and the patient, is still acceptable as long as there is informed consent on the part of the patient.
Senator Seth: Yes, but in this case it was not. When it came onto the market, it was not written that there is a high risk of blood clotting. It came in December 2011. At the time, it was recalled. It was not relabeled.
Dr. Berthiaume: For all birth control pills, as you know —
Senator Seth: This is a common side effect.
Dr. Berthiaume: Yes.
Senator Seth: It is not enough for a patient to go on this. It is clear who should not be on this and who should be.
The Chair: We are not going to get into a debate on a specific compound, but you could follow up with any information with regard to the senator's question that revolves around the specific compound. I do not want to battle back and forth on an individual application.
Senator Seth: All right.
The Chair: I thank you for your detailed response, Mr. Glover, and particularly for your indication that you have an even more detailed analysis of your progress in many of these areas that you will provide to the committee. Did I hear that correctly?
Mr. Glover: Yes, it is in response to the Auditor General's report; absolutely.
The Chair: Excellent.
I will not ask quite as many questions as I would have asked otherwise, but I do want to highlight some that appeared in the Auditor General's report, which my colleagues have picked up on here, to perhaps add another phraseology to the way we look at it, and ask that you respond in detail.
First, I have a question for information. You referred to the various pieces of information made available when a drug is prescribed to a patient. You also said that in addition to the label, there are two sheets, but I am seeing today that they run to several sheets, even for relatively routine drugs.
Are those sheets prepared under the guidance of Health Canada or is that what the pharmacist and/or drug company develop and provide to be handed out with the prescription? I am going to the question that I thought you handled extremely well with regard to the nuance between having the right to force labeling versus persuasion. My question is: Do you have the authority to require that information on those sheets before it appears on the label?
Dr. Berthiaume: These sheets are distributed at the point of care, so they are under the practice of pharmacy. We do not have direct authority over the content of these sheets. Often these sheets are prepared by providers who update them as a summary of safety information. They provide the patient with some of the information, but as Mr. Glover mentioned before, it is often relatively short and focused.
The Chair: In addition to your forms of encouragement to bring the information forward, do you have the ability or the authority to provide the information to the pharmacist directly and, as you have indicated, leave it to them to include it in those documents?
Dr. Berthiaume: The Canadian product monograph or the Canadian label was modernized a few years ago. The third section of it is totally focused on information for the patient. That part of the product monograph can be printed easily, although it may be too long for certain drugs. Information already developed by Health Canada is aimed at the patient. How this will be used by health care professionals is at their discretion.
The Chair: I understand. Can you make the issue that this relates to the labeling available to the pharmacist before it appears on the label?
Mr. Glover: No.
The Chair: Okay. I hear that as a no.
Mr. Maxwell wants to come in on this.
Mr. Maxwell: Yes. I may be anticipating where you are going with this line of questioning.
One of the things we talked about in the audit is how important it is for the department to know how effective these risk communications are. Are 80 pages of dense text actually getting through? Health Canada had made a commitment in its post-market surveillance strategy to do that effectiveness evaluation. We made the comment that they had not gotten very far with that. I noted that in his opening statement, Mr. Glover referred to the fact they are still at a fairly early stage with that.
Our sense is that understanding how these things influence behaviour is not an established science. This is something that various regulators have struggled with.
The Chair: Thank you very much.
I would like to come back to an issue that Senator Seidman began to explore. She focused on groups that are under-represented in clinical trials and the prescription of drugs for them. The Auditor General noted on page 18 of the report, and we are aware that this occurs generally in any event, that once the drug is approved, it is reported that physicians often prescribe the drug for conditions for which it was not specifically tested.
In that situation, as well as in the prescribing of the drug for populations that were not part of the clinical trial — children, pregnant women, and the elderly — do we have or should we have a requirement that the behaviour of that drug be automatically reported and not simply wait for a phase IV trial?
Mr. Glover: Mr. Chair, that is an excellent question for which I suspect there will be a wide range of opinions. It speaks to provincial jurisdiction, practice of medicine, and a range of other things. I can offer my personal perspective and some of the regulatory tools that we currently have.
As I said in my opening remarks, we can do a notice of compliance with conditions. If we see that there is early benefit for a drug that is needed quickly, we can make it available with conditions, which can restrict its use. It is not done often and there are some thoughts in the international regulatory community about things like progressive licensing; the drug can be licensed for this use and not anything else to allow it to come to market and prevent off-label applications. There are new techniques being thought about to deal with being on the market, off the market. Once it is on the market, it is professional discretion and judgment about how to use it.
I believe France is considering legislation that would require the physician to inform the patient that they are prescribing a drug for what we would describe as off-label use. It is not part of the indication for which it is approved, but in their professional opinion — they would be required to disclose that to the patient. The health system is considering things like that.
The Chair: I am not concerned about that aspect. I am concerned about the fact that this occurs. When the drug is prescribed for a woman who is pregnant, my question is: Should the physician be required to automatically report on how the patient responded during the time that drug was being consumed?
Mr. Glover: As the regulator, it is my personal opinion that the health system has a requirement to contribute to the overall effectiveness of the entire health system. I would suggest that any adverse event is significant and should be reported so that any safety signal can be picked up. Any Canadian, any citizen around the world can contribute to the safe use of these drugs and when they should not be used. All adverse events are incredibly important and I think there is an obligation for all parts of the health system to be reporting those to contribute to that knowledge base.
