Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology

Issue 13 - Evidence - March 28, 2012


OTTAWA, Wednesday, March 28, 2012

The Senate Standing Committee on Social Affairs, Science and Technology met this day at 4:15 p.m. for a study on prescription pharmaceuticals in Canada (topic: Clinical trials).

Senator Kelvin Kenneth Ogilvie (Chair) in the chair.

[Translation]

The Chair: Welcome to the Senate Standing Committee on Social Affairs, Science and Technology.

[English]

My name is Kelvin Ogilvie. I am a senator from Nova Scotia and chair of this committee. I will have my colleagues introduce themselves, starting on my left with the deputy chair.

Senator Eggleton: Art Eggleton from Toronto.

Senator Merchant: Pana Merchant from Saskatchewan.

Senator Peterson: Rob Peterson from Saskatchewan.

Senator Demers: Jacques Demers from Quebec.

Senator Seth: Asha Seth from Toronto.

Senator Seidman: Judith Seidman from Montreal, Quebec.

The Chair: First, this is the first meeting of a new study; and second, this is the first segment of study in the area of pharmaceuticals in Canada. Specifically in this section, we are looking at the clinical trial process.

I am delighted that we have Health Canada with us to start this session and that Mr. Paul Glover and his colleagues, Ms. Barbara Sabourin and Dr. Robert Cushman, are here to help answer questions from the committee.

It is my understanding, Mr. Glover, that you will start off the meeting. You are Assistant Deputy Minister of the Health Products and Food Branch. I am pleased that you have agreed to provide some background with regard to the clinical trial process, after which we will follow up with questions. It is extremely critical that the members of the committee understand the elements that make up this important process. I am sure that you and your colleagues will enlighten us on that today. Mr. Glover, please proceed.

[Translation]

Paul Glover, Assistant Deputy Minister, Health Products and Food Branch (HPFB), Health Canada: Thank you, Mr. Chair. I am happy to be here today to talk to you about our role in the drug approval process in Canada.

[English]

We are very happy to be here today to share with you the role that Health Canada plays in the approval of drugs in Canada. I am joined today by Dr. Robert Cushman, who is the Director General of the Biologics Directorate within Health Canada, and by Ms. Barbara Sabourin, who is the Director General of the Therapeutics Products Directorate.

I would like to begin by acknowledging that this is slightly different than the norm in this kind of context. I will be taking some time to walk you through a PowerPoint presentation, which I believe has been distributed to you. I will try to do that fairly expeditiously to allow for as much time for your questions as possible. I do want to take some more time than is normal, given the complexity of the drug approval process and all of the various steps that are involved. Given the quite extensive study that you have proposed, I hope this will be helpful and will set a solid foundation for the committee as it begins its work.

Turning to slide 1, we will talk about the approval process that we use for prescription drugs. We will describe the method that we use for monitoring those drugs once they are on the marketplace; and we will explain how we deal with off-label prescription pharmaceuticals and what happens in that regard.

On slide 2, we have tried to depict graphically through that little circle how this process works. At the top, you will see a drug is discovered and through that there are preclinical studies to say does it actually do what the innovator thinks it may do. They then come to us, and this is where the regulatory role begins, with a proposal for a clinical trial to validate on a larger scale that the drug does do what they believe it does. We actually have a role in approving the safety of that clinical trial in its design to make sure that it will provide the evidence necessary for us to later approve that drug and that the trial and its method for conduct does not compromise patient safety along the way.

Once the studies are completed, as you can see, we actually get into drug submissions where we then review the drug submission — what happened as a result of the clinical trial and other safety data that they provide. Then, we provide a licence to allow that product on the market. It moves from there to how it is introduced into the marketplace and, with adverse event reporting, AER, we follow up after the drug is in the market to see if changes are required to labels or to remove the product from the market in extreme instances where it is necessary to provide further guidance. If over time there are further therapeutic uses for that drug, we encourage the submitter to come back into the process so that we can follow it up with further label updates. I will explain all of that as it moves forward. There is a life cycle to these drugs and how we view them.

On slide 3, there are three very distinct roles that we play in reviewing the drugs. It comes back to those very different steps that I described previously. They are each done by different parts of my organization. Health Products and Food Branch is a large branch that deals with not only prescription drugs but also foods, natural health products, medical devices, biologics and a range of things. We can touch on those if you are interested. However, there are three main directorates involved. The Therapeutic Products Directorate gets into the pre-market review — a clinical trial, its study and design and the actual submission. Post-market surveillance is done by the Marketed Health Products Directorate, where they get into dealing with the AERs, what the label says and what the problems are while it is on the market. Then, we consult and work with the Therapeutics Product Directorate if there are problems that need further label updates. Finally we have the inspectorate — Health Products and Food Branch Inspectorate — where we literally have inspectors who go out and check the plants. Are they making the drug in a safe way? Are they meeting the standards that are required? We inspect clinical trials as well. These are the people that go out. They are three separate and distinct entities. They talk to one another, but there are some very important reasons for those separations, which we will get into.

I will spend a minute talking about clinical trials on slide 4. The main purpose of the clinical trial is to provide research about these new treatments that will inform the review, the safe use of that drug, the appropriate use and what should be on the label. Before a clinical trial is begun in this country, we sit down with them, look at those clinical trials, the design, what they are trying to test for, and how they are looking at that, and we provide comments on the protocols for the clinical trial and how it will be conducted. Part of our process in doing that is to ensure that the participants are not exposed to any undue risks, because these are experimental drugs at this time and they are not certain that they work.

The knowledge that we gain from those clinical studies then serves as a basis for future approvals as we move forward. There are quite a few challenges with respect to clinical trials as we move forward. If you think about it, it is quite intuitive. One of them is the notion of testing a drug on a pregnant woman or on a young child. Those are not traditionally done in clinical trials for obvious reasons. That then leads to further challenges, which I will come back to, as it moves forward. Pregnant women, in particular, breastfeeding mothers, genetically challenged populations, and seniors, who often are the most frail, are the ones for whom it is hardest to develop a safe clinical trial. That further lends itself to some of the challenges as we move forward. We have developed guidance on all of these things, and I will come back to each of these points.

Slide 5 is the pre-market review. The clinical trials have been conducted, and we have worked with them on how to design it and run it safely. They have conducted that and are ready to come in. At this point, they come in with what they believe is an appropriate indication of what the drug is used to treat and data to support that. We review that, plain and simple. Our reviews are based on three basic tenets as we look at safety, efficacy and quality. Is the drug safe? Does it do what it says it will do? Is there quality so that each pill is the same pill and people are receiving the same amount of medication? We are looking at that at this time as we move through this.

At slide 6 we will take you briefly through what that looks like and how complicated that can be. The drug submission comes in and that first top box is processing. We literally spend 10 days processing the application to ensure that it is correct and complete and to get it into our system. We then spend another 25 to 45 days doing screening to make sure it is complete — that the data is accurate and the studies are reputable, and that we have what we need before we put it to reviewers. Up to 45 days are spent just looking at that before a reviewer to make sure that it is appropriate for the technical staff to start going through it.

Our performance standard is 180 days for the review of a generic drug and 300 days for a new drug. The reason for those differences is that for a generic drug, the clinical studies and all those things have been done, and we know what the drug is supposed to do. We are looking to ensure that it is a good and safe copy of the brand name drug. We want to ensure that it is bio-equivalent, which is the technical term we use. Does it interact with the brand in the same way that the brand drug did? It is a different review because we are not going through whether the drug is safe and does what it is supposed to do, which has already been done. We look to see that it does the same as the brand name drug. We look at safety, quality and at what is on the label — the product monograph — as those things move forward. Those are the performance standards that we have. It sounds like an incredibly long time. I completely understand that because most people are quite surprised when they hear that. We think that 10 to 45 days, even before it gets to a reviewer, to ensure that the data are good is a significant amount of time.

I will move now to slide 7 where you can see a typical drug submission. There literally are 18-wheelers that back up and off-load boxes and boxes of data. It is remarkable. We build hallways a little wider than normal so that carts can move those palettes of boxes to some poor reviewer who off-loads them and starts plowing through them, page after page. That is a typical new drug submission. The amount of data is really just to make sure we have everything we need.

We open up all those boxes and log them into the system. You get a sense of the amount of time. Then, does the submission have what it claims it has so that a reviewer does not start going through seven or eight boxes to find that a critical piece of data is missing and we have to send the whole thing back to the company? We really try and ensure that before that gets to the reviewer or the team of reviewers that go through the submission it is very complete, but these are very large files as it moves forward, just to give you a sense of the complexity of this.

That gives you a sense of what is involved with the drug approval. We will then speak about post-market surveillance and what we do.

