Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 18 - Evidence - May 30, 2012
OTTAWA, Wednesday, May 30, 2012
The Standing Senate Committee on Social Affairs, Science and Technology
met this day at 4:14 p.m. to study prescription pharmaceuticals in Canada.
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
The Chair: Welcome to the Standing Senate Committee on Social
Affairs, Science and Technology.
I should point out that this is a very busy day in the Senate, so there
are issues before the Senate that are continuing and some of our colleagues
will be a little late arriving. Nevertheless, your testimony is so important
that I want to make sure we get it on the record and it is not interrupted
by any unusual events in the Senate this afternoon.
We will move forward. My name is Kelvin Ogilvie; I am a senator from Nova
Scotia and chair of the committee. I will ask my colleagues to introduce
Senator Eggleton: Art Eggleton, senator from Toronto and deputy
chair of the committee.
Senator Martin: Yonah Martin, from Vancouver, B.C. Welcome.
Senator Verner: Josée Verner, from Québec.
Senator Seth: Asha Seth, from Toronto, Ontario.
Senator Cordy: I am Senator Jane Cordy, from Nova Scotia.
Senator Wallace: John Wallace, senator from New Brunswick.
Senator Callbeck: Catherine Callbeck, from Prince Edward Island.
Senator Dyck: Lillian Dyck, Saskatchewan.
The Chair: We are rapidly filling up here. I will remind my
colleagues this is our last meeting in our series of 11 meetings in which we
have been studying various aspects of clinical trials in Canada. This issue
will focus on the research ethics board and we are absolutely delighted to
have such a distinguished panel with us today.
By prior agreement, we have an order of presentation. I will introduce
our witnesses as I invite them to speak, which means I will start with the
Ontario Institute for Cancer Research and Dr. Raphael Saginur, Chair,
Ontario Cancer Research Ethics Board Governance Committee, who will be
speaking, and Janet Manzo, Executive Director, Ontario Cancer Research
Dr. Saginur, please.
Dr. Raphael Saginur, Chair, Ontario Cancer Research Ethics Board
Governance Committee, Ontario Institute for Cancer Research: Thank you
Mr. Chair. We would like to thank the committee for the opportunity to
present an REB perspective. In the interests of time this oral presentation
is an edited version of the written submission.
Earlier witnesses have raised concerns regarding reduced R & D investment
and a number of clinical trials in Canada. Lack of coordination and delays
and inefficiencies in ethics review of multi-centre trials are of great
concern to REBs.
We refer this committee to the March 2012 paper prepared for Health
Canada by Marianne Vanderwel, which we have circulated. Our presentation
will focus on developments in the REB environment in Ontario, as well as
opportunities for broader improvements, including recommendations for
accreditation and alignment of the rules governing research, leveraging work
already in process and a higher degree of national coordination.
In 2003 the Ontario Cancer Research Network, now the Ontario Institute
for Cancer Research, created OCREB in response to concerns with the
traditional REB model. Alain Beaudet made reference to OCREB when he
appeared here on March 29.
For multi-centre trials the traditional REB review model is inefficient
and duplicative, with no evidence that it provides additional protection for
research participants. OCREB represents a paradigm shift in Canada.
As an expert oncology centralized REB, OCREB is able to reduce delays and
eliminate duplication while providing quality ethics oversight for
increasingly complex research. OCREB's credo is: "Do it once and
do it well. "
Essential to the development of OCREB was the building of trust with
partner organizations. In the absence of standards or accreditation this was
a time-consuming process for all. OCREB now has 24 member centres
representing the vast majority of the province's hospitals conducting
With the rollout of an online system last year, OCREB has reduced the
average time from submission to approval from 13 weeks to 8 and is on track
to 6 weeks or less within the year. When OCREB improved its timelines the
investigator response time also improved.
Once the provincial applicant receives provincial approval, each of the
multiple collaborating centres can submit an abbreviated application and
obtain OCREB approval in less than 10 days. Centres are not all ready to
open the study at the time of provincial approval and sponsors may add new
centres months or years into the study.
The OCREB model allows for flexibility in that centres can submit at any
time after provincial approval. Negotiation of the contract or the study
budget often is the rate-limiting step to study initiation at the centre.
OCREB has been working with multiple external partners to further
streamline the cancer research environment in Ontario and Canada. For
example, the National Cancer Institute of Canada Clinical Trials Group, BC
Cancer Agency REB and OCREB recently came to an agreement on a common
consent form template.
OCREB and the BCCA REB have been collaborating on policies and procedures
for several years. Informal discussions around the potential for share of
reviews have taken place with REBs in other provinces as well. With the same
technology platform at UBC, the University of Alberta and OCREB, there is
potential to share reviews.
OCREB has been collaborating with Ontario pediatric groups to work
towards OCREB becoming the REB for multi-centre Children's Oncology Group
trials at five centres in Ontario. Thus, through successful partnerships,
OCREB has demonstrated that excellence in research ethics is consistent with
efficiency and timeliness.
In principle there should be nothing to prevent a shift to alternative
models of REB review. In practice there are multiple barriers, none
insurmountable. One such barrier is lack of trust among institutions and
REBs, and unwarranted concern about outsourcing ethics review to an REB
outside the institution. The development of common policies, procedures and
standards will facilitate collaboration, cooperation and trust.
There is an opportunity to create a national coordinating structure that
would include a list of all REBs, common education and training, shared
policies and procedures, compatible technology platforms and forms,
performance benchmarking and evaluation, and use of standards and best
Accreditation also is needed. However, it should be approached as a broad
Human Research Protection Program that includes the institution, the REB and
REBs are not solely responsible for protection of research participants
and for the ethical conduct of research. I refer you to an article by
Anderson and others in Health Law Review, which contextualizes the REB. We
have circulated that, Mr. Chairman.
In its 2002 report, The Health of Canadians — The Federal Role,
this committee recommended a governance system that includes an
accreditation or a certification process.
The need to serve multiple regulatory and legal masters with inconsistent
requirements adds complexity to the research environment. It is not uncommon
for REBs to address five different sets of Canadian and U.S. rules for a
given trial. The new CGSB standard will add to the complexity.
REBs are left to follow the most stringent requirements for all research
or create different policies for different types of research.
Many provinces have different privacy legislation or other legal or
policy requirements that would pose difficulties for a single pan-Canadian
REB decision. National privacy legislation, PIPEDA, does not address
research ethics, whereas PHIPA in Ontario does. Alignment of privacy
legislation is needed and it must address research ethics.
In the past, American regulators have indicated their openness to deeming
foreign standards as equivalent, waiving the need for their extraterritorial
jurisdiction. Canada must initiate discussions leading to recognition of
Canadian standards. This committee also recommended pursuit of equivalent
protections in its 2002 report.
The Canadian Cancer Research Alliance 2011 Report on the State of
Cancer Clinical Trials in Canada recommends the creation of a
pan-Canadian infrastructure program to support cancer trials, streamlining
of the regulatory environment and consolidation of REBs. In the absence of
national coordination of research, the work of valuable grassroots
organizations such as the Network of Clinical Trials Networks and CAREB
should be leveraged in best practices, SOPs and training, QA initiatives,
patient involvement, et cetera. CIHR's Strategy for Patient-Oriented
Research, SPOR, promotes this approach.
Harmonization efforts must transcend provincial and national borders. Ten
years has passed since this committee's 2002 report and many of its key
recommendations remain unfulfilled. We have an opportunity to capitalize on
the current willingness for change. OCREB has demonstrated that REB
centralization works. The time to act is now.
To summarize the key recommendations, create a national coordinating
structure for REBs, support and build on the work of other initiatives and
partners, implement accreditation, and work to align the provincial, federal
and international rules governing research ethics.
My colleague, Janet Manzo, and I would be pleased to answer any
The Chair: Thank you very much.
I will now turn to the Canadian Association of Research Ethics Board,
Sharon Freitag, Past President.
Sharon Freitag, Past President, Canadian Association of Research
Ethics Board: Mr. Chair and honourable senators, on behalf of the
Canadian Association of Research Ethics Board, furthermore referred to as
CAREB, I would like to thank you for the invitation to appear before this
committee and provide the CAREB perspective on the state of clinical trials
To put our perspective in context, CAREB is a national organization
dedicated to promoting human participant protection in research. Since its
formation in 2000, CAREB has created a community of research ethics
professionals across the country. We currently have over 300 members
representing over 200 research ethics boards across Canada, which review the
full gamut of human participant research including, significantly, clinical
The CAREB membership includes REB chairs and members with expertise in
science, law and ethics, community members, who bring the patient or
participant perspective, and REB administrators. Over the past decade CAREB
has built a strong community with a reputation for trust, transparency and
cooperation across this country.