Some people describe our work as looking for needles in haystacks. We get less than 10 per cent — some people say less than 1 per cent — of adverse events reported. The more adverse events, the better we are able to advise how to use these drugs safely. I am not sure I can go beyond that.
The Chair: I appreciate your answer with respect to the adverse reaction, but there is a positive side. If there is a requirement that when a drug is prescribed to a subgroup that was not included in the clinical trial, or for a symptom for which it was not formerly approved, that the positive information is collected it enhances the ability of our health community to treat populations who are not included in these trials. It will be a long time before anybody gives the authority to include certain subgroups in clinical trials, yet the drugs are prescribed for them once they are approved. I am not just going after the bad side of this. There could be a very good side of this, which is that physicians — if the information was being collected because it is out there — might have the ability to prescribe to these sub-populations with confidence that a new drug could benefit them. I will not pursue that, but I have made the point and if you have further information I would welcome it.
Mr. Glover: Thank you for the further elaborating and I understand better where you were going with your intervention. Yes, any information on the benefits and the risks help regulators advise the medical community about when and how to use a particular drug safely. Perhaps it is the cynic in me, but the one thing we would want to avoid with that kind of situation — not that all drug companies would do this — is creating a mechanism that would allow companies to avoid conducting the appropriate clinical trials and coming forward from the outset with a regulatory submission about the safety. It is illegal to promote off-label use; that is prohibited. We want to ensure an incentive is not created for the drug companies to bring a drug to market with one indication, which should have been done through a controlled study, and is done through other mechanisms. I am not saying what you are proposing does not have merit but there are other considerations.
The Chair: We will look at that off-label issue as a focus study so I appreciate that, but I am not going down that road either. I am looking at monitoring and the more specific issue is the under-represented populations in any drug trial. These drugs get approved for use in these sub-populations. If there was simply a requirement that when physicians have prescribed the drug in this area, they provide feedback to Health Canada with regard to the application it might well be of benefit. Again, I will not pursue that further.
There was another aspect of this I wanted to pick up on but I see our time is moving along and Senator Eggleton has an additional question.
Could you state the questions and we will see if you can answer the question in the time we have left and if not, follow up with the answer to the question. Let us get the questions on the record.
Senator Eggleton: I have to give a preamble to the first one because it deals with openness and transparency, which has been a big issue around here when we were dealing with the last phase, particularly doing comparisons to the European Union and the United States with respect to that.
These issues keep coming up. There was an article in the Vancouver Sun a couple of weeks ago about Health Canada's secrecy regarding drug manufacturing plants, which means Canadians cannot be sure medications are safe. Comments were made by a professor at a Victoria university as well as a pharmacist and director of the Applied Health Research Centre at St. Michael's Hospital in Toronto.
When it comes to the question of label changes, Health Canada does not make the safety or effectiveness concerns that prompt labelling changes public unless you consider it to be a serious matter. I wonder where you draw the line here in terms of what is serious.
I also want to pick up on something you have said on this same issue of transparency. You spoke last time you were here about the protection of proprietary rights of the manufacturer. Are we in line with what the European Union and the United States are doing on that? Are we behind in terms of how much of that we divulge, or how much we use this proprietary rights issue as a means of not divulging information? Perhaps you can talk a bit about transparency.
One further question I have is about Bill C-51 that was tabled in 2008. When Parliament dissolved, the bill died. I have not seen it since. At that time, it was considered to bring us up to date on some of the same kind of provisions they have in Europe and the United States. It is up to the minister and the government about whether it comes back, but I would like to get your perspective on whether there are problems you see in your department with respect to the provisions of C-51? Is that why this bill has never been brought back?
The Chair: You cannot possibly answer those first two questions in the time remaining so I would like you to provide us, to the degree you can, a detailed answer to those. They are important. In addition, the electronic health record is an issue that we explored in considerable detail with regard to our review of the 2004 health accord. It is astounding the amount of money, in the billions of dollars, that we have deliberately expended in an attempt to develop an electronic health record that would also provide information that you have touched on here today and my colleagues have asked about.
I know that human nature is one the biggest factors in that having not been achieved to this point, but I would also appreciate if you have any thoughts with regard to the questions that have been asked, particularly with regard to monitoring, the reporting of adverse reactions, in addition to those you would be intending to have submitted in the document you referred to.
Mr. Glover, the questions that Senator Eggleton has asked are important and I know the answer is not trivial in terms of response. We would welcome you following up with that.
Mr. Maxwell, in addition to your testimony, in hearing the questions that have been asked today, if there is any information that provides insight that the Auditor General thinks or that your office thinks could be helpful to us with regard to the questions my colleagues have asked, we would welcome that as well.
To all of you, I want to thank you for your efforts in clarifying the questions that have been asked and the thoroughness with which you have attempted to answer the questions.
I was really pleased, Mr. Glover, with your frank statement of where you are and the amount of additional information that you have promised you would give us in the document that you refer to, and we will really be looking forward to that.
To the witnesses today, on behalf of my colleagues, I want to thank you, and I want to thank senators for the clarity of their questions.
(The committee adjourned.)