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.

[Translation]

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

[English]

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 themselves.

Senator Eggleton: Art Eggleton, senator from Toronto and deputy chair of the committee.

Senator Martin: Yonah Martin, from Vancouver, B.C. Welcome.

[Translation]

Senator Verner: Josée Verner, from Québec.

[English]

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 Ethics Board.

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 clinical trials.

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 practices.

Accreditation also is needed. However, it should be approached as a broad Human Research Protection Program that includes the institution, the REB and the researcher.

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 questions.

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 in Canada.

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 trials.

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 issue.

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 safety.

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 may have.

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 appropriately.

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 board.

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 proposing here?

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 national organization.

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 matters.

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 adhering to.

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 rules.

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 patients.

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 country.

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 coming from.

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 straight-across-the-board legislation.

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 in Ontario.

Senator Cordy: It certainly seems workable just getting people together.

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 benefits.

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 strategy?

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 member.

Senator Seth: This is really interesting. I do not know where to start.

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 other factors?

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 director.

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 presentations.

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 the plate?

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 unfortunate.

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 different stakeholders.

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 jurisdiction.

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 federal policy.

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 lead?

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 another question.

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 behind.

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 field.

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 patient recruitment.

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 decisions.

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 medications differently.

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 clinical trials.

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 adverse reaction?

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 like ours.

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 related.

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 with this.

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 directions?

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.)