CAREB's ongoing engagement and leadership are demonstrated through its
position statements and guidance documents, participation in the development
and evolution of regulations and policy, and recognition by other major
stakeholders that we have in fact earned a seat at the table in numerous
national and international policy discussions.
CAREB has long recognized the need for change in the Canadian research
ethics landscape, particularly with respect to how clinical trials are
initiated, reviewed and administered, as members of our association continue
to express frustration with the ever-increasing workload due to the rapidly
changing regulations and added legal and regulatory complexity in ethics
review. Unfortunately, much of the regulatory burden has no bearing on
patient or participant safety and, conversely, detracts from the primary
purpose of the REB — to protect humans in research.
As a significant example, one area that CAREB identified and addressed
was the issue of management of non-local adverse event reports. Every site
involved in the clinical trial would receive adverse event reports on an
individual level. REB chairs and administrators were expected to wade
through the hundreds of reports for each trial, not knowing how to interpret
the data and what action to take. Recognizing this was an important area of
concern for all Canadian REBs reviewing clinical trials, CAREB took the lead
in bringing together Health Canada, Rx&D and other interested stakeholders
from across the country to discuss a national strategy on dealing with this
The result was CAREB's guidance on reporting of unanticipated problems,
including adverse events, to research ethics boards in Canada in July 2010.
This guidance has been adopted in part or its entirety by many REBs across
this country. Both Dr. Saginur and Ms. Manzo were instrumental in this
successful endeavour. CAREB recognized that while the guidance documents
alleviated burden for administration of clinical trials in Canada, there are
numerous other obstacles to promoting streamlined ethics review nationally:
First is the lack of a Canadian accreditation system. Much work has been
done to date on the Canadian General Standards Board standard, but it has
long been CAREB's position that the development process was flawed and that
the resulting document is overly prescriptive. It is likely to significantly
add to the burden and extend the time lines of review of clinical trials by
research ethics board with little impact on participant safety.
Second is the interprovincial difference in privacy legislation, which
was referred to by Dr. Saginur as well.
Third is the disjunction of research ethics policies and guidelines with
Health Canada regulations, CGSB standard, USFDA, et cetera. The issue of
equivalent protections between Canadian policies and American regulations
have been considered for years, yet no significant progress toward equal
acceptance of review systems has been made.
Fourth, is the lack of a national body to oversee and champion all
aspects of human research protection. The recent changes in Health Canada's
bioethics portfolio calls into question who will be leading the promised
evaluation of the newly approved CGSB standards.
Fifth is the utilization of a clinical trials registration system that is
error-prone and relies on the researcher's buy-in to yet another
administrative process, again with little to no impact on participant
In CAREB's perspective, the most important obstacle to tackle is the
issue of REB accreditation as this is the basis of streamlining,
harmonization and recognition of quality. As such, in January 2012, CAREB
responded to a letter of interest on the development of an accreditation
system for REBs and Human Research Protection Programs issued by Health
Canada. In the letter of interest, we proposed a model of accreditation that
would involve the creation of a national advisory council made up of
representatives from key stakeholders: Health Canada; Industry Canada; the
Interagency Advisory Panel on Research Ethics; CIHR; CAREB; the Association
of Canadian Academic Healthcare Organizations, ACAHO; and Rx&D, Canada's
Research-Based Pharmaceutical Companies, to oversee the process. CAREB
envisions that this council would choose a lead organization to ensure that
the accreditation/certification program is implemented and governed
appropriately. The proposal as outlined also outlined the need to establish
an inventory of REBs and research ethics experts across the country — a
central REB registry of all REBs, not just those reviewing clinical trials
and development of operational requirements.
CAREB contends that the development of a process that applies to a single
category of research, i.e., regulated clinical trials, is short-sighted and
counterproductive because the attributes necessary for highly regulated
research are not transferable to areas that are not subject to comparable
requirements. If only one standard for REB operations exists, that standard,
by virtue of its very existence, will likely influence the perceptions of
what constitutes an acceptable standard for all REB operations. Our concern
is that because the majority of REBs operating in Canada review a range of
human participant research in addition to regulated clinical trials,
standards for the ethics review of research needs to encompass the entire
human research protection program of an institution or organization.
We recognize that major considerations for accreditation of REBs are
funding and sustainability. In fact, we believe that financial resources for
any form of governance and accreditation related to Human Research
Protection Programs have been the major barrier in the establishment of an
accreditation system to date. REB accreditation in Canada has been in
discussion for well over a decade, with several government-led initiatives
beginning, then being shelved as a result of expected cost. However, what
needs to be considered, which is at the root of our meeting today, is the
financial impact of not having an REB accreditation system. The lack of
recognized consistency in ethics review and associated processes continues
to have a chilling effect on sponsors, particularly with respect to clinical
trials. Several countries have had accreditation for years and represent an
easier alternative to the Canadian patchwork system of review.
It is important to add that while REBs and their work are an important
part of the clinical trial process, we are just one part of a large puzzle.
All stakeholders must commit to the willingness to work together on all
aspects of the puzzle. Transparency, collaboration and communication are the
key to success in moving forward. CAREB has a strong track record of
leadership in the field and impact on the ground. We have never shied away
from a challenge or an opportunity to move forward, and we would welcome the
opportunity to work toward the common goal of regaining our competitiveness
in attracting clinical trials.
Thank you. I would be pleased to entertain any questions or comments you
The Chair: I will turn to Clinical Trials Ontario and invite Mr.
Ronald Heslegrave to present.
Ronald Heslegrave, Executive Director, Clinical Trials Ontario:
Thank you, Mr. Chair and honourable senators, for allowing me to tell you a
little about Clinical Trials Ontario. You have the presentation before you
that I will run through.
Clinical Trials Ontario is an independent not-for-profit organization
established very recently by the Ministry of Economic Development and
Innovation as part of Ontario's Life Sciences Commercialization Strategy. I
say "very recently " because Clinical Trials Ontario became an entity only
in late December. It did have stakeholder involvement for the last two years
coming together to the point where Clinical Trials Ontario could act as its
own entity. Our mandate is to provide the life sciences industry with a
streamlined approach to conducting multi-centre trials in Ontario, while
ensuring the highest ethical standards for patient safety. Through this, we
hope to ensure greater investments in Ontario from industry sponsors, access
for patients to leading-edged medical research, local access to the best and
most advanced evidence-based care, and opportunities for economic growth and
job creation by investment through industry.
The problem, as you are well aware from your last 10 sessions I am sure,
is that significant investment is decreasing from the pharmaceutical,
medical devices, biotech and other industries. The pharmaceutical industry
invested close to $500 million in Ontario alone, with about half of that
being dedicated to clinical trials. Between 2009 and 2010, there was a drop
in clinical trial investment of about 12 per cent; but this drop in
investment has been occurring for a number of years. The global trend over
the last five years has been a shift in investment away from Canada and
other Western economies to other countries because of the advantage of
reduced costs, increased speed to start up complete clinical trials, and
enhancement in patient recruitment. Many developing economies are providing
public sector support to reverse this trend and bring clinical trials back
to Western economies, established economies and North America. Clinical
Trials Ontario is a new venture that will help us to do that.
It was recognized in Ontario that there was a need for a call to action
really on the basis of government intervening and providing some resources
to help support bringing clinical trials back to Ontario and, by that
nature, back to Canada. We used to rank second in the world in clinical
trials activity. We are now down to about fifth in terms of the number of
clinical trials conducted in Canada. We have a steeper rate of decline in
trial sites that are being opened, and we rank tenth in terms of site
capacity. Canada has a greater rate of decline in recruitment reliability in
that we are not as reliable at recruiting as other jurisdictions, and we are
a much higher per-subject cost in terms of carrying out trials.
Global companies have been attracted to emerging markets on the basis of
lower absolute costs; relatively comparable quality, given the cost
differential; and less bureaucracy in respect of the necessary approvals to
initiate a clinical trial. Ontario's view is that we need to reform the
clinical trials infrastructure, and Clinical Trials Ontario intends to
realize this opportunity.
Our vision at Clinical Trials Ontario is to make Ontario a preferred
location for global clinical trials, while maintaining the highest ethical
standards. CTO intends to mobilize all the partners to move quickly and in a
coordinated, streamlined, seamless fashion to launch and approve clinical
trials. Through this, we hope to ensure greater investments and,
particularly, access to patients to leading-edge medical treatment. This
will have economic spinoffs for Ontario and, by virtue of Ontario, for
Canada as well if we do this right.
