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.
The Chair: Welcome to the Senate Standing Committee on Social
Affairs, Science and Technology.
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Mr. Glover: Industry.
Senator Seidman: Is it pretty much industry?
Mr. Glover: Pretty much. There are CIHR government-funded trials,
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
Senator Seth: My next question is about off-label medication on
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
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
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
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
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
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
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
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.
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
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
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
Senator Eggleton: Is it an extensive one? Do you need 1,000 or 100
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
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
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
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
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
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
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
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
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
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
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
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