There are currently about 22,000 drugs, and that is drugs as defined under the Food and Drugs Act. That would include a wide range of things. There are about 16,000 prescription drugs on the market that we deal with, so those would have a DIN, an authorization. They are out on the market for work.

We make sure that all drugs we authorize are available on a drug product database. Anybody can go to our website; they can look this up; they can search about what drugs have been approved on our website, so we do that.

We do require, under the act, that any adverse events that occur are to be reported to us, so any serious adverse events where there could be serious side effects are required to be reported to us, and MedEffect is the system we use to do that. We will accept adverse events from consumers, from patients, from health professionals. We really look to make sure that we have this, and then we report out through that on the Canadian Adverse Reaction Newsletter on a regular basis about what we are seeing.

I would just like to take a minute to give you a sense of what we are dealing with. We received 33,000 domestic adverse event reports in 2010-11. In addition to those 33,000, we received 350,000 adverse events that happened outside of Canada. The manufacturer of that drug told us about an adverse event that occurred in some other jurisdiction. These are huge numbers — 33,000 just in Canada and another 350,000 internationally.

We sort through all of that data. We could see a number of adverse events repeating themselves. Some could be very minor, not worthy of follow-up, a person for whom it did not work well, and last year we narrowed all of that down to about 1,500 potential safety issues that we really felt needed further follow-up. For those, we thought that, as we moved through this, if you boil it down, we did about 130 drug safety issues and about 60 risk communications or label changes, so you are just constantly sifting through data looking for needles in haystacks from that 33,000, 350,000 — from what does that tell you, to, okay, how do you lump those together, to those are common events, they are related to the same drug, the same type of population, to investigating that, to it is on the label, we just need to remind people to use it correctly, to the label needs to change, to "Dear health care professional" notices. It is a range of things that we do as it moves forward, so that gives you a bit of a sense of what we have to deal with.

It is worth pausing on this point because it is, candidly, one of the biggest challenges in the whole life cycle approach that I showed you, and that is the estimates about how many adverse events are reported, and some groups have it as less than 1 per cent. Some groups think that decimal point is in the wrong place and it is 0.1 per cent of all adverse drug reactions, so there is a range of opinion, but it is universally believed that it is low, that most adverse events are not reported not just to Health Canada but to any jurisdiction globally for a wide range of reasons: the patient just stops using it, the patient sees a different doctor, the physician is busy, moves to another therapy. There are a wide range of reasons, but it is widely believed that the number of adverse events is significantly less in terms of what is reported to us than what is actually occurring in the marketplace, and that is a global phenomenon.

I will then turn to slide 9.

The Chair: Mr. Glover, I hate to interrupt you, but I should make it clear to my colleagues on the committee that the issue of post-market surveillance and the compliance and so on that you are dealing with now is to help inform us with regard to the overall process. It will not be part of this study, and so I will not be entertaining questions on that because we will have you back for those segments of the study that deal with those specific aspects. Today you are giving us an overview of the total from beginning to end in the overall process, and then we will come back and focus only on the clinical trial part today, and you and your colleagues will be back for each of the subsequent stages, one of which is specifically on post-market surveillance.

Mr. Glover: Thank you, Mr. Chair.

In looking at that whole cycle that we deal with, you will hear often the term "off-label use," and that is really what slide 9 is attempting to describe for you. When the drug companies come forward to us, they will have run a clinical trial that is based on a hypothesis that this drug is used to treat this illness. They will then ask for approval of that drug based on its treating that particular indication. We review all the data against that indication and make a decision, and in all drugs, we want to ensure that the benefits outweigh the risks. There are always side effects; there are always challenges with these drugs. They are meant to interact with the body in a biological way. That is a given, so they have to on balance do more benefits than harms, and there are scales in all of that, depending upon the severity of the issue, the needs of the patient and the risk tolerance given those.

It is important to note that we approve an indication or we can approve a series of indications. That drug is then turned over to the marketplace for use. Off-label use is when a physician decides on his or her own to use it for something which is not in the indication. We have approved the drug for X, and they believe it is also good for Y, and that is completely allowed. That is a practice-of-medicine issue. That is under provincial jurisdictions with the colleges and how they train physicians, and if we go back to what I raised earlier, you would not run clinical trials on young children. The vast majority of drugs used to treat pediatric patients are off-label use because there have been no clinical trials on children, and this is how they deal with that.

Therefore, we watch this issue very carefully. If we see concerns about off-label use, if we get adverse events reporting, we can intervene and put warnings on products. We can introduce appropriate measures to deal with those off-label uses.

What we are concerned about, obviously, it is not legal to promote an off-label use, but there is an awful lot of off- label use that occurs. We encourage the companies to come back, run a clinical study and put it on the label, go through that process again. If the drug has other uses, prove they have those other uses, run the study to show it can be done safely. That helps the physician in prescribing. Rather than have this happen sort of by osmosis, we would prefer that a trial is done, the label is updated and brought forward to our attention.

There are some obvious things that happen with off-label use and how drug companies come to us for approval of drugs, and do they take the most common indication, do they take the one for which they feel they have the most likelihood of success based on the clinical trial, and then once it is out there, it becomes a practice-of-medicine issue. There are lots of things as you look in this and dive into it you will further uncover.

In a nutshell, that is off-label use. It is using the drug for something other than what we approved it for, but that is entirely a practice-of-medicine issue and it is allowed for in the way we practise medicine.

On slide 9, compliance and enforcement, there is a continuum here, but we have approved the product. One of the other things we want to do is approve where the product is made. That is really what we are trying to do with this compliance and enforcement. We will go out and inspect the plants that make these drugs to make sure that every pill is the same pill with the same amount of medication, dissolves at the same rate, metabolizes; all those sorts of things are incredibly important.

You will hear about GMP, which stands for good manufacturing practices, where we go into the plant, make sure sterile areas are sterile, et cetera. If you think about it, we approve the recipe to make the drug and then we want to approve the kitchen that uses the recipe so that the end product has been approved in terms of both what it is and where it is manufactured. We look at all of the active pharmaceutical ingredients that go into it, how it is mixed and how it is made, and we inspect on that. There is compliance and enforcement even after the drug has been approved by us where we will be going out and inspecting.

A couple of things to set the stage for your quite extensive review, on slide 11, with respect to program funding, the Food and Drugs Act has a lot of history in this country. It has worked very well to protect the population. It has set the framework within which drug safety is measured, monitored and executed.

One of the challenges we faced were the fees that were charged to companies. They were 14 years old, and it was only this past April that we introduced new user fees. That is something you may hear about as you conduct your study. It is significant because when running a program on fees that are 14 years old, we had a hard time meeting those performance standards that I talked about earlier because we simply did not have the resources.

The other important point to note is that we were trying to top that up to ensure we could meet performance standards and approve drugs in a reasonable time. That skewed the relationship between what is charged to the company and what taxpayers were essentially paying through the government appropriating money to my branch to do drug reviews.

With the new fees, we have obtained a 50/50 split, so there is a benefit to the health system and there is a benefit to the companies. It is viewed as equally shared, where 50 per cent is A-based funded through appropriations and 50 per cent is charged through fees.

That is also significant because if the fees are too low, the incentive to come to us is not particularly expensive for the company. We have seen a change in behaviour as the fees rose to our actual costs, where the companies think very carefully about submitting approvals to us and what that costs.

We have introduced new fees. We have hired a lot of new staff, and we are meeting our performance targets in all but one area. We hope to soon be caught up in that one area, which is the review of generic drugs. It is a very significant advancement for us.

On slide 13, you will hear about transparency. Is the system transparent? Is it easy to understand? Is it easy to interact with? We would acknowledge that is an area in which there is significant room for improvement.

We have started to post summary bases of decisions for some of our key drugs because the actual drug approval is a very large document and the product monograph is also a very large document. They are not easily accessible to the average Canadian. Why did we say yes? What did it mean? We are doing summary bases of decisions to make that information more accessible.

As I said, every drug approved is published on our website. We are trying to ensure the system is more transparent about what we do and how we do it, and we will continue to improve in that area.

Finally, on that slide is international cooperation. This is also relevant from a clinical trial perspective. International cooperation is important because this is a global industry, and we have to behave as a global regulator in this country. The large clinical trials are not just Canada-based; they will be multinational. They will be running in a number of countries concurrently as it moves forward.

The drug companies will be submitting dossiers, that big picture we showed you on slide 7, to different jurisdictions with very deliberate orders about which markets they want into first for business reasons and a whole bunch of other reasons that they can explain to you. It is critically important for us to collaborate with our international partners on those drug reviews so that we are not plowing through all those boxes separately, country after country.

