There has been a flurry of activity in recent years to address some of the challenges in Canada’s ability to compete globally for clinical trial participation. It is encouraging to see the broad range of stakeholders from provincial and federal governments, to academic research institutions to industry associations join together at conferences, workshops and discussion forums to address Canada’s languishing rate of clinical trial participation. These efforts are vital if we are to improve the business climate for Canadian clinical trials.
Multiple Players-Who Does What?
From the perspective of an industry sponsor looking to initiate a multi-site trial in Canada, however, the plurality of efforts can be confusing as a singular united national coordinating voice has not been established yet. Nonetheless, solid advances are being made, albeit in a patchwork manner. A quick guide to some of the multiple resources follows.
First, at the national level, the CCTCC (Canadian Clinical Trials Coordinating Centre) was established in April 2014 and is responsible for implementing the recommendations from the 2011 Clinical Trials Summit. The outcome of the summit brought forth nine recommendations and three organizations (Rx&D, CIHR and HealthCareCAN) have joined together to fund the CCTCC to implement these recommendations. The most recent notable accomplishment of Rx&D and the CCTCC was the rollout of the CCTAM (Canadian clinical trials asset map) in June 2015. The CCTAM is a real time database containing information on investigators, research institutes etc. across the country- a useful tool for an industry sponsor looking to initiate a national multi-site clinical trial. Also at the national level is the N2 network (Network of Networks). Membership in this network facilitates knowledge sharing in operations (SOP’s training etc.), and also networking among specialty knowledge networks. However, industry sponsor membership in this group is currently quite limited, and perhaps there is an opportunity for further industry engagement.
At the regional/provincial level there are also promising developments. Clinical Trials Ontario (CTO) has been one of the most active organizations. CTO is a non-profit organization funded by the Government of Ontario with a mandate to provide a streamlined approach to conducting multi-centre clinical trials in Ontario. There are three strategic initiatives that CTO has outlined in its strategic plan to achieve this goal:
1. To streamline the Research ethics board (REB) review process
2. To engage/educate patients and other stakeholders in order to enhance clinical trial recruitment rates
3. To increase the number of global clinical trials in Ontario
CTO’s Streamlined REB Process in Ontario
In March 2015, CTO launched the CTO streamlined research ethics review system. The REB review model in Ontario is aimed at one REB review per protocol in the province of Ontario. It is not a centralized single review, instead, it relies on a network of member organizations that formally join CTO so that an REB review at one institution is recognized at all member institutions, acting as a “Board of Record.” This model provides for efficiency, flexibility and capacity balancing in the REB system so that investigators and study sponsors do not need to rely on a local REB approval for every research site activated. CTO works within the largest clinical trial infrastructure in Canada, covering 75 REB’s reviewing clinical trials, 250 hospitals and multiple academic research institutions. Currently, within the first six months from launch, CTO has qualified nine REB’s with sixmore REB’s in review and has signed up 40 research sites into the system. Their extensive pre-consultation is likely reaping the benefits in the solid level of uptake and engagement in the CTO process.
The engagement on the REB participant side is matched with active participation by study investigators and sponsors. As of September 2015, there are 16 studies in the system under review and approximately 20 studies in the pipeline. In June 2015, CTO announced that a GSK multi-centre trial had received province-wide ethics approval in just two months from the time of submission—a definite and very welcome first for Ontario’s clinical research environment and proof of concept that the CTO model works. As the number and diversity of protocols submitted through the system increases over time, it will be interesting to monitor the performance metrics to ensure that the core timeline savings can be retained. As Susan Marlin, President and CEO of CTO, states, she “would like to reach a state where a protocol is submitted and receives province wide ethics approval within a month to two of submission and trial sites are approved merely days after.”
With this single improvement in cutting red tape and needless duplication of effort, Ontario would be able to begin to compete competitively on the global stage for protocol start up.
CTO’s REB Model Benefits Study Sponsors as well as Emerging Research Centres
One of the clear benefits of the CTO model is simplifying duplicative processes and paperwork which results in savings of time and money. However, there are additional benefits to the Ontario clinical research landscape. For example, the participation of some community hospitals such as Southlake Regional Health Centre in Newmarket, Ontario is a case in point. Southlake is a community hospital but it also runs regional centres for both cancer and cardiac tertiary care. As a result, there are very talented specialized staff and a pool of well-characterized patients available at this centre. However, as a community hospital, there are limited funds available to build the clinical research infrastructure required to participate in major global clinical trials. As Gary Ryan, Chief Innovation Officer at Southlake stated “Southlake sees three key benefits in participating in the CTO process:
1. Participate in a functional system that improves the operating standards of all participating REB’s
2. Potentially have increased numbers of studies come to the Southlake centre
3. Leverage the CTO’s electronic resources so that Southlake does not have to invest in an independent electronic system”
Southlake has completed its prequalification and has a scheduled on site review this fall. It is expecting CTO certification by the end of this year. Once certified, Southlake will be one of three community based hospitals, in addition to Markham-Stouffville and Peterborough, participating in the CTO system.
Future Developments of the Streamlined REB Model –Taking it to the National Stage
Although it is still early days in the implementation of CTO’s model, it appears that they are off to a good start. However, from an industry perspective, there is a desire to conduct Canada-wide trials so that physicians and patients have access to the newest cutting edge treatments and an appropriate diverse Canadian patient population can be included in the trials. The ideal state would be to have a national network of REB’s where a single REB review could be recognized at research centres across Canada. For a number of reasons, that ideal state does not yet exist. There are, nonetheless, hints of interprovincial cooperation—CTO and BCCRIN—Alberta and UBC—for example.