Clinical Trials Ontario has three strategic pillars for reform. The first
is to improve the speed and reduce the cost of multi-centre clinical trials
by streamlining the research ethics approval process, bringing that down to
a single review for the province, and harmonizing other administrative
processes and platforms.
The second is to leverage partnerships with investigators, industry and
government to gain access to global decision makers for clinical trials and
attract clinical trial investment, based on the success, from a business
perspective, of Clinical Trials Ontario, CTO.
The third is to engage patients and the public to recognize the benefits
of clinical trials for their own health and that of their families and of
society and to improve patient recruitment through education about what
clinical trials are all about.
I have outlined the three strategic pillars. In terms of improving speed,
we have five main objectives to establish an integrated system to bring the
necessary clinical trials REB review process down to a single REB review for
multi-centre trials. We have goals of implementing standard operating
procedures so that we are consistent across trial sites and of improving
communication and coordination between clinical trial sites to support
clinical trial initiation and the ongoing oversight of REBs. We need to
develop and track, document and benchmark our strengths in terms of metrics
that will allow industry to see the improvement in the initial review and
ongoing review and metrics associated with clinical trials. Our goal is to
move towards CTO being representative of a single port of entry for clinical
trials in Ontario.
In terms of the second pillar, we want to leverage strategic
partnerships, and we intend to do this by building a provincial network of
investigators, institutional and industry leaders to build and promote
common processes, platforms and communication strategies, to promote
clinical trial investments in Canada, to promote the benefits, quality and
efficiency of our new Ontario streamlined system and connect with
stakeholders who can influence key policy decision makers to locate clinical
trials in Ontario.
The third important strategic pillar is to engage patients. We intend to
work with volunteer associations to build public awareness and distribute
educational material to support the social value of clinical trials. We want
to establish educational strategies to support more successful patient
recruitment and retention by building trust in the safety and importance of
clinical trials for the public and for patients.
Where are we now? The status of funding is that the Ministry of Economic
Development and Innovation in Ontario only established CTO, as I said, in
December. We have now secured, from the Ontario ministry, three years of
funding, based on a strategic plan we put forward. However, in the future,
it is expected that industry will provide ongoing financial support to
Clinical Trials Ontario, through the demonstrated success of the CTO
initiative, such that if we can reduce clinical trial start-up times, that
will be a cost savings for industry. Industry has expressed a willingness to
offer financial support for any improvements that we can make in the
clinical trials infrastructure.
I have noted our board of directors. This is a partnership board based on
skills, and you will see that the executive is made up of an academic
clinical trialist, a regional director from Pfizer and the associate provost
of one of the universities, representing the university academic centres. We
also have the CEO of MaRS Innovation, Dr. Ray Saginur, and Anne Snowdon,
from the Ivey School of Business, on our board. Amgen is represented. MEDEC,
the medical device association in the country, is represented, as is Michael
Wood, from Thunder Bay, who is the CEO. We intentionally put a board
together in this way to develop a partnership that can work together and
have industry, academia, and clinical trialists represented.
What is the way forward? I think, from what I have presented and what you
have heard, that there is a need to reform the clinical trials
infrastructure and oversight system, not only in Ontario but also in Canada,
as clinical trials represent important access to new treatment alternatives
for patients. Clinical trial sites are awarded to countries, not to regions
or provincial jurisdictions, so we need to influence at a global level to
have Canada play a more important role in the clinical trials environment.
Ontario has made an investment to reform its clinical trials
infrastructure, but there are various infrastructure initiatives being
pursued across Canada with regard to streamlining REB with review, common
contracts, national standards, et cetera. We need to continue to work
nationally on a pan-Canadian solution for clinical trials, with
investigators, industry and government. I would suggest to you that the
witnesses testifying before the Senate committee represent initiatives that
are tackling different parts of problem. More importantly, these and other
organizations could be enlisted to enable a Canadian solution if resourced
Thank you for your attention.
The Chair: Thank you very much. I will now turn to my colleagues
for their questions.
Senator Eggleton: I have two questions. I will start with Clinical
Trials Ontario and Mr. Heslegrave. This is quite an ambitious undertaking,
and yet we have heard, through much of the testimony, of many of the
barriers that exist. How will you overcome these barriers? This is a
provincial endeavour. You have Health Canada. You have the important role
that they and others play in all of this. How do you overcome that? What are
the barriers that you have to overcome? How do you overcome them?
Also, one of the concerns that we would always have in trying to make
Ontario or anywhere else in Canada a preferred location and trying to
reverse the trend, which has been a decreasing number of clinical trials in
this country, is whether we are going to sacrifice safety or efficacy in
terms of our examination of drugs in any of this? At one point in your
documents you say that you are looking to do things that will be acceptable
to industry. Industry has its own objectives and directions. Some people
might consider "streamlining " a code word for taking shortcuts on the
regulations, which could mean shortcutting the safety aspects of things in
order to attract industry.
Could you talk about these barriers and the trade-offs?
Mr. Heslegrave: Absolutely. That is a very good question. There
are, as you have also heard from the other witnesses and the ones that you
have heard from in the past, significant barriers. What we have done in
Ontario is enlisted the support of the Council of Ontario Hospital
Associations, the CAHO group, where most of the research is done in Ontario
at the academic centres. The CEOs of CAHO, through presentations we have
made to them, are on board with changing the culture. We have done this with
a variety of other groups, VPs from a number of organizations, et cetera.
There is a willingness to move to a different type of system and to reform
the current system that we have to allow research ethics review to take
place at fewer centres. Ideally, there would be only one centre for the
province. This will allow us to work with other provinces better, in a
streamlined approach, for initiatives that are going on in other parts of
country. We do have the institutional support in Ontario.
Of course, a big issue will be trust amongst the institutions, but I
think there is a willingness to move in that direction, in part because of
the experience with the Ontario Cancer Research Ethics Board, which has been
doing that for some time. There is certainly a recognition that we need an
improved approach. Again, there are barriers; it is an ambitious project,
and we are just getting off the ground now. I think that the time is just
right because of the willingness of all of the institutions to come on
In terms of sacrificing safety, as you heard from OCREB and CAREB, there
is no evidence that suggests that reviewing the same protocol 10 or 50 times
around the country leads to any greater patient safety than doing it well
and doing it once. That was the mantra of the Ontario Cancer Research Ethics
Board, which I chaired for seven years. There is a willingness to move this
forward. There is no intention at all of reducing the safety in the system.
Health Canada will still have its role, and the institutional or other
research ethics boards will still have their roles. However, we do not need
the redundancy in the system.
In terms of benefits to industry, they already have metrics on the
research ethics boards and the institutions, et cetera, and their clinical
trial infrastructure that tells them if they are competitive in Canada or
should be going elsewhere. We are not introducing anything that will
streamline or make ethics review easier, but we are reducing the redundancy.
Dr. Saginur: Senator Eggleton, your point is well taken. It is of
primary importance to add to what Mr. Heslegrave said. I think you should
look at this with a historical perspective. A number of years ago, slow
meant thorough. Repetitive meant that the lonely person at the back of the
room would have a unique idea. This was a bit of an urban myth and the
evidence was to the contrary; that repetitive review added complexity,
delay, cost, and little else.
To a large extent, the barriers were built out of inertia and
complacency, rather than active antipathy. Now that there is a fire lit
under the stakeholders of Canada, I think there is new recognition and
willingness to work together. I think the very nature of Clinical Trials
Ontario is to bring the stakeholders together, and they are willing to talk.
Part of the premise of Clinical Trials Ontario — and it remains to be seen
that it will defend this — is to maintain the robustness of REB review.
Senator Eggleton: Let me bring this up to a national level. One of
the things we had been talking about is the standardization of clinical
trials in Canada. I hate to use acronyms, but the names of your
organizations are so long that I will call them CAREB and OCREB. This is
primarily to you, but all of you can answer.
You have touted a national body to oversee and champion all aspects of
human research protection, in the case of CAREB. In the case of OCREB,
create a national coordinating structure for REBs that includes common
education, training, et cetera.
Are you on the same wavelength here? We have run across language — I am a
layperson, so I am reading this and trying to understand. Are there
differences here? Are you all coming to the same conclusion? Is this a
standardization of not only REBs but the whole clinical trial process that
we should be imposing by legislation? Are you talking about voluntary
coordination? Are there any differences in what the two organizations are
Dr. Saginur: I will not speak for CAREB, but I think there are
great similarities. OCREB is a provincially funded organization and does not
intend to become national. As such, it is not a candidate to become a
Senator Eggleton: You proposed one.