There are challenges. They do not submit the same dossier to us universally. There are tiny differences in the indication they ask for from country to country. There are tiny differences in the label they ask for and the product monograph. There are tiny differences in the data to support their claims. We are working very hard with our international partners to try to limit the possibility for that so we can collaborate better on that post-market surveillance, on those clinical trials and on the overall safety of the drugs. However, from time to time there are some very significant differences in the dossiers that we see compared to the USFDA, compared to the EMA and others. Therefore, we are starting to ask the companies why the differences, those sorts of things.

International cooperation, because it is a global industry, is critically important for us. As we see, most of the active pharmaceutical ingredients come from other countries as they are made here.

The final slide I will speak to is what we see as some of the current and future challenges facing the drug system, and then we can delve into any questions you may have that focus on, as the chair has suggested, clinical trials and other things.

We do see, as everyone knows, that the population is aging. Obviously, that has an impact given the number of drugs the average senior citizen is taking, the number of drug interactions and the challenges that poses. As the population ages, how we respond to those challenges is something I think we are very cognizant of.

There is a term you will hear called the "patent cliff," and that is where many of the brand innovators' blockbuster drugs are coming to the end of their patent and they are looking for what they have in the pipeline. There are some challenges with that patent cliff, so they are looking at how they can diversify their lines of business. We understand that is happening.

On the issue of preventive medicine, this is the notion of immunizations and other things, but it is the idea of giving medicine to someone when they are not sick to prevent them from getting sick. We certainly see the potential for that from the conversations we have had with industry as an area for expansion.

Right now, the vast preponderance of drugs we approve is based on when someone is ill to make them better. There is an increasing push towards preventive medicine, which is more difficult when you think of clinical trials and other things, to give someone something to prevent them from becoming sick. We are certainly gearing up for what we think will happen there.

With respect to personalized medicine, your genetic makeup, your marker, how do you run a clinical trial for something like that where each one of us is unique? We have the same illness, but the drug and the way it is mixed for us can be a little different based on our individual makeup. How do you do quality control? How do you inspect that kitchen I talked about earlier when by its very nature it is meant to be a bit different for each one of us? How do you design safe trials to look at that as we move forward?

I have already touched on globalization. The industry is, frankly, consolidating. They are moving to fewer and fewer plants serving more of the continents and marketplaces. The active ingredients are coming from fewer sources. If there are interruptions in any one of those, as we have seen, it creates huge implications for the whole system.

The final two points I would raise with you are public awareness and interest in drugs. We see increasingly where people are interested in why their physician is prescribing. The old tools we have like the monograph do not exactly help a patient understand why their physician chose that particular drug for them and what some of the side effects are. They are looking for different types of information than currently exist. We think that will continue as people get more involved in their own health care moving forward. That is a trend we are seeing.

Finally, as I spoke about that patent cliff and other things, it is the complexity of the innovations coming forward. The environment will become increasingly complex. When you take all of those factors together, the types of trials we will see and the types of hypothesis that will be tested we think will continue to challenge us as the regulator, but we will evolve and adjust. We certainly look forward to the quite extensive study this committee will be doing and the outcomes of that to help guide us as we move forward.

The Chair: Thank you very much, Mr. Glover. We really appreciate your giving us the overview of a number of the stages in dealing with pharmaceuticals.

I want to remind our committee again that what we have is a four-segment study, and each segment will be completed in its own right. The first segment is this process of approving prescription pharmaceuticals, with a particular focus on the clinical trial aspect. Next will be post-approval monitoring of prescription pharmaceuticals, a completely separate study, and Health Canada will be back to help us in that area. Next will be the off-label use of prescription pharmaceuticals; and finally, the nature of unintended consequences in the use of prescription pharmaceuticals.

We have a number of issues we want to raise with Health Canada and to have them further expand on the background today. If questions emerge that relate to a subsequent study, I will interject and rule that that will come later. However, if there were time today, we could come back to some of those general questions. I want to make sure that we get all the questions out that relate directly to the clinical trial phase that we are currently studying. We now have the context, as provided by Health Canada here today, for the scope under which this issue falls.

With that, I will call upon my colleagues, starting with Senator Eggleton.

Senator Eggleton: Thank you very much. It is nice to get a good study under way. We just finished a good study, and here we are getting into another one. I will try to get in three questions, all on clinical trials. For my first question, I hope you will get into a more paperless kind of situation, that you are not still doing this. Yes? No?

Mr. Glover: No.

Senator Eggleton: You still have all this paper?

Mr. Glover: We are moving very aggressively into digital electronic submission. We have, through the Regulatory Cooperation Council, just reached a deal with the USFDA that had us submit a process for electronic submissions, and we will be using that system. We will be shared between the two jurisdictions. However, we still have a number of companies who prefer to submit in paper to us. We will eventually be turning that off over time, but we are not there yet, believe it or not.

Senator Eggleton: Well, good grief.

Anyway, you are saying it is a global business. If a lot of these new pharmaceuticals are produced in other countries, such as the U.S., Europe or wherever, and they have gone through all these clinical trials and everything, why would you not just be accepting? If you look at their clinical trials and find them to be similar to the kind of thing we have, a similar profile of the population or whatever, why would you go through all of this again? I do not really know what percentage of what you look at has already been approved in another country, but I would be interested in knowing that and why you do not accept. For example, the United States' regulations must be similar to what we would find quite acceptable. Tell me about that. Why can we not cut the process substantially, particularly in the clinical trials area?

Mr. Glover: We agree completely with that premise, and that is part of that international agenda that we have, where we are working to make sure that we are not duplicating unnecessarily the work of other jurisdictions. We have launched very aggressively a number of projects so that we do not have to go through that process over and over.

There is the review process, where we would want to collaborate with our colleagues in the FDA and the EMA to make sure, first, that the submission is the same, that the company intends to make, produce and sell the same drug with the same label here. We work with them to make sure. Oftentimes that is not the case and we have to do our own review or modify the review that we do.

With respect to the clinical trial, we still have a role to play there if the trial is conducted in Canada to make sure it is done safely. The trial will be global. There will be protocols. The practice of medicine can be slightly different in each country. Anyone who is running a clinical trial in this country, we want to make sure that it is done in a way that meets the standards we have with respect to our view of ethics, how medicine is delivered, and that the protocol is safe for our population. We work very closely with international partners to collaborate on that, but there are some differences. We get involved in the trial design to make sure that it is safe for the patients in this country.

Senator Eggleton: If you looked at their clinical trial, how it is structured, the safety and efficacy issues, and you came to the conclusion that the population that was part of the different phases in the clinical trials was very similar to ours, you would accept it then, would you?

Mr. Glover: Yes.

Senator Eggleton: You do not get into duplication unnecessarily?

Mr. Glover: No, not at all. We will review that decision from the other jurisdiction. If it satisfies us and answers our questions, then we are fine and we move forward.

Senator Eggleton: What percentage would you take from some other country, as opposed to doing it from scratch here?

Barbara Sabourin, Director General, Therapeutic Products Directorate, Health Products and Food Branch (HPFB), Health Canada: I am not sure we have a percentage in terms of trial applications that are multi-jurisdictional. Certainly we are seeing a trend for that.

If I could suggest, tomorrow morning we will be back for more detailed information about clinical trials, and perhaps one of my colleagues who will be there, Dr. Pat Stewart, will be able to answer that. What I can tell you is that we do not require in the drug submissions that clinical trials are conducted in Canada.

Senator Eggleton: I am interested to know whether this is just a thought or whether it is actually carried out, and to what degree it is. I would hope we would not be duplicating.

You ran into a backlog, apparently starting in 2008, in terms of the timelines of processing. You went from a median approval time for new drug submissions of 433 days to 536 days for generic drugs in 2010. You are taking longer to do that. Have you corrected this backlog problem? Why did you have the backlog problem?

Mr. Glover: You are absolutely correct; we had the backlog, and it was due to the fact that we were working on a fee structure that was 14 years out of date. With the new fee structure, we have been able to invest in our internal processes and move, as you saw, away from a lot of the paper-based submissions, give our staff some technology to scan that paper if it comes in that way, and deal with it electronically.

We have been able to significantly improve our performance, to the point where we are meeting or exceeding our performance standards in all our business lines except generics, where the backlog was quite significant. We have been working hard to reduce that backlog and meet our performance standards. One of the ways we are doing that, as you said with your last question, is working collaboratively with international partners to try to move through this.

Senator Eggleton: You have corrected the backlog except for generics; is that what you are saying?

Mr. Glover: That is correct.

Senator Eggleton: Why do you still have the backlog with generics?

Mr. Glover: It was the size of the backlog that we started from. It was significantly larger than the others.

Senator Eggleton: When will that backlog be gone?