It appears that this grassroots approach to a national collaboration may be what is required to build the bridges and further evolve the system so that it can be both robust enough to serve as a nationally recognized system, but flexible enough to accommodate the regional differences found in our provincially influenced health care infrastructure. As Susan Marlin of CTO stated “ CTO ‘s mandate is to improve Ontario’s environment for clinical trials, but we also recognize that we need to reach out nationally to improve the Canadian environment as well in order to truly succeed in Ontario. There is a tremendous will and excitement to work towards a national solution.” However, that solution may not necessarily be a national body per se, but rather a quasi-national system built of a coalition of willing partners.
Recently, Health Canada has established an advisory committee on REB’s to review potential standards that may result in a regulatory requirement for REB accreditation. This initiative could also help to move to a more national vs inter-provincial/provincial approach. At this point in time, the provinces have not been invited to the committee-hopefully that consultation will occur before final recommendations are made.
CTO is also looking at initiating an REB council in Ontario to look at differences in reviews and practices at different institutions in Ontario in the hope of identifying the differences, the underlying need (if any) for the difference and a potential solution or revised new best practice. Perhaps some of the findings and recommendations from the Ontario experience could then be taken to the national level to address inter-provincial differences.
CTO’s Patient Engagement Strategy
One aspect of study protocol initiation is the institutional ethics review of the protocol- but study sites must be selected. Site selection involves a number of factors; the reputation of the investigators at the site, quality of research personnel, access to specialized equipment and, perhaps most importantly, access to the right types of patients for the study. Given the amount of money and time invested in study site start-up, it is important that the site meet a minimum patient recruitment level in order to remain economically competitive with other trial sites on a per patient costing basis. The CCTAM and CTO asset maps could assist in identifying sites with appropriate expertise, but how can the site recruitment rates be improved? Another strategic imperative for CTO is to increase patient engagement in clinical trials and address this very question.
To date, CTO is still in early stages of this initiative. They have started conversations with patient advocacy groups and health charities to begin to understand the perspectives and attitudes of patients towards participation in clinical trials. They have also partnered with BCCRIN on a public survey to examine attitudes towards and perceptions of clinical trials. CTO intends to seek more public and patient engagement and will soon appoint an individual representing the patient perspective to their board and reach out to industry stakeholders to discuss patient centricity in trial design and operations. CTO will also work on patient education initiatives to increase awareness of clinical trials and address some of the questions that may be serving as barriers to participation.
Industry Pain Points-where are we on the journey to global competitiveness?
A quick pulse check of the Canadian clinical trial environment, and specifically the work of CTO seems to indicate that we are strategically on the right path, but, more importantly, the strategy is being implemented. The typical industry pain points of REB paperwork and process duplication are being addressed through initiatives of CTO like REB streamlining which promises to reduce both time to study initiation and costs. Understanding the clinical trial resources available across the country is being addressed through asset map initiatives like the CCTAM. However, we still have gaps in terms of national standards and national/interprovincial collaboration—so although it may be possible to get ethics approval within a couple of months in Ontario, it is unlikely at this time that this single approval could be adopted across a multi-site pan-Canadian trial. In this regard, and with other start-up issues like clinical trial agreements, there is still work to do to increase Canadian competitiveness overall.
Patient recruitment is another important aspect of the equation. New therapies in development tend to be highly targeted at the molecular level, and the era of “personalized medicine” has truly arrived. What does this mean for clinical trials in Canada? The ability for study sponsors to access patient pools that are well characterized from a disease and biomarker perspective will be key-often these tests will be performed as part of the standard of care, if not, then having patients located in tertiary care centers that could handle more advanced diagnostic testing will be key.
Another industry trend is to focus on the development of treatments for rare diseases. However, the challenge in finding these patients in Canada is inherent to their condition. Given the small Canadian patient population relative to other countries, by sheer numbers and statistical probability, more rare disease patients may be enrolled in global trials from countries other than Canada. This is sadly a lost opportunity, as often these rare disease patients have no treatment alternatives, or, if treatments are available, due to their high cost, patients cannot afford them. Participation in clinical trials for rare disease conditions gives these patients an opportunity to access potential treatments that they otherwise could not afford or access. The development of the PTC (Permission to contact) database in Canada may help to bridge this gap—but only if it is truly adopted across the country.
Another complication when it comes to pan-Canadian multi-site studies is that the standard of care may vary significantly from province to province. As a result, there may be a provincial bias in recruitment that is dependent on what treatments patients may have access to in their province. One of the key drivers of this difference is the inter-provincial differences in pharmacare formularies. A discussion has been underway for a national pharmacare strategy that perhaps may level the playing field between provinces in the future, and contribute to the “nationalization” of Canada’s clinical trial landscape.
Why is it important to continue to push for a Canadian agenda?
Canada clearly has the intellectual horsepower, talent and research resources to continue its legacy of making some important contributions to science and medicine. It is encouraging to see so much activity and the engagement of multiple stakeholders to improve Canada’s competitiveness. What is not clear at the moment is the sustainability of funding for these various provincial and stakeholder led initiatives and if a truly national approach will emerge over time. In the interim, hopefully government support and funding will continue so that we can build an infrastructure that will serve not only patients by providing them the opportunity to access cutting edge medicines and treatments, but also serve our Canadian researchers who can benefit from global networks and knowledge. As they say, if you build it…..they will come!