Dr. Saginur: We certainly support that and strongly advocate for
it. We want to work with partners outside of Ontario. We think it is vitally
important in order that it happen. I personally think this should be an
independent organization outside of government. We have to contend with the
reality of the federal-provincial split in terms of responsibilities. I
believe that has been an excuse for a lack of leadership on the part of a
lot of parties. I think it is time for someone to step up to the plate, work
with other partners and have shared jurisdiction for these very important
Ms. Freitag: I totally agree with what Dr. Saginur has to say. We
have found that although each REB is operating in a silo, we are operating
doing the same things. I think part of what has been lacking in the
infrastructure is a set of guidelines, a common set of rules that we are all
It is difficult because we have different privacy legislation across this
country. How we, in Ontario, would review something would be totally
different from a privacy point of view in Alberta. Right now, that is
causing a lot of trouble. I am chairing a committee for SPOR for CIHR that
is made up of people across the country. One of the things we have all
brought to the table is that it is not that we do not trust each other; we
do not know what each other is struggling with in their own jurisdiction.
The levelling of the playing field could be started with a basic set of
Senator Eggleton: Who establishes the rules?
Ms. Freitag: I think it has been bantered about even before my
time; a governance body made up of all stakeholders and people such as
myself. I am on the ground. I am dealing with this every day. I am the
director of a research ethics office. People like CTO, who will now try to
marshal a whole group of people together and people like OCREB, who
represent 24 different hospitals, including my own. We have worked together.
We have started to see there is a willingness and an understanding that
there are barriers. We are starting to break down the walls. You do not get
200 REBs represented at a table without having some shared interest in
moving this endeavour forward.
Senator Martin: I am on the same wavelength as my colleague
Senator Eggleton in terms of the line of questioning. One of my first
questions was going to be: The total number of REBs is about 200?
Ms. Freitag: It is a really good question, as a matter of fact. I
will be honest with you. No one knows how many REBs are in Canada. I can
tell you how many boards there are that review animal research, but I cannot
tell you how many review clinical trials. CAREB has a website and we have
members, so we have started to count that way.
As part of the initiative with SPOR, all the different members have
agreed to go out to their own jurisdictions and start counting the REBs. I
thought it was going to be an easy endeavour. Believe it or not, it is not.
For every one, we find another. Right then and there, we should know. I am
embarrassed to say that, as the past president of the Canadian Association
of Research Ethics Boards, I bet that we do not even have some boards that
are represented at the table.
Dr. Saginur: To add to that, the FDA has a publicly available list
of U.S. IRBs, the equivalent of REBs, that they deal with. In order to
conduct research, I once personally tried to compile a list by requesting it
from Health Canada, knowing that I have to sign an attestation form when my
hospital is the site for clinical trials. I thought that, through Health
Canada and their good graces, I would be able to get a list, and they were
unable to do so. I think this is an embarrassment and it is impossible to
manage a system without knowing what the system is.
Senator Martin: I was looking at the background paper you
submitted and the international and Canadian activities related to the
ethical review of clinical trials. On page 60 in your document is a table of
oversight systems by country.
I kept wanting to see this in comparison to Canada, and I am assuming the
number of ethics committees in the final row are the REBs in these
jurisdictions. When I asked that question I was curious because Australia,
which is a comparable jurisdiction, has 221 registered REBs. I was trying to
make sense of this chart. It was very interesting to look at the information
and I wanted to compare it to Canada — although this is about Canada as well
— and just to have it in this chart.
I like the motto "Doing it well and doing it once. " That is a key
point. I want to know if there is congruency in the different initiatives
you talked about, Mr. Heslegrave. Regarding making Ontario a preferred
location, we have heard from past witnesses about making Canada a preferred
location. How does what you do for Ontario translate to other jurisdictions?
Would what is good for Ontario be good for Canada?
In terms of clinical trials, are you facing similar barriers and
challenges, or is there also interprovincial competition in Canada? I think
there would be, but I am curious about the congruency of these initiatives
and whether it is good for Canada, as well.
Mr. Heslegrave: As was said earlier, this is an opportune time to
bring this congruency together. Everybody knows we want to change and we
want to change together and do this in the right way, not only for
administrative and economic reasons, but also for the health of our
We can move forward in a very cohesive manner. Ontario has the larger
number of sites for carrying out clinical trials in the country. If we
manage to pull it together in Ontario, the lessons learned from that should
be equally applicable to the rest of country. We intend to share those
lessons as we go through the process.
It is very important. We can move together in a way that will be
supportive of the country. We at Clinical Trials Ontario, because we are
funded by the Government of Ontario, need to begin our focus there. However,
anything that Ontario can move forward with will be of great benefit to the
I think some of the issues that need to be dealt with are probably some
of the different legislative issues that exist in different provinces.
Quebec has legislation that they changed very abruptly from the first
go-around. Newfoundland and Alberta have some legislation.
However, I think all of those things are management. In talking with my
colleagues around the country, no one sees these as insurmountable barriers
to working together.
As I said in my presentation, when we are talking about global clinical
leaders, the big pharma, et cetera, are looking for an allocation of sites
to Canada. Then it is up to Canada where they distribute those sites within
Canada. We need to be looking at this from a Canadian perspective. We will
start with an Ontario perspective because that is where our funding is
Senator Cordy: Thank you, each of you. You have given a lot of
really good information. Some things we have heard before but some is new,
so thank you.
I would like to go back to the issue of privacy legislation. At least two
of you mentioned it, I know. Dr. Saginur, you spoke about the provinces
having different privacy legislation and the challenges. I thought that in
our 2000 report we also talked about privacy legislation and coordinating
it. I will have to go back a bit — it was 10 years ago — and reread it. I
know you made a number of references to our report in your comments today.
How will we get it all together so that we get all the jurisdictions to
work together, align all of them so we respect what the provinces have done
but also we look at things from a national perspective? We want clinical
trials taking place in Canada. If we are making it too cumbersome, which we
appear to be doing, we will certainly start losing market share now, unless
we start to work together on things. Let us deal specifically with the whole
issue of privacy.
Dr. Saginur: My impression is that it is doable by bringing people
together. There was an initial wave of health- related privacy legislation,
province by province, across the country a number of years ago.
I believe that we will bring people responsible for privacy together in
their respective provinces, along with their federal counterparts, to talk
about it with a view toward looking for best practices for having excellence
in privacy practices as a first goal, and to have harmonization as a second
goal, in order to facilitate commerce. That would appeal both to the
altruism of people involved in privacy who believe it is a very important
right of individuals. Also, it would appeal to people who recognize the
importance of economic development.
I think that there would be great willingness to share and by exposing
and discussing I suspect they would find greater alignment and perhaps
commonality. Even if it is a provincial jurisdiction, it could still be very
similar or identical from province to province.
Ms. Freitag: When we are looking at health, per se, we can look
south and look at the HIPAA legislation, which is for the entire United
States. I am not saying we should adopt that type of stringent legislation,
but I am saying that no matter what state you are in, you are all subject to
the same legislation when it comes to health. I think it would build trust
in the system and make it easier to look at the one board point of view —
one board for all of Canada, for example.
We are talking about CTO. It is easy to within the jurisdiction of
Ontario, as OCREB and CTO are both dealing with pre-HIPAA legislation.
However, once we go beyond those borders, we have to deal with different
types of legislation. When it comes to health, it should be
Mr. Heslegrave: The only thing I would add to that is that the
Privacy Commissioners in the provinces and the federal Privacy Commissioner
get together on a regular basis. Even though the legislation is different,
the similarities in approach, how they understand privacy and how they
regulate privacy in the different provinces are not that different. I think
these barriers can be overcome.
That is a willing group that can work together on this. As far as I know,
Ontario is the province that built research components into privacy
legislation. I know there is talk about this in other parts of the country.
The Privacy Commissioner for Ontario is a strong proponent of privacy in the
research setting. That has not been an impediment to how we conduct research
Senator Cordy: It certainly seems workable just getting people
Mr. Heslegrave, I am very impressed by your ambitious and well-organized
plan that you have brought forward today from Clinical Trials Ontario. I
would like to look specifically at pillar 3 about engaging patients. There
is some overlap with pillar 2 when you talk about educating, also.
It is becoming a challenge to get patients to participate in clinical
trials for whatever reasons. I like your idea of working with volunteer
associations. I am not quite sure what your definition of a volunteer
association is, though.
Mr. Heslegrave: We are working and we have relationships with the
Canadian Partnership Against Cancer, for instance, and the work they are
doing with their cancer volunteer associations, et cetera. We are working
with the Canadian Rheumatology Research Consortium across the country, as
well, so that is a different patient population.