Mr. Glover: If I may add one other point. The other thing we do when managing the queues of drugs in submission is we look at the public health need for it. We look at new therapies, a new treatment, and we will prioritize that over a "me too" drug.

Senator Eggleton: They are paying for it, though. They have to pay more now. You should be processing it faster.

Mr. Glover: We understand that. That is why the performance standard is about half as we move forward, 180 days instead of the 300, and that is why we are working to get caught up. We wanted to make sure that Canadians, when we were in backlog, were not suffering from not having access to appropriate new therapies. Now that we are caught up, we will get caught up with the generic backlog and we will meet performance standards.

Senator Callbeck: Senator Eggleton asked what I wanted to get at about the clinical trials, which is that we do not always do a clinical trial in Canada for a particular drug.

You say that clinical trials can be going on in different countries at the same time but they do not necessarily always come up with the same data at the end. Mr. Glover, I believe you said that you are asking companies why there is a difference in that information. Would it not be the country that determines what information they have to produce?

Mr. Glover: The drug companies have the choice of what dossiers they submit to which jurisdictions for which indications. That is a business decision they make about which markets they want to get into, at what pace, and what are the indications coming out of the clinical trial that they will prioritize and put forward the submission.

I will turn to Barbara Sabourin to further elaborate.

Ms. Sabourin: In addition to what Mr. Glover said, it would not be unusual for a company to submit a drug submission with, let us say, four to five clinical trials. Each of those clinical trials may have been conducted in several sites in order to get a sufficient number of patients who met the criteria needed to show that the drug worked and was safe. All the information from all those sites is summarized and put together so that we have the results for the clinical trial as a whole showing that it met the end points it was supposed to meet. That is the information we use to then determine whether the drug meets our requirements in Canada and can be marketed here.

Senator Callbeck: In Canada there are certain things that have to be met, but that varies with countries, does it? Canada requires certain things but does France require some other things or fewer things?

Ms. Sabourin: Certainly there are some differences in the requirements between countries. We participate in a number of international fora for standardizing the requirements. For example, good clinical practices are pretty much standardized around the world, and we also look for evidence that trials conducted in different jurisdictions meet the standards that we have in Canada.

Senator Callbeck: Are there a lot of differences in these trials, then, between countries such as France and Germany?

Ms. Sabourin: Most of the requirements in the European Union are now harmonized and, in addition, through the International Conference on Harmonization, requirements for clinical trials world-wide in general are fairly standardized.

The Chair: Just before we leave this, could you comment on the issue of data from the other countries in the sense of seeing adverse reactions, things of this nature? If you were aware of it, one would assume that that kind of data would be part of the information you would bring to evaluating the data provided in Canada.

Ms. Sabourin: Mr. Chair, absolutely. We get information in the clinical trial application that would outline not only the benefits of taking the particular medicine, but also the adverse events or the adverse reactions that are associated with the medicine. In addition, we have access to information on adverse events that have happened in other jurisdictions through various databases. We also maintain networks of contacts with other jurisdictions so that we can discuss various issues should the need arise. We have rapid alert systems as well in case there are difficulties.

Senator Callbeck: On page 6 you have a chart about the time frame. What is the average time frame from a drug submission to an approval?

Mr. Glover: In short, very close to that performance standard. As the previous question illustrated, we were in backlog so we have been working very diligently to get out of that backlog. At this point in time, our performance is meeting that standard, but it is closer to it than we would like, and we would obviously like to do better in that and we hope we will be able to over time.

Senator Callbeck: Are the figures here the standards you want to meet?

Mr. Glover: Correct.

Senator Callbeck: Are you doing that now, except for generic?

Mr. Glover: Correct.

Senator Seidman: I have a series of questions that I hope will elicit extremely short responses and then a couple that might not be quite so short. My first question would be on clinical trials. Who funds them generally?

Mr. Glover: Industry.

Senator Seidman: Is it pretty much industry?

Mr. Glover: Pretty much. There are CIHR government-funded trials, yes.

Senator Seidman: That would be a small proportion, so you would say, what, 85 per cent or 90 per cent of clinical trials are funded by industry?

Mr. Glover: I do not have that information. It is the majority, but I am not sure.

Senator Seidman: How many clinical trial applications do you get a year? Does the number grow? Is it growing?

Ms. Sabourin: I can tell you that we get in the order of between 500 and 600, sometimes up to 700 applications a year.

Senator Seidman: Is the number growing? Is this an increase in the number of applications over time or is it stable?

Ms. Sabourin: It is relatively stable. It has been shifting a bit to the biological side of the house, so we are seeing a little bit of a trend there but it is a little bit early to say that that will continue.

Senator Seidman: What do you see as Health Canada's role; that is the prime function of a regulatory agency? Is Health Canada's role to facilitate the development of new products or to ensure a high standard of effectiveness and safety?

Mr. Glover: The latter. There are others that do the former, such as CIHR. Our role as a regulator is the safety of the trial and the information out of that trial to benefit the review process.

Ms. Sabourin: I will add a bit of precision to the previous answer about the number of trials. We also get in the order of up to a thousand trials that are a shorter time frame that would support generic drug approvals.

Senator Seidman: Does Health Canada monitor existing trials in Canada? There are lots of trials that are done by CROs now, for example. Do you monitor the existing trials in any way?

Mr. Glover: We have what we call a risk-based approach given the sheer volume of them, so we prioritize based on vulnerable populations. We take a look, and we will go in and inspect. We do follow all trials, but we certainly more actively follow what we would call the higher risk trials to make sure that our emphasis is on safety, where it is most needed.

Senator Seidman: How would you define a higher-risk trial?

Mr. Glover: It is a new, innovative product for which there is not a history of use. This is not a product that has a lot of use and somebody is attempting to expand the indications available and update it. That would certainly be an area.

If a product was dealing with populations that were particularly vulnerable or at risk, we would certainly pay more attention to that trial and follow it more closely than something that was dealing with a different type of population.

Senator Seidman: What proportion of trials would you say Health Canada monitors?

Ms. Sabourin: Internationally the standard for monitoring trials is in the order of 2 per cent of sites, and that is about what we monitor through our inspection program. However, just to add, we also receive adverse event reports for all the trials at any time.

Mr. Glover: The reason I was hesitating is it somewhat depends on your definition of monitor, because they all report to us. It is how active we are in inspecting the trials and following up.

Senator Seidman: What does Health Canada do with the data that is submitted by pharmaceutical companies; that is all data on all trials, whether it is done in Canada or not?

Mr. Glover: That would be submitted to us as part of the review process. That is part of what we factor in as we make our decision about the approval of the drug or not.

During the actual trial period, if we see problems, we will go back. We can shut down a trial if we are concerned about the signal we are seeing. We can ask for changes in the protocol. We can issue alerts if we think that there is something else, so it depends on the nature of what we were seeing through the course of the trial in our monitoring, but we do intervene if we see safety signals. We can shut down a trial, ask for changes in the protocol design of the trial, and we have done that. Then ultimately, when the trial is completed, that data helps inform our review.

Senator Seidman: I guess my question is, what do you do with the data? For example, you talked about transparency issue and you talked about the summary basis of decision documents that you are now looking at. However, if you look at the U.S. and the European Union, their reviews are public; their information from hearings is publicly available. The European Union maintains a public database with their lists of drugs awaiting review, approved, suspended, withdrawn, post-approval and even refused drugs.

I guess I am asking what are you doing in terms of going beyond the summary basis of decision documents in terms of transparency and looking at what U.S. and EU do already?

Mr. Glover: We certainly acknowledge that in transparency we have not kept pace in all areas and have further to do. We believe that now that we have gotten out of backlog, we would like to continue to expand our transparency initiatives to come to that international standard that we see and that you mentioned. It is very variable, though. If that is a short question, I can stop, but there are a lot of pieces there that deserve unpacking.

With regard to the issue of what we approve, we certainly post all of those. We are interested in communicating what is in approval. We ask the companies if they claim that CBI were unable to under current law, so we do deal with and we try and are encouraging the companies to do that.

We also encourage all companies, once we have approved the clinical trial, to make all of that data publicly available. We encourage them to actually post that on a WHO website so people do not have to scurry around from website to website in different countries to get a global picture of what is happening and where trials are operating, so we do encourage that of them as it moves forward.

There are differences about what happens with respect to trials that are withdrawn and other things like that that we are working on to try and ensure there is greater transparency. We did just this week publish a summary of all clinical trials or inspections and what we found, and we are looking to expand that based on the reaction that report received. We continue to try and move the bar forward on transparency.

Senator Seidman: Well, we will try to unpackage that later when I have my second round. Thank you.

Mr. Glover: Sorry.

The Chair: Before I go to Senator Merchant, I want to interject at this point on a couple of points that Senator Seidman raised and then to put a couple more issues on the table at this point.

With regard to the number of clinical trials in the country, my understanding is that over the last five years the total number of clinical trials has declined slightly over the period of time, if you take all clinical trials.

There has been some publication that part of that issue is the lack of cooperation among the university research hospitals, the fact there is no organized system dealing with the contract research organizations and no harmonization of contracts of ethical boards. Now, that is not something specifically in Health Canada's jurisdiction, so perhaps the question should be: Is Health Canada seeing that the Canadian research and clinical trial infrastructure is not being as competitive, perhaps, as it could be with regard to hosting clinical trials here?

Mr. Glover: If I may, Mr. Chair, I think what we have seen overall is a number of reports with varying degrees of outcome around general R&D, research and development in this country, in the drug industry. The drug companies say that is going up. Other groups say that is going down, and so I guess it depends on the author of the study and how you interpret the numbers as it moves forward, so we see conflicting stories based on who you ask and who authors the report.

The Chair: I wanted to get the issue on the record here with regard to the things that we look at over time.

With regard to another issue that Senator Seidman raised, and that is the issue of transparency, the question I guess that I would have you mention, truncated trials or trials that do not go to completion and so on; and then there is also the issue of patients who may leave a trial before it is completed. Does Health Canada have the authority to demand information on truncated trials and information on patients who leave a trial before it is completed and, therefore, would not be included in the final trial submission?

Ms. Sabourin: Mr. Chair, we have the ability to get information on patients who have left a trial during the drug submission review process certainly. What was the other part of your question?

The Chair: Do you have the authority to require submission of data on truncated trials, trials that are initiated, approved to be carried out by some authority within Canada but are pulled by the sponsor, perhaps, before they are completed?

Ms. Sabourin: To my knowledge, we certainly are informed of truncated trials. Whether we have the regulatory authority to demand that, I will be honest, I am not sure right now.

The Chair: However, you feel you are being informed on those on an ongoing basis?

Ms. Sabourin: We definitely are, being informed, yes, and we can find that out.

Mr. Glover: Mr. Chair, because it relates to the last question, what we do not have the authority is to compel making that public.

The Chair: Thank you very much. That is a very helpful clarification.

I will interject two other issues before I go back to our list. You referred to the issue of pregnant women and children with regard to them not being included in clinical trials. This is a real issue of debate in some circumstance, probably in your situations as well, but the reality is that once a drug is approved, unless there has been some definitive contraindication, my understanding is that there is the authority to prescribe the drug once it is approved to pregnant women and children.

My question to you is, in this area, is there a move to try to find ways to bring younger persons in to a carefully controlled clinical trial and subsets such as pregnant women, for example?

Mr. Glover: I will turn to my colleague in a moment, but just to say we are very concerned about this particular issue. We have been working with the community about this. We struck an advisory committee on pediatric issues to try and advise us and to work on this particular issue. We have produced guidance that we made available, so we are concerned and working with the community and trying to move forward in a constructive way.

Ms. Sabourin: I would add that traditionally drugs that were used for children were not studied in children. That is changing, and we are seeing some trials for use in children, and we really think it is important so that safety information can be put on labels eventually for those products.

The Chair: Are these trials in Canada or in other jurisdictions?

Ms. Sabourin: I believe in Canada, but my colleague tomorrow, Pat Stewart, will give you more information.

The Chair: If at any point a question occurs that you say will be more appropriate for tomorrow's meeting, please do not hesitate to interject that.

The final thing before I go to Senator Merchant, just to again get it on the record, you mentioned, Mr. Glover, the issue of the pressure for drug companies because of the blockbusters going off and their desire to bring in replacement and so on.

It comes back to the issue of the clinical trial process which traditionally has measured the efficacy of a proposed submitted drug versus a placebo, and there is considerable discussion, I understand even some examples, where a new submission for treatment in a particular area where there are other drugs in existence, there is the possibility at least, and possibly some examples, where the new submission is being tested against existing approved drugs. Could you comment today or suggest it will come up elsewhere with regard to is there any trend in this and what is your view of that possibility?

Mr. Glover: If I may, Mr. Chair, certainly one of the witnesses who will be with you tomorrow will be able to further elaborate on that. Just to reiterate, we look at safety, efficacy and quality, so the notion of is a drug better than another drug, is the drug safe, does it do what it says it is supposed to do, and can it be made with quality and introduced into the marketplace. The notion of incremental benefit is a payer issue. That then becomes an issue that provinces and large private insurers decide if they want to list this drug on their formulary or not. We still make the product available. That is what we have for you today.

The Chair: I appreciate very much that answer, Mr. Glover. Perhaps this is an area you may not wish to comment on, but there are those who perceive that it would be of benefit to society and the payer to actually know the comparative value of a new submission versus drugs that are already on the market. Would you want to make any comment on that?

Mr. Glover: Mr. Chair, absolutely. The Canadian Assessment for Drugs and Health Technology, CADHT, plays that role. It is jointly funded by the federal government and provinces and territories for that very reason. There is a deliberate distinction between our role as the regulator and the choice of payers on the different therapies and their effectiveness as a first-line versus second-line or third-line therapy. Is this the drug you use first? If it is not working, how do you escalate up? CADTH plays that very important role.

It would be my personal view that what we are seeing is increasingly an attempt to market to smaller and smaller segments of the population, the incremental benefits. Yes, there are lots of drugs out there, but, for this small group, this drug does this better than others.

The Chair: Closer to the personalized medicine approach.

Mr. Glover: Correct.

Senator Merchant: Another group that you exclude from the clinical trials are the elderly, I think you said. Yet, they are the segment of the population who seem to be using a lot of medications, and sometimes there are reactions between medications.

I am a little bit curious. I know that you have to take certain precautions, but we will not run clinical trials in the segments of the population who will be using those drugs. Is there a solution to this?

Mr. Glover: My colleague will elaborate. There are a couple of elements that I would just first like to clarify. It is not that we never see them. Those are the areas where we pay the most attention, so it comes back to the previous senator's question about what are those areas we would deem highest risk. A trial on a pediatric population would be something we would watch very, very closely. A trial on seniors, where they already have a number of pre-existing conditions for which an experimental drug could exacerbate problems for them, is something where we would pay particular attention to the design and safety. It is not that they are by design excluded. It is that the safety concerns we have are significant.

I should also note, though, that the trial sponsors are looking to test a particular hypothesis, and there are those who suggest that there is culling of populations and that they do not want people that will skew the results negatively of their trial. That can happen for a variety of reasons, not necessarily seniors. They could look at this, hmm, this trial excludes smokers. In the real world, probably there will be a smoker who will take that drug. There are a number of things that the sponsor is also thinking about as they design the trial to test their hypothesis about the discovery they have made and how well it will work on the population in question.

Senator Merchant: There is the notion that if a company is carrying on clinical trials, then they can fashion the trial in a way. You said if it is a smoker, if it is somebody with a heart condition, they exclude all those people, so it is a self- fulfilling prophecy. They sometimes can get the results that they want to get by setting up the trial in a way.

I do not know how many persons you think is an adequate number of persons to test, but if you test 1,000 people, if you do a clinical trial with 1,000 people, you can design it in a way that you get the results that you wish to get. You are excluding all these people because of other conditions, and yet, as you say, when you are then distributing the drug to the general population, you have people that smoke and people that have other pre-existing conditions. I just wonder if the design of the trial predetermines the result that you get.

Mr. Glover: I think by the very nature the answer is yes. The trial is designed to test if the drug treats what the innovator believes it will treat. We look for the safety of that trial. We also look to make sure the population is representative. Will the size of the trial be one that will lead us and other regulators to have confidence in the outcome? There is this absolute potential for tension between what we as a regulator are looking for and what the sponsor may be advancing. That is why sometimes trials will be concluded — because we are concerned about safety or because the sponsor is not seeing the results they want and shut it down early. There is a range of outcomes, absolutely, that are possible in this kind of scenario.

Ms. Sabourin: We do have a team of biostatisticians that look at the statistical methods that are used in determining whether trials meet their endpoints, and they need to be satisfied that there is not the introduction of a bias through the selection criteria, the inclusion criteria or the exclusion criteria for the patients who may benefit. We do look at the results of the trials through the lens of the biostatistics to make sure that they meet the requirements.

Senator Merchant: You said that adverse effects are under-reported. Were you speaking from a Canadian point of view, or is this something that you have noticed just generally in the world? At the same time, I think you said that, in Europe, the population has a better understanding or is more aware of what is going on. Maybe I misunderstood that. I am just wondering, if that is so, what are you doing to encourage people to report the adverse effects, and how can they report them? Maybe it is because people do not understand. This is a mysterious kind of thing that is taking place, and maybe people just do not understand how to go about it.