Patients can be best our best advocates. Certainly, when we have had
patients in the past at public presentations who have participated in
clinical trials, they are persuasive about the benefits of clinical trials.
One of the unfortunate things is that the public often hears what comes out
from the media, which is when something went wrong, rather than the
We want to change that perception about the potential benefits, but it is
clearly everyone's right to decide whether they want to participate in
research or not and in clinical trials in particular that come with often
greater risks than other types of research.
Senator Cordy: We heard from some witnesses who appeared before us
about the challenges of competitive enrolment. In fact, most of them spoke
against it. You did not mention where sponsors would entice you with
incentives to participate. Have you thought about that when developing your
Mr. Heslegrave: Competitive enrolment is a reality across the
globe. Sites are given certain recruiting mandates, if you will. Canada has
been very bad in terms of meeting the targets they said that they would
voluntarily meet to recruit people into studies and retain them in those
studies. Certainly from an ethical point of view, REBs are very much against
any kind of incentive. In fact, over the last number of years, we have taken
off incentives as part of the contracts between sponsors and their
investigators. There are strict policies against those kinds of incentives
because participation in a study is about respecting the dignity of the
individual involved in the study. We would not expect that, but we are not
promoting clinical trials in a positive way in the country either. If what
you hear most of the time is that something went wrong in this trial or that
drug is not as good as they thought, many people are benefiting from those
new drugs as well, and we do not hear that end of it. It is unbalanced view
at the moment, and we are hoping to bring some balance to that, with
patients heavily engaged in it.
Senator Dyck: I have a supplementary to the patient question. I
noticed you were, in your strategic pillar, engaging patients, and your
board of directors is skill based. In terms of patient safety and
recruitment of patients, have you considered putting a patient advocacy
group or community group on your board of directors, either to address the
idea of safety or to sort of enhance the idea of clinical trials? That might
help with recruitment and retention of participants.
Mr. Heslegrave: We have talked about that. We have formed the
board only in February, and what we were looking for was stakeholders that
could actually help us try to achieve our goals in this. We are certainly
not against moving in that direction. Our board members have terms which
will expire. Certainly the idea of a patient representative or a patient
association representative is not something we have excluded. In the first
go around of board members, we did not do that. That is not who we had
before us in terms of making decision about who would be on that board.
Ms. Freitag: I want to remind you that every REB has their own
community members, and I think that is an important aspect to what every REB
brings to the table. You would not want to single out one patient group. I
think that is always an important thing to bring, and what makes the
research ethics process so rich is the fact that it allows so many different
voices to be heard at a table, and one of them of course is a community
Senator Seth: This is really interesting. I do not know where to
I read an article in the Canadian Medical Association Journal
suggesting that there is sometimes limited cooperation with the Ontario
Cancer Research Ethics Board guidelines due to lack of trust. Are medical
centres reluctant to use a centralized REB due to distrust, or are there any
Dr. Saginur: I was involved with OCREB from its inception. When it
came about, there had been a repeated hue and cry from industry about the
need for centralization of ethics review, and there was no particular
institutional response. After OCREB was launched, and Mr. Heslegrave was
chairing it and I was watching closely as the worried parent of it, what
seemed to happen was that there was risk avoidance on the part of industry
until more bold sponsors would test the waters, and when things worked out
well, then others joined in.
Among institutions, smaller institutions with less academic affiliation
and further from major centres seemed to be the first to join in. Ms. Manzo
can correct me if I am wrong. Then the suburban hospitals or the smaller
city hospitals and the large academic hospitals were the last to join in. I
think the short answer to your question is no, all the important players in
terms of cancer research in Ontario are involved and there is excellent
cooperation, which has been engendered by the chair and the executive
Senator Seth: In your presentation, Ms. Freitag, you mentioned
that there are hundreds of research ethics boards across Canada. These REBs
do not follow a standardized process of accreditation. CREB suggests that a
standard process will make REB accreditation easier. Can you tell us how?
Ms. Freitag: I think I had spoken to it before in the fact that it
is not that we do not think we are not doing a good job. There is just no
standard to measure ourselves against. We all like to think we are doing a
good and the best job. Amongst my colleagues, I think we would agree that
over the time you think your REB is the best one, but we do not really know
that. We would like to see us set the bar and everybody meets the bar. It
begins to open up the dialogue for trust. Many of us who get federal funding
have to adhere to the Tri-Council Policy Statement. There are some REBs that
do not receive any funding. Therefore, they are a REB but do not necessarily
have to adhere to the Tri-Council Policy Statement. I think we have to look
to a broader sense of developing a set of standards with which we are all in
agreement and look at it as a broad human research protection program.
Dr. Saginur: To add to that, I just want to make clear to this
committee the link between accreditation and centralization. It is hard for
an institution that is an independent corporation with its own liability to
delegate to an outside entity in the first instance. How can it know that
the other REB, the other institution, is doing a proper job? Having a good
housekeeping seal of approval in the form of accreditation is one such
mechanism. Another such mechanism is a history of working together.
OCREB at its inception, for example, had a graded system of delegation,
which was dropped when it no longer became necessary. Initially,
institutions reviewed studies after OCREB had, in the sense that they were
checking on it, and when their checking showed that OCREB met to their
satisfaction, they dropped that checking step.
Senator Seth: There should not be a single national research
ethics board instead of having so many? Is it better this way?
Ms. Freitag: I can say right across the board there is no way that
one ethics board for this entire country will ever work. I can speak from
experience. I have lived in several jurisdictions, including the Northwest
Territories, and have been a researcher up there, and in Alberta as well,
and again we speak to the differences.
What makes Canada such a special place is we are different across this
country. The research ethics board process, the community members and the
different way health is delivered in different places are all things that
the REB takes into consideration. Having one board of record for the entire
country will never, ever be. It would be nice, but thank you.
Senator Seth: Thank you.
Mr. Heslegrave: If I could just come back to the issue of
standards just briefly for a moment. One of the mandates for Clinical Trials
Ontario is to begin to develop an Ontario standard for REBs within the
province. We are certainly going to leverage existing efforts in that way,
but we see developing a standard by which REBs can be credentialed or
accredited is important for us to move forward to have a single REB of
record for a given clinical trial. Standards are important, and we are
working towards that at Clinical Trials Ontario as well.
Senator Callbeck: Thank you for coming today and for your
Mr. Heslegrave, I am looking at the status of funding. You have a
five-year strategic plan. You have funding from the provincial government
for the first three years. Is that 100 per cent?
Mr. Heslegrave: Yes.
Senator Callbeck: You expect after that that industry will pick up
the tab for the other two. How many dollars are we talking here?
Mr. Heslegrave: We are not talking a lot of dollars. We have
funding of $1.5 million for each of three years, but we did not enter into
this without a lot of discussions with industry to say if we do a good job —
and I repeat that, if we do a good job — and we can reduce start up times,
et cetera, in the province, are the member companies willing to step up and
supply funding to CTO to carry on this effort.
Senator Callbeck: How much discussion have you had? Do you feel
you have a firm commitment there? Did you talk about certain benchmarks?
Mr. Heslegrave: We will develop the benchmarks along with industry
to measure where we are now and where we are in three year's time.
Another important part of that benchmarking will be also to say where we
are now and how are we comparing to other jurisdictions. The clinical trials
will be distributed globally, and if we want our fair market share of those
clinical trials, we will not only have to be doing better than we are doing
now. We will also have to be doing better compared to other jurisdictions.
Senator Callbeck: Are you confident that industry will step up to
Mr. Heslegrave: Yes, but I would not go to the 100 per cent level,
as one can never do.
Senator Callbeck: On the accreditation, you mentioned that Health
Canada asked for proposals and that you responded, suggesting that there
would be an advisory board and the advisory board would pick a lead
organization. Have you had any response back from Health Canada?
Ms. Freitag: Unfortunately not. That is disappointingly so because
a lot of time and effort went into those discussions. In part of the
discussions we engaged Accreditation Canada to understand their process as
well. It is my understanding now that there have been major cuts to the
bioethics portfolio, and I am not even sure if the people who actually
issued the LOI are even responsible for this at all anymore, which is
Senator Callbeck: With the advisory council, I think your
suggestion was the advisory council would pick a lead organization. Would
that be a difficult thing? If the advisory council did pick a lead
organization, do you feel that the other organizations would cooperate?
Ms. Freitag: All the groups I mentioned to you came together at
the Canadian Clinical Trial Summit. There is a willingness to work together.
We are building partnerships as we speak. CGSB was the start of discussions.