The Chair: Could you address that with regard to the clinical trial? It is actually an issue within clinical trials as well as in the larger issue that you commented on in your general remarks.

Mr. Glover: Absolutely, Mr. Chair. There were a number of questions. I will try to be as brief as I can. I know this is complex.

With respect to Europe, what we see there, because of the European Medicines Agency, there is greater consistency in the different countries that make up the European Union, so they have kind of worked together on that, so the standards are better.

The issue of adverse event reporting is a problem globally. It is lower than any jurisdiction would like it to be, and we are no different than most other jurisdictions in feeling that the number of adverse events is underreported in that.

How are they reported? We are taking a number of steps. It is a form a physician fills in and a patient fills in. It is on the MedEffect website. We are looking through transparency to try and ensure that is easier to find so that any person taking a medication would know where and how to do that. We have been publishing and trying to ensure people are aware of MedEffect and the adverse event reporting we do.

The results of that are that we do paediatric journals. Some of the things that physicians read remind them. We have seen significant increases in the number of adverse events that have been reported to us, 30 or 40 per cent increases year over year, but when the number is so small to begin with, even a 30 or 40 per cent increase still means we are getting significant under-reporting.

With respect to adverse event reporting and clinical trials, Ms. Sabourin can elaborate further.

Ms. Sabourin: Some of the same rules apply in the mechanism for reporting on an adverse event, and certainly the MedEffect website can still be used.

Through the clinical trial process, however, the proportion of adverse events that are captured is much higher because the sponsors and the health professionals running the trial are required to report all the adverse events associated with that.

[Translation]

Senator Verner: Good afternoon and thank you very much for coming today. I will be speaking to you in French.

The chair has already asked a number of my questions on clinical trials for drugs for children. So I will not ask them again. I assume, however, that, in the case of personalized medicine, clinical trials must be particularly challenging because this deals with medicine that is tailored to the individual rather than to a group of individuals. I would like to hear what you have to say about this because, from time to time, we read articles about it in magazines or newspapers and there seems to be some rather interesting progress being made.

I would like you to begin by commenting on clinical trials. Second, I would like to know whether or not other countries such as the United States or those in the European Union are more advanced than we are in this area or whether we are all at about the same stage.

Mr. Glover: I would say in response to your question that personalized medicine is a new area that offers many possibilities and significant potential for the population as a whole. For now, there are no clinical trials for these kinds of drugs because it is still an area of exploration and innovation. It is a new area that we are working on in collaboration with the industry in order to establish procedures. It will clearly be different because of the goals and the process. Did you want to add something?

Dr Robert Cushman, Director General, Biologics and Genetic Therapies Directorate (HPFB), Health Canada: Mr. Chair, as Mr. Glover stated, this is a specific market with many more opportunities. For example, now people are being treated for high blood pressure and there are even contraceptive medications.

We acknowledge that specific populations are different. There will be benefits for some and greater problems for others. However, in terms of clinical trials, there will be problems with surveys and there will be fewer individuals in whom to record differences. There is also the issue of distinguishing between the effects of a placebo versus the effects of a drug and the effects of drug X versus drug Y.

There is a future for these drugs but challenges remain in terms of clinical trials.

Senator Verner: Can you tell us whether or not other countries, the United States or the European Union, for example, have done more work in these areas? Are they ahead of us?

Mr. Glover: In my opinion, other countries are at more or less the same stage as Canada. Clearly, industry has the ability to develop specific drugs for individuals. But the challenge is to figure out how to confirm that the process is working and how to try to evaluate that process. This is a new technology that is currently being developed and countries are working together in order to identify a verification process and to establish regulatory frameworks.

[English]

Senator Seth: I have a few small questions. What I am hearing seems quite interesting.

Once you have done a clinical trial on a medication and it has been approved on the market, do you do a follow-up if there is any problem with it? I will give you an example. Fifteen years ago when Thalidomide was being used for morning sickness and vomiting during pregnancy, it was extremely popular —

The Chair: I will rule that that is the post-approval and surveillance area you are getting into. I am concerned that we stick to the clinical trial period.

Senator Seth: Okay, but it is still about clinical trials. What happened after you approved Thalidomide? Is it fine? Do you ever look back? That is my question.

The Chair: We will look into that as an entire study. What happens after approval is the post-approval surveillance, and we will be doing a complete study on that. I will rule for you to move on to your next question.

Senator Seth: My next question is about off-label medication on the market.

A lot of medications, especially vitamins, are off-label. They are from different countries at the counter, not necessarily from the pharmacy where other drugs can be bought, such as at grocery stores. Patients take various medications, and sometimes they say they are taking something and feel better. Those medications do not have any ingredients written on them. Who is the regulatory authority for those types of medications? How are they allowed to be put on the shelf? A lot of times, patients take —

The Chair: He may provide a quick comment about the regulator, but we are dealing with prescription pharmaceuticals. We are not dealing with any health products at all.

Senator Seth: Thank you, Mr. Chair.

My next question is, if all medication is to be globally industrialized, why does medication always come to Canada two to four years later than other countries? Why is medication available more quickly in the U.K., the U.S. and European countries? Why does it take medications so long to come to Canada? Patients often go to different countries to buy certain medications. Why is that?

Mr. Glover: There are two parts to that. First, how do those drugs legally get into this country? There is the ability for someone to import a short amount of supply for their own personal use. That is for obvious reasons. If you are travelling to the U.S., they allow you to import your medications, and we reciprocate. We allow personal use to facilitate natural travel that occurs among folks. That answers part of your question.

More specifically, why does it take longer for medications to come to Canada? That is a very broad generalization, of which we understand the perception. Frankly, that is the decision of the company, when they choose to bring a product to which market. Canada is estimated to be 2 to maybe 3 per cent of global supply for a large multinational. When they look at the markets they wish to penetrate, they may choose to come to us first because we have provincial programs, they can get on a formulary and there is a market that pays. They may choose to go to the U.S. first because it is a larger market. They may choose to go to Europe. They may see the issue is actually more prevalent in other continents. There is nothing that dictates when the drug must come to this country.

That is the decision of the company for a wide range of business decisions that only they can explain to you.

We approve the drugs when they submit them to us. We do have evidence of drugs we have approved that never come to market. We have spent the time, they have paid the big fee and they choose not to market them in this country.

Frankly, it is a decision that the companies make on their own.

Senator Seth: Criteria for choosing the participants for clinical trial: I know you do not take pregnant women, of course, we cannot. We do not take pediatric. I know the elderly do not come into the picture because in the same trial, if we approve it, they give a lower dose in order to make them comfortable. This is our only option. We, as doctors, do it. How do you choose in a healthy population? Who comes forward?

Ms. Sabourin: I am not positive that I totally understand the question.

The Chair: I think the question was how are the participants in a clinical trial chosen because there is a wide range of characteristics of the human population. How is it that the participants are chosen for a given clinical trial?

Ms. Sabourin: For each clinical trial, the design will include some inclusion criteria — criteria that the patients must meet in order to be considered for the trial — as well as some exclusion criteria. Those would be criteria that would rule those patients out from participating in the clinical trial. That is all part of the design and is a way that the company or sponsors can determine that the population they have will help them to meet their goals in terms of determining: whether the drug has an effect, whether there is a dosage related effect, what the side effects are on the safety side, as well as whether the drug works. We can provide more detail on that tomorrow if you would be interested in that.

Senator Seth: Thank you.

The Chair: Before I move on, I would like to again follow up on a couple of issues, one in particular, where earlier I asked with regard to the use of the placebo versus an existing drug and a given indication for the pharmaceutical.

There has been some publication that suggests that in clinical trials potentially up to 50 per cent of the participants — as well as somewhere in the vicinity of 80 per cent of the participating physicians — are able to determine fairly soon after the trial gets under way as to which patients are on the placebo and which are on the new drug. The principle reason for that is most people anticipate there will be some reaction from the drug. If they get no reaction whatsoever, they assume they are on the placebo; the so-called sugar pill.

I want to put this question back to the answer that Mr. Glover gave me to the question in the first place, and that is looking for efficacy of a drug. We know there is a genuine placebo effect. That is to say if in fact the placebos were causing some irritation, there would perhaps be a higher tendency for people to believe that the placebo actually gave them some benefit.

I am trying to formulate the question slightly different. Would there be an advantage to determining the true efficacy of a drug given this circumstance by using already marketed drugs as, say, the placebo or to help elucidate the ultimate value of the drug?

Ms. Sabourin: I could start to answer that question. The design of clinical trials is evolving with the different sort of theories in the scientific world. This is one area where there has been quite a lot of evolution.