The clinical trial summits, SPOR, the patient-oriented research focus of
CIHR is bringing together partners. I believe that all these individuals do
see their role at the table and see that they can work together.
Senator Callbeck: Does everybody agree with that?
Dr. Saginur: Yes.
Mr. Heslegrave: Yes.
Senator Callbeck: Thank you. That is great to hear.
Senator Seidman: Mr. Heslegrave, you referred to the need to
reform clinical trial infrastructure and the oversight system across Canada.
I think all of you talked about the oversight system. I would like to ask
you a very specific question about clinical trial oversight. Could you
please tell us what you mean by that? What is clinical trial oversight? Do
ethics boards play a role once a trial is started, and if so, how does it
work? We can start there.
Mr. Heslegrave: I will take a stab at this one. Oversight is
complex, and research ethics boards play a vital role. In fact, they are the
first level in the oversight role. They are monitoring clinical trials,
patient outcomes and adverse events at their institutional level.
Health Canada plays a role in that the same sorts of issues are sent to
Health Canada, so serious adverse events go to Health Canada as they do go
to individual research ethics boards as well.
Companies have independent data safety monitoring boards that are also
monitoring the safety and efficacy of these trials, and those are set up
largely as independent of the sponsoring organization.
There are many levels of oversight, but certainly, the research ethics
boards take that role very seriously in terms of providing that local
oversight. There is a spirit of cooperation between the research ethics
boards that are conducting the same trial, for instance, in case there are
any issues that need a broader oversight of this.
OCREB, for example, because they have so many sites participating, has a
more centralized view of it. Health Canada has the most centralized view of
the oversight, but probably does not have the staffing to do justice to
providing that oversight.
Senator Seidman: I do not know if anyone else has anything to add
because I know the others said something about oversight.
Dr. Saginur: There are a variety of functions, and this came out
in the Experts Committee of the Sponsors Table a number of years ago in
terms of the functionalities that you want, in terms of policy setting and
education of the various parties involved.
What we are seeing now increasingly is developing communication and
cooperation type systems and getting people to work together. I think there
are a lot of different functionalities that are required for a number of
Senator Seidman: What happens in a multicentre trial, for example,
where the monitoring is ongoing as patients enter the trial, and there are
some adverse events or something that the research ethics board feels is
problematic? What signals go out? What actually happens?
Dr. Saginur: It depends on the nature of the adverse event. First,
in a well-designed trial, usually, there is some anticipation of the degree
of risk. For example, I have been involved for a number of years in data
safety monitoring boards for hepatitis C studies. Initially, there was great
concern about potential risk, both in terms of the nature of the patient
population, as well as the nature of the drugs that were being used. There
was a proper, independent data safety monitoring board set up, which met
frequently initially, and adapted its frequency of meetings as the frequency
of risk and the severity of risk were better understood. That reported at
the highest level of the trial. The Research Ethics Board has an opportunity
to demand of the sponsor and the investigators to have a proper system to
recognize and interpret toxicity.
As we have heard from Ms. Freitag, there is a big problem with noise in
adverse event reporting. When we have old, frail people who are studied for
their response to feather dusters, some of them will die, not because of the
feather dusters but because old people have limited life spans. There is a
lot of interpretation that has to be done.
It is particularly difficult in the context of blinded trials, when most
people outside the safety monitoring board do not know what exposures the
participants have had. Safety monitoring boards, however, have the
opportunity to "unblind " patients. As such, a properly designed trial,
then, will have a plan upfront, and it will execute.
There is ongoing monitoring of adverse events and responses in proportion
to the nature of the problems. The problem can be as simple as a minor
change in the wording of a consent document to better explain what has in
fact been experienced. It can be much more drastic in the elimination, for
example, of one arm of a multi-armed trial because, for example, of
excessive toxicity, or it can be the complete cessation of a study because
it is too toxic or the answer is already in; we need not continue the study.
Ms. Freitag: From an administrative point of view, from someone
who works in an office that receives hundreds of serious adverse event
reports, it is difficult because you are one site, without having an
understanding of the magnitude of that adverse event and what is going on,
if it is an international trial.
By centralizing some of these reviews, as we had suggested with CAREB,
either relying on a centralized mechanism such as the DSMB to look at it,
which is a much better way because they can contextualize it for us. I have
1,300 ongoing studies at my institution, probably 400 or 500 of them being
clinical trials. I can tell you that on any given week, I get a pile of all
the different studies. You would have to have the ability to remember every
single study without having to go back to the file to remember if it is an
expected event or if it is not and to contextualize it in the broad sense.
Mr. Heslegrave: I just wanted to emphasize that the research
ethics boards also have the authority to stop a study. A few years ago, when
I was chairing OCREB, we seemed to have a cluster of unexplained adverse
events arising out of a single institution. OCREB was the research ethics
board of record for that. This was across three different studies, and these
were all late-stage breast cancer patients. In fact, we stopped the study at
that site so we could more thoroughly investigate and have a better
understanding of whether these are expected, not expected, and whether this
is something that is just not looked at in regard to other sites
participating in the study.
To emphasize, the research ethics boards in more extreme cases have the
ability and exercise the authority to stop a trial over which they have
Senator Seidman: The bottom-line question is would a national
accreditation system or a national standards system improve oversight?
Mr. Heslegrave: I think it would because then you could put rules
in place for a common reporting. There is a rule in place for common
reporting to Health Canada at this point. However, again, I think this could
be done better. Having an accreditation system so that we can have similar
rules, similar definitions of what is expected and not expected, et cetera,
could be put in place as well as a national system, perhaps building on what
Health Canada currently has.
Dr. Saginur: I had mentioned in passing the article of which the
first author is James Anderson. Part of the point of that article is that
research ethics is too important to be left only to research ethics boards.
There is a broader context, for example, setting a scientific agenda where
there might be a broader societal role. A variety of these functions might
be more institutional roles and not research ethics board functions per se.
It is important to realize that research ethics boards have been asked to
take on a lot of issues that perhaps are not properly their remit, and we
might want to look more closely at the whole cycle of research and who
should be taking care of what.
Senator Wallace: My comment follows up on Senator Seidman's
comments. When I listen to all of this — and all of it is quite new to me,
being a layperson — it seems there are so many groups involved in clinical
trials that have their own turf. They have their own vested interest,
well-intentioned, but the areas they want to protect from the research
facilities themselves, there is competition there. There is the private
sector involvement. There is provincial competition, Ontario doing an
excellent job to attract as much of the clinical trial business to Ontario
as possible, and there are other provinces wishing to do the same. There are
the REBs, who wish to maintain their own standards, having some common
standards, but their own turf as well.
When I think about all of this, there seems to be a willingness, at times
I hear expressed a willingness to have common standards and perhaps, as you
referred, Mr. Heslegrave, this national accreditation system would be
helpful. However, is this a pipe dream? You have professional associations,
associations of the REBs that are working together, but it does not seem to
be coming together. These bits and pieces seem to be disjointed. I would not
suggest totally ineffectual; they certainly are not.
How do we bring this together in order to have a truly Canadian approach?
We want to as a country be competitive with other countries, but because of
jurisdictional issues between the feds and the provinces, we do not seem to
be able to bring it together. We have the different organizations involved
in all of this that have their own interests. Is it a pipe dream? Is it
possible to have a common national approach to the approval and
standardization process of clinical trials? It is nice to say that everyone
is well-intentioned, but is it a pipe dream with the way the rules and laws
are and the intentions of all of the parties involved? Is it even possible
to bring it together?
Mr. Heslegrave: My response would be without national leadership
on this, it could very well be a pipe dream. However, it is time to have
that national leadership. You have willing partners in all areas of the
country who are willing to come together to work on this, Clinical Trials
Ontario being one of them, CAREB being another, OCREB being another. There
are many other groups as well. Industry is willing to work on this. There
are a lot of things we can leverage here, but we do need a national mandate
and approach to it.
As I said in my presentation, we are three examples of groups that are
willing to work together, and there are many more examples out there.
However, we need a mandate and resources at the federal level to make this a
reality because it is really a reformation of the system rather than a
tweaking of the system to improve it ever so slightly.
Dr. Saginur: To add to what my colleague said, I think you are
describing the status quo as of a few years ago. There has been an
attitudinal change, perhaps born of necessity, that a fire has been lit
under the country that there needs to be a change or we will lose all this
enterprise. With all these initiatives, they come both as competitors and as
close colleagues. I do not think there is a fundamental conflict with that.
As such, the important thing is the momentum that these individual
organizations bring to the table. There is much more interest and desire for
collaboration and cooperation than there ever was.