Right now in Canada, we think that if there is a standard of care that is given to patients, it would be unethical to demand a trial that used a placebo and withheld that standard of care.

We can provide more information on when placebo controlled trials are appropriate in our view tomorrow with our colleagues, but there are times where they are not appropriate.

The Chair: Thank you. That would be helpful.

Mr. Glover, you mentioned earlier, and I cannot remember where it exactly came, about the authority to make information from trials public. I wanted to have the committee hear whether there is any requirement for clinical trials to be registered in Canada. Subsequent to the answer to that question, is there any requirement that the details of the trial be made public with regard to the transparency issue?

Mr. Glover: The short answer is there is no requirement that exists today. We encourage it. We would like it. The government did have this in the former Bill C-51 piece of legislation that never passed. As a result of that, at this point in time we encourage and we are unable to compel or make it a requirement.

The Chair: Thank you very much. I think that is a very positive indication from you. You think that would be valuable?

Mr. Glover: Absolutely. That is why in every clinical trial we approve, part of our approval letter encourages them to post that information and make it publicly available. We even encourage them to post to the WHO website so there is one site anyone can go to for any clinical trial anywhere around the world and get a full, comprehensive picture of what is occurring.

The Chair: Thank you.

Senator Eggleton: My main question was asked by Senator Verner about personalized or individualized medicine, but I will go into a couple of other things.

First, I want to clarify something I thought I heard. Perhaps I did not hear it right. You have trials on generic drugs? Why would you do that? Is that true?

Mr. Glover: That is correct. We do because we are looking to ensure that the generic drug is, in simple terms, a good copy of the brand. That does not necessarily mean it is identical in chemistry. It means that it is bioequivalent, so it would be anything from how they make it, or it could have different fillers or packing agents, any number of things. We want to make sure that drug is equivalent in terms of how it interacts with the body to make sure it is equivalent to the brand drug. I can turn to Ms. Sabourin.

Ms. Sabourin: If you think about a pill that you take, many of the drugs take effect once the active ingredient reaches the bloodstream. We want to ensure that active ingredient is released at the same rate as the innovator product. That is one of the determinations of bioequivalence that we would use, as an example.

The Chair: It is important for the committee to understand what you have put forward: It is the understanding that just because there is an active chemical ingredient, that is only one part of the composition of a pill, as an example, that actually enters the body. The rate and place at which the drug is released in the body will be dependent upon the composition of the packaging of that particular material.

If I understand you correctly, you are pointing out that the way in which the pill is composed for delivery into the body can have a significant impact on its efficacy?

Mr. Glover: That is correct. In addition to that, there is this assumption that maybe I should take a moment to clarify. A generic is not an identical copy of a brand, and just because it has come off patent, that does not mean the generic maker will choose to make that drug in exactly the same way.

In fact, what often happens is that the generics know when it is coming off patent and they want to be ready the very second it is off patent to introduce that product. They will be working on their own formulations ahead of time, coming to us with approvals so they can be ready to go at the second it is possible for a drug that is equivalent in terms of what it does. It may have identical or it may have slightly different make-ups in terms of how it is made. However, in order to be classified as a generic, it must have the same impact on the body. That does not necessarily mean it is 100 per cent identical in terms of how it is made.

Senator Eggleton: It sounds to me like it is a whole different process. You have to go through the same process as you would for a new drug. Do you do three phases of clinical trials for a generic drug?

Ms. Sabourin: No. What you have to do for a generic, depending on the particular generic, are studies that show the bioequivalence. These are much shorter studies in duration. There is not the same kind of effort to follow whether the drug works in the population. They are often using healthy volunteers to see that the blood levels of the active ingredient in the drug are identical. That pattern is the same for both the brand name and the generic.

Senator Eggleton: If you are not following the three phases of the clinical trials, do you have a special clinical trial formula?

Ms. Sabourin: Yes.

Senator Eggleton: What is that? Does it relate to Phase I, Phase II or Phase III in any way or is it completely different?

Ms. Sabourin: I would call it a different one — bioequivalence trial.

Senator Eggleton: Is it an extensive one? Do you need 1,000 or 100 people?

Ms. Sabourin: More like fewer than 50, probably. It would depend on the statistics needed to prove in your study to show that it is the same as the brand product.

Senator Eggleton: Even though the chemistry may be virtually the same, and you can analyze it to that effect, you still do not take that chance. You think a small variance is enough to require that kind of process. Is that what you are saying?

Mr. Glover: The chemistry is not virtually the same. They manufacture it differently and they use different fillers. A number of things go into it that all have the potential to impact. Some of these things are time-released, so how they develop that, integrate it into the product and the rate at which it is absorbed are factors.

The Chair: It is important, Mr. Glover, in dealing with the chemistry of it, to indicate that you are referring to the total chemistry of the package. In the overwhelming number of cases, the patented active principal ingredient is intended to be identical, but it is the total composition of the pill in most cases. Is that not correct?

Ms. Sabourin: I will give some clarification. We look at a couple of different aspects. We look at the active ingredients to make sure that the quality of those is appropriate for use in humans. We look at the creation of the drug substance, if there are any processing steps until then and then into the drug product, which is the final form delivered to human. The chemistry is looked at in all those phases.

The Chair: Senator Eggleton, it is the total chemistry of the package of the pill. It is an important aspect.

Senator Eggleton: I am glad we got that cleared up.

Senator Seidman: Senator Ogilvie broached the topic I had for my second round, and it may be more appropriate for tomorrow but let us see what happens. It is about women and children, who you said are under-represented in clinical trials. We have already established that industry funds the bulk of the trials. We know that it is probably more costly and ethically more complicated to deal with those two subgroups in trials.

In the U.S. around 2002, the Best Pharmaceuticals for Children Act was passed. It provided incentives to pharmaceutical companies that invest in designing and conducting trials in children for certain products. My question to you is: Do you see some benefit in that approach?

Ms. Sabourin: Certainly in Canada we would like to see that the drugs to be used in children are tested in children. We have a framework where we grant six months of additional data protection, I believe, for drugs when trials have been done in children in order to give some incentive for doing those trials. There are some requirements that need to be met to do the trials in children, and I would prefer that those specifics get answered tomorrow.

Senator Seidman: What about women and pregnant women, for example?

Ms. Sabourin: Similar fashion. We do have some guidance available on doing clinical studies on women in special populations. We also participate, as I mentioned earlier, in terms of networking with regulators from around the world, including the United States, to get a sense of their ideas of the best ways to go forward with clinical trials using women.

I would add that earlier I mentioned inclusion and exclusion criteria. We want to make sure that the trial is designed in a way that would support the indication that the company is asking for. If the drug is to be used for a condition that affects both women and men, we would expect the trials are done in both women and men. There is a way to look at things so that the results can be very clear in terms of whether the indication is supported.

Senator Seidman: If I might ask you another question about the drug approval process, the use of clinical trials and the whole issue of positive results — drugs that demonstrate they actually work at the end of a Phase III trial. Recently there has been a lot of controversy about the whole suppression aspect of studies that show no result or no effect of a drug. In fact, quite recently a study showed that a drug was approved with 2 positive results and 10 no-effect results.

My question is about the whole credibility behind the recording of clinical trial results, the interpretation of data and statistical analysis, which is somewhat subject to interpretation on both sides of the coin, so to speak.

Mr. Glover: I am not sure I got the question in the commentary. I am not taking issue with the senator's observations; I am just not sure of the question.

Senator Seidman: I guess I am making my observations, and I am asking if you have comments about this particular problem and the fact that we rely on clinical trials for approving drugs. I am asking you to comment on this very fact. Thank you.

Mr. Glover: My apologies. Thank you. That is very helpful.

As the regulator, we are always concerned about the data presented to us, the clinical trials and equally the indication. It comes to your 2 positive and 10 negative. As the regulator, we are concerned about whether the bar is set at the appropriate level to allow this product into the market. We feel we do that based on the data provided to us. They say it is indication X, and we assess if it is good to treat indication X.

The problem is, if they really want Y but came in with X and have the data to support X, once it is in the market, it is off-label use and we are trying to catch up. That comes to what studies they have designed, how they have used them and evidence presented to us. They are very deliberate in their choice of which countries, which indications and how they move these things forward.

Are we concerned? Absolutely. However, we deal with the indication they are proposing and whether there is enough data to support that indication. Is that the best indication or is that the only indication? Will there be others post-market? Those are real challenges for us when off-label use is a practice-of-medicine issue. Do you want to add anything?

Ms. Sabourin: Sometimes a drug submission will come in front of us and it looks like there may be some benefit for the drug but it is unclear. We use science advisory committees — panels of experts — to help us in our decision making.