Senator Wallace: What it reminds me of are circumstances with
other professional organizations in the country, whether it is engineering
associations or law societies, that have their own individual provincial
interests, but they do have a national focus as well and they do influence
With the role of the federal government to create a stronger national
mandate, do you see the federal role simply to be a facilitator to bring all
the parties together or do you see that it would ultimately lead to the
imposition of more than guidelines, standardization of process and
requirements that would be imposed on the clinical trial industry?
Ms. Freitag: Both Dr. Saginur and Mr. Heslegrave spoke to the REB
community being a very small community. I would not say we are incestuous,
but there are times when you see the same people at the same committees. Dr.
Saginur would say he is on the OCREB Governance Committee; he is on the CTO.
Mr. Heslegrave was chair of OCREB. I was a researcher at PMH. It is a small
community. We all know each other. We know how to find each other and we are
willing to work together.
From a federal perspective, we see the federal government, Health Canada,
as a partner, because, as I said before, REBs are not just working on
clinical trials. For the majority of REBs that are not an OCREB or a CTO, 25
per cent of our business is clinical trials; 75 per cent is everything else.
We cannot have a disparate set of standards. We have to set a standard that
everyone will adhere to and make it reachable for everyone, so that everyone
wants to come out and be part of that REB community.
Senator Wallace: Would that be a standard imposed by the federal
government on the process?
Ms. Freitag: Just as Accreditation Canada looks to engage all the
stakeholders, bring all the stakeholders together, we are talking patients
here. We are talking the voice of patients, to understand whether we are
being paternalistic in saying we think REBs should set this standard, but as
a patient, I would be comfortable with this standard. Those questions need
to be asked. There are stakeholders right across the board, from Health
Canada to ACAHO, to privacy. Privacy should sit at the table. They sit at
the table in Ontario, because the PHIPA legislation asked them to be, but
they are not sitting at the REB table across the country.
Dr. Saginur: Health is mostly provincial, and with limited federal
role, but importantly in regulation of drugs and devices. I believe there is
no constitutional standing of research. I think there is an absolute
necessity for everyone just to play in the same sandbox together. I have
been at numerous meetings with federal and provincial representation that
seem to end in bickering over turf. As a taxpayer, I found it offensive.
Senator Wallace: At the end of the day, everyone seems to want to
get to the same place. When I hear all of this, I just wonder, with the
players we have, who leads? Who does what? We know where we want to end up.
How will we get there? We can put everyone in the sandbox and hopefully they
figure it out, but as in any group there has to be a leader. I had a sense
you are looking to the federal government to play a lead role.
You are shaking your head "no. " Maybe I am wrong in that. Does anyone
The Chair: With this response, we will move on. Could you give a
direct answer to the question?
Dr. Saginur: In a nutshell, it is no one's jurisdiction, and it
requires leadership on the part of a national organization.
The Chair: I will come back to this in the end with regard to an
issue, so we will revisit this.
Senator Hubley: I apologize for being a little late getting here.
We may be overworking you today; I am not sure. However, I do have
What country or countries would be considered your competition in
securing clinical trials, and why would that be?
Mr. Heslegrave: Our most reasonable competition here would be
western economies, because of the pricing structure of carrying out clinical
trials. We are not going to compete in absolute terms with China, India,
Brazil and those sorts of countries, because they are just much cheaper to
carry out the research, or Eastern Europe, for that matter. However, we can
be competitive with western economies from an absolute cost point of view.
In terms of other issues, we produce high-quality research and research
data in Canada. Companies say that it is not all about costs; it is about
quality of the data that is coming out of clinical trials and also about the
market size. Where will you market these drugs if they are successful enough
to hit the market?
There are a number of factors. Cost is also related to speed. The faster
you can get a clinical trial accomplished, to get an answer to that clinical
trial from a global perspective, it is a tremendous cost-saving for
sponsors. If we can be part of that solution, we will be better off.
Certainly, Western economies have a similar cost structure, although we
are amongst the most expensive there, but we can mitigate that by improved
efficiencies within our system. I can tell you that other countries are
talking about the same issues: How can they become more competitive. It is
not just taking place here; it is taking place in Singapore, Denmark, and
everywhere. If we do not move on this, we will get further and further
Senator Hubley: I was interested in reading that in fact the
Ministry of Economic Development and Innovation was your creation.
Mr. Heslegrave: I did not create the ministry.
Senator Hubley: I know that, but is that a shift in direction for
government's view of clinical trials? Is it usually a Ministry of Economic
Development and Innovation that would fund these?
Mr. Heslegrave: That is really tied into the fact that it is a
loss of access to clinical trials, a reduction in the ability to have
clinical trials within the province, that impacted then on job creation and
the loss of revenue associated with this. That is how Economic Development
and Innovation became interested, because it was related to a decline in
pharma investment, for instance, in the province, and in the country, for
that matter; it is happening all across the country.
Their involvement came out of the global trend that clinical trials are
beginning to go and have gone for some time to either emerging economies,
where the costs were cheaper, and to areas where health care is not as
accessible, and so the clinical trials become the health care.
The interest from an economic point of view is to try to stop the decline
in economic activity in these areas. The interest from the health point of
view I think is more about getting access to these innovative therapies for
patients. It is not surprising that Economic Development and the Minister of
Industry federally have had an interest in this for some time.
Senator Eggleton: Senator Wallace was on a good line of
questioning. I hope you will pursue it, Mr. Chair, because I think that is a
very important thing to come to some conclusion of where we want to go in
terms of federal involvement.
I want to ask, though, a couple of quick questions. Coming back to the
national accreditation system, Ms. Freitag, in your presentation, you said
that the Canadian General Standards Board had been involved in this process,
but you said it was a flawed process and that it resulted in a document that
was overly prescriptive. Is that a total washout? Is there no point in
proceeding to try to correct that? Do you think the process needs to start
all over again in terms of an accreditation system?
Ms. Freitag: I think it was started with good intentions. I think
that it started and volunteer stakeholders came to the table. There were
many people missing through the process. What it resulted in is a document
that basically is overly prescriptive. It becomes a tick box exercise as
opposed to a human research protection program. The American system is now
recognizing that their tick box solution to accreditation and to standards
is actually not protecting participants, and they actually have to go back
and rethink it. Why are we moving in the direction that the United States is
moving away from?
Senator Eggleton: We need to get off that.
Janet Manzo, Executive Director, Ontario Cancer Research Ethics Board,
Ontario Institute for Cancer Research: If I could add to that, that
standard actually only applies to those trials that are overseen by Health
Canada Division 5 or that fall under that jurisdiction. I think it was
Health Canada's attempt, because REBs are not under legislation, to get some
control and be able to inspect REBs. However, it is only one portion of the
clinical trials that are seen by REBs, so it is not levelling the playing
Senator Eggleton: Let me get to patient recruitment. The action
plan to help attract more clinical trials to Canada, which came out from
CIHR and a number of organizations, rolled out of that summit you previously
mentioned. It called for a national — national, once again — patient
recruitment strategy, including the development of a database of registries
to identify eligible patients. Let me roll into that another aspect of
Senator Cordy raised earlier the question of incentives or compensation
to people involved in clinical trials. Where do you draw the line in terms
of that compensation, not only to the participants but also the clinicians
who perform the recruitment? It is a two-part question about patient
recruitment, to anyone.
Dr. Saginur: In a nutshell, the purpose of participating in a
clinical trial should not be the undue incentive of money. The reason to
participate in a clinical trial should not be undue payment so that there is
a disconnect between what a physician would be paid to treat a patient
through a clinical trial and treat a patient outside of a clinical trial.
From an institute at the level of the REB or enforced at the level of the
REB, there is a generally regarded prohibition on undue incentives.
There is a particular exception, and this is an area of great
controversy. It is an early phase I first in human studies in a lot of drugs
where there is great concern about exploitation of vulnerable, poor people.
This has arisen in a variety of places, but particularly in the U.S.
Senator Eggleton: You probably allow for compensation of cost or
expenses or something like that, but just not any incentives.
Dr. Saginur: Yes. The idea is not to bribe people so they make bad
Senator Eggleton: What about this action plan idea, the national
patient recruitment strategy? Does that sound like a way to go?
Ms. Freitag: It depends on what we look at. If it is a way of
having a listing of all currently active clinical trials in this country so
that everyone knows what is going on, and transparency, what research ethics
boards exist, then I am totally in favour of it. If it is just a way for
industry to get their flag out there, then I do not think that is really the
way to go. To me, we should be looking at highlighting what we do well, and
that is have a wonderful health care system and hopefully a listing of REBs,
a listing of clinical trials that are available and ongoing in this country.
If you are in a small community, if there is a clinical trial for your
disease in Ontario, it would be really nice to know. If you are looking at
it from that perspective —
Senator Eggleton: Including the development of a database of
registries to identify eligible patients. Does that sound reasonable?
Ms. Freitag: I think people are doing it now. They are going on
the Internet. I have to say that people are going on the Internet now and
looking to see. We get phone calls all the time. I get phone calls from
patients. I have to say I work in the largest multiple sclerosis centre in
North America. I am a child of a person with multiple sclerosis. Let me
assure you: I can tell you that not a month goes by that I do not get a
phone call to find out what we are doing. Yes, already people are doing it.
Mr. Heslegrave: I would just like to add to that in terms of a
patient registry. I think we have to be careful as well not to take the
rights away from patients to become voluntarily involved in a registry. As
Ms. Freitag pointed out, patients are scanning the Internet all the time
looking for trials that might be appropriate, either for themselves or for
their relatives or for people they know. We have to have strict controls
over it. However, I would not want to take away the patient's rights to sign
themselves up for a registry that could be searchable for trials, because
trials are long- term processes. When they finally get to the point of being
registered, people have been talking about them and doing preliminary work
on them for several years. Those are opportunities for people to contribute
as well. Then we go through the regular process of recruitment, research
ethics board approval, et cetera.
Dr. Saginur: I would only add that a listing of patients with
particular diseases raises other problems, such as privacy. Such listings
have to be managed.
The Chair: I will come back to some questions. First, I want to
put a question to you that has not come up today. It is not directly related
to the issues you are presenting, but you represent a tremendous knowledge
base in this area.
One of the things that has become apparent during the course of our
hearings is that there are clearly identifiable, under-represented groups
included in clinical trials in general: youth, pregnant women, the elderly.
I do not want to open up a full debate here, but I do want to get your
reaction on the following question: Do you see these as groups that are
reasonable under the right conditions to be brought into the clinical trial
process in larger numbers than they are to this point?
Dr. Saginur: My son is a pediatrician, and he cannot prescribe an
approved drug for children, or seldom can, because all the studies have been
done in adults. That exposes children, I think, to undue risk. Our concerns
about these three groups — children, pregnant women, or women in general,
since it has been vague, and the elderly — we have to turn around and say
these are people that are at risk of certain conditions and we must
understand the treatments and the investigations that we propose to use in
them. It might be that they are not the first order of business. If it is a
study of a condition that is most common in the elderly, pregnant women
might be uncommonly involved.
The Chair: I am just asking the general question, and I interpret
your answer to be yes, it is reasonable.
Dr. Saginur: Yes.
Ms. Freitag: As a case in point, we can look in recent history
with the H1N1, when pregnant women were one of the most vulnerable. Within
the year we had suggested that all pregnant women have the influenza vaccine
the subsequent year.
Had we excluded them or left them out, whatever these clinical trials
are, they have to be "generalizable " going into the future. When we first
started doing cardiac drug trials, we were only using males. Then we found
that, lo and behold, women have the same issues, yet the trials were done in
males, and obviously there are genetic differences. We now know with
pharmacokinetics even within certain ethnic populations we react to
Mr. Heslegrave: I would agree with my colleagues here that it is
absolutely essential to include these various groups in research trials,
because we will prescribe to them regardless of where the evidence is coming
from. I would draw the committee's attention to the fact that one of the
crises that we will be facing before too long is in the elderly,
particularly in the brain health area.
We need to do much better research and be prepared for that, and the only
way to do that is to work with and recruit the elderly into some of these
brain health studies to do with Alzheimer's and other sorts of dementias.
The Chair: From your answers, I think I know the answer to this
question, but the results of a trial are presented as the overall results of
a trial. Where numbers are statistically useful, would you see the
additional presentation of results from the subgroups as well as the total
results for the overall trial?
Dr. Saginur: That is a methodology question. Sometimes those
subgroup analyses are hypothesis-generating for a next study, but they can
certainly raise red flags at times.
The Chair: I want to follow up on a question. Senator Seidman had
you go through, in some real detail, and I do not want to go back over that,
I want to focus the question on the adverse reactions identified during
Dr. Saginur, you gave a very good example of the complexity in
interpreting sudden behaviour of a patient. You used the example of a death,
but sudden, unusual behaviour of a patient in a clinical trial.
I will start with Mr. Heslegrave. As you set up this Ontario clinical
trial process, and as you have recognized the difficulty in identifying
clearly or getting clear indication of the adverse reaction or potential
adverse trial, have you thought about an electronic means or some other
modern technique to more efficiently deal with the information coming in so
as to look across your trial system with regard to the issue of identifying
Ms. Freitag gave us a clear example of the enormous amount of data that
comes in that must be filtered to try to determine whether something is, in
fact, an adverse reaction, or even to detect it.
Is there a movement in an organization such as yours to include that as
one of the outcomes you are looking for?
Mr. Heslegrave: That is not one of the areas we are going in right
now, given the funding envelope we have available to us. I would also say it
is a much broader issue.
Certainly the issue of technological advances associated with the
analysis of serious adverse events is a highly complex one. If we were going
to employ technology to help us with that, this would be more at a national
or perhaps international level.
We received these adverse events from all over the world. In the area
that we are moving into, in terms of issues such as personalized medicine or
precision medicine, however you want to call it, we will have to do much
more fine-grained analysis. Absolutely we need the technology to support
this, but it will be at a much bigger level than a provincial initiative
Dr. Saginur: The technology is there. The information is known.
The questions are of the interpretation of the information. Oftentimes, the
way to decide if there is a causal role of a particular drug is to compare
it with a comparator drug, or device or whatever, both in terms of efficacy
and toxicity. If there is a difference one infers that it might be causally
We have also heard of the mechanism of a data safety monitoring board, or
data monitoring committee to use the FDA terminology, which is built in
within individual studies.
This is all properly within the regulatory role of Health Canada, and
this Health Canada can well address.
The Chair: I want to carefully come back to the questions that
Senator Wallace was asking with regard to a central point here. I think you
gave the elements of the overall answer in your responses, and that is the
issue of who should be involved in working together to develop these
protocols within the provinces and then, more generally, across the country?
Part of that is what incentive there is to move in that direction. In
fact, I think you gave clear examples of the incentives to move on that,
because you are in fact moving in that direction. We have heard from
individual researchers who have appeared before us that there is a clear
motivation and recognition of the need to move to some standardization,
particularly in the research ethics boards, the contracts developed, patient
forms and so on.
It clearly appears that, within the research organizations and
institutions that are involved in clinical trials, there is an emergence of
an awareness that there is a need to move in this direction.
We have also seen that similar sorts of situations have occurred, as
Senator Wallace indicated, in professional organizations, themselves
regulated separately at provincial levels but also having national
organizations. You, in the medical professional, are within one of those
very large organizations where there are provincial regulations and then
there are national bodies, national accreditation. Those are often within
the professional organizations themselves.
We have seen emerging technologies, such as biotechnology, which emerged
much more recently than the idea of clinical trials, in which the drive has
come from within the provincial organizations, the research organizations
and the businesses to develop provincial and then national bodies to deal
I will try to ask the question directly. Do you see your own bodies, and
your colleagues in research ethics boards and provincial clinical trial
organizations and individual hospital research centres, as the reasonable
basis to move this forward outside of government directives to move in these
Ms. Freitag: Absolutely. I think we have seen it in the animal
care setting. The CCAC governs themselves. I think we have seen it within
the medical professional and within the legal professional. Who better to
know than yourself? If you cannot look at yourself in the mirror and start
to ask the questions, then we should not be asking them at all. I think that
we are starting to see the players come forward.
Over the past 10 years we have seen the Sponsors Table, CGSB and NCEHR.
Every single exercise has come to the same conclusion: We need some form of
standard, but it will cost money. The thing is, right now, no one has the
financial wherewithal to bring that to the table. That is what it comes down
to. When the rubber hits the road, it comes down to dollars.
The Chair: Thank you.
I want to say, on behalf of my colleagues, that I think this has been a
very successful meeting, from our point of view. You have helped clarify a
key central theme that has emerged, as you clearly would have expected,
during the course of our hearings on clinical trials. You bring exceptional
expertise in this area, and especially from the point of view of being
involved in organizations that are attempting, have attempted, and have
succeeded to degrees, in bringing about some clear organization and
standardization, and a recognition and identification of the issues faced in
moving in that direction.
You have been extremely helpful to us and very clear in your responses to
all of our questions. On behalf of my colleagues, I want to thank you for
your contributions to us here today.
With that, I declare the meeting adjourned.
(The committee adjourned.)