I just wanted to flag that to the committee, and also that the records of those meetings are made public through the website as well as the short bios of all of the members. We try to get real clinical expertise into our decision making in that manner.

Senator Seidman: I thank you for that. In fact, that was the next part of my question because I note that on page 6 you have shown the new drug approval process. In fact, you have the scientific review right there in the process, so I was going to ask you exactly, if you could explain — I am sorry to use the word "exactly" — in some fashion what that scientific review involves. How many people do you send it to? Do they have a checklist? What are the issues?

Mr. Glover: If I may, Mr. Chair, I will certainly turn to my colleague. You do not want an exact answer to that. It is really rather painful. We will look at the reviewers, their experience in-house to determine when we go and seek external experts to complement. If the data is new, if we are the first jurisdiction looking at it, what is our confidence, we may turn to outside experts. There may be, frankly, some scientific debate internally. You can look at the same data, and you may say science is science. Science is subject to interpretation, always is, always will be, so we will look for greater certainty if there is some very healthy, we would call it healthy, internal debate, to help us resolve some of those issues.

We have standing expert committees, and we will strike specific expert committees if we are presented with a particular problem and seek experts domestically and internationally to provide advice to us. We have standing committees and we have specific ones that we charge with specific questions, and again all of those are made public.

Ms. Sabourin: I would just add that the format that the submissions come in is fairly standardized now around the world, and that was done through the International Conference on Harmonisation. That format is called the common technical document so that reviewers can find information in the same part of a submission no matter which submission they are looking at.

We use that as the basis for our review templates. It is not a checklist, but it is a way that we can provide some sort of structure to our review documents so that if we are looking for something in a review document we can find it all the time.

Senator Merchant: There was mention made to Bill C-51. Now I know that the bill died on the Order Paper, but in that bill they were going to move certain regulatory provisions to the statutory level. Vis-à-vis clinical trials, is that a desirable way to go and would that have changed your role in conducting these clinical trials?

Mr. Glover: Bill C-51 proposed some additional powers that, in short, would have allowed the government to compel, greater transparency, information when we needed it, wanted it. Those additional authorities certainly would have allowed us to not encourage, as we are sort of doing now, but require.

At the time, it definitely was viewed that a legislative route was the preferred route. We continue to take a look at what, as a regulator, we will be able to do to improve transparency and, where we need additional authorities, how we might seek to obtain those.

The question boils down to if legislative or regulatory is preferred. The lawyers — I am not a lawyer, I apologize — will certainly have preferences about that. We will take a look at the range of options with their pros and cons and continue to explore what we can do to improve the tools we have to bring us in line with other jurisdictions. Legislation is great, but if you wait too long for legislation, then you have to advance the regulations, so there is, frankly, trade-offs in all of those.

The Chair: I want to come back to a couple of things. Senator Seth asked a question that is very useful for the committee to have a general understanding of the business aspect of it. This is not your role, but you gave a very good answer to a certain degree in that issue, and I think it is important that the committee understand that drugs are brought forward by private enterprise for the testing in various countries, and they do look at the markets that exist. Therefore, if you have a market that contains 350 million people versus one that has 35 million, then the motivation for getting a drug approval in a given jurisdiction may fit a business plan that says we will go to the larger potential market. That is not always the case, obviously, for many different reasons, but it can factor in.

Then there is another issue that affects the business decision, and that deals with the ability to have the clinical trial done, and that gets into an area that we touched on earlier, but it is not really for Health Canada to answer on today, but that is the coordination of the research institutes and their processes within a country as to whether they can actually organize a trial that meets the objective within a reasonable period of time for the business plan.

That is not something we are dealing with directly with regard to these issues today, but those are, in fact, factors that influence a company's decision as to where it might go for a clinical trial.

I raised that issue a little earlier, Mr. Glover, with regard to there are some reports that we are not terribly well organized in the research institutions and that the ethics bodies in each research institution have not coordinated their requirements and so on. Is that an area you want to make any general comment with regard to the attractiveness of Canada for clinical trials? Things that are I think beyond your total control.

Mr. Glover: I will make some very general comments, Mr. Chair. I believe you have Alain Beaudet coming who will be able to give you a much more detailed and comprehensive answer. He will probably correct me on a couple of the answers I am about to give.

The first thing I would say is, in addition to the factors you raised, increasingly when they are looking to have a niche product you have to have enough people. For particularly challenging illnesses, where they are rare, it might not be possible, feasible, to even have enough people in a small country to conduct a trial and you have to go to a larger population. You just do not have the number of people to run the trial. We are seeing that as particularly an issue, and then do you have the framework to allow for that to happen. For rare disorders, those sorts of challenges definitely do exist.

As I am sure you will hear from the innovators, the patent protections that are extended both in terms of the end result and the data are things that they hold very dear to them, and that environment certainly influences part of their business decisions absolutely.

The Chair: Those were excellent additions. Thank you very much very much, Mr. Glover.

I wanted to raise another issue with regard to the point you have made a number of times, that in the phase I, in the clinical trial, you are really looking at efficacy. You are looking at the real potential benefit of the drug under a particular study.

There have been reports that indicate that there may be factors that might influence the physicians who are supervising a trial in a given location to perhaps want to be encouraging of the drug's success. Do you see any of those kinds of issues in Canada? Are we sufficiently transparent with regard to the fees that supervising physicians receive, for example, to manage a clinical trial that you feel confident that there are no factors that might influence the evidence brought forward with regard to aspects of a clinical trial?

Mr. Glover: I am not sure I am really able to comment fully on that, but at a broader level, we do hear things like adverse event reporting — not on clinical trials but more broadly — where some physicians say, "Not paid to do that; I am not doing it." Certainly compensation models factor into physician behaviour. I can say that with all confidence at a general level.

Dr. Cushman: Mr. Chair, that is a very good question, an interesting question. It is one of the issues you will have to deal with as you go forward.

The gold standard is a double-blind study, which is truly double-blind because no one really knows what is going on, the patient or the physician. However, as you said, the physicians often want to know, and in fact the clinicians want to know too because they want to advance the science, and they may have other interests just in terms of advancing the science and advancing the level of care.

It really is a big challenge. I think clinical trials have really been with us for about 40 years, and we are beginning to see some of the problems with them. I noticed one of the senators is an epidemiologist. I think it came out very clearly in the questions just in terms of everything, your point from placebo versus standard of care, the whole exclusion/ inclusion criteria, the seniors who get most of these medications who also have co-morbidities, what are the drug interactions, getting right down to the cost-benefit analysis and measures that are for seniors are really maybe less objective in terms of physiological parameters but more qualitative in terms of quality of life parameters.

This is sort of the new era of clinical trials, and I think Health Canada, in terms of our branch and our functions, it is really the sort of roles and responsibility of the regulator which are, in effect, one small piece of the pie.

The Chair: Thank you very much. I guess just to finish that off, we have just completed a study of the health accord, and we found the term "silos" used continuously throughout our review. We also saw a lot of traditional practice. It may not have to do with any deliberate, unethical behaviour; it is just the way things have happened over a very long period of time.

One of the issues within the clinical trial is that often the actual management, day-to-day management of a trial may be turned over to a nurse. The nurse may be the one who observes an unusual reaction in a given patient. Does the supervising physician then identify that observation as an adverse event at the clinical trial or not?

It is human nature; it is the nature of practise in the past and so on. It is a very complex kind of system. We will attempt to bring out a number of these issues as we move forward and have witnesses who are dealing right at that level with these issues, so I am not putting this back to you overall. Ultimately, it is of interest to you, of course, and I know that you follow all these things very carefully because you do make that final decision with regard to evaluating the evidence that comes forward to you, and the better the evidence, the better decisions that can ultimately be made.

You have been extremely helpful to us today in terms of giving us the background. This meeting was really to help us get some breadth of background with regard to the clinical trials and the various issues, and our colleagues have brought out a number of these aspects. We will begin to move forward starting tomorrow with details into each of the aspects of this clinical trial, and hopefully in the end we will, as you implied at the outset and hope, come up with some information that would be helpful in the long run.

Just before I thank you on behalf of my colleagues, I would like to remind you, and I know that you are all aware because a number of times you have appeared directly or indirectly before us, that we always welcome subsequent information. If an issue has occurred during the meeting that you subsequently reflect on and say, you know, they should really know this, or this is an example of something that might really be valuable to them in helping to interpret the information, if at any time you become aware of something that occurs to you along those lines, we would most welcome your ongoing input in this study.

Now on behalf of my colleagues, I would thank you for the clarity that you have brought to this background session and indeed have gotten into some really important detail. We are looking forward to how this study unfolds.

With that, colleagues, and distinguished witnesses, I declare the meeting adjourned.

(The committee adjourned.)