As an Immunology alumna, I was exposed to incredibly innovative science during my PhD. I have no doubt that much of the science here has the potential to be translated to the clinic and help patients. This is true for many Canadian universities that are conducting research with increasing applicability. However, instead of seeing more research being brought to the clinic, we are seeing a decreased number of clinical trial applications in Canada. Why is this happening? According to the experts, it is a matter of barriers that exist in our clinical trial system that prevent or discourage entry into clinical trials. And without clinical trials, some of the most exciting findings at the bench will never see the light of day at the bedside.
Going back 15 to 20 years, Canada was relatively new to the clinical trial scene. A 2009 review paper entitled “Clinical trials: the muddled Canadian landscape” reported that Canada had 4.1% of clinical trial sites in the world, ranking fourth internationally after the United States (48.7%), Germany (5.7%) and France (4.3%). Given the overwhelming monopoly of the US at the time, this seemed like a reasonable position to be in; however, more recently, the frontrunners are being challenged by rapid expansion in countries such as Russia, Argentina, India, Hungary, and China, and Canada risks falling behind.
At the heart of this issue is the enormous barriers in place. To understand how burdensome these barriers are, we have to first understand the drug development process. The standard drug development process starts in the laboratory, generally at the bench of a university lab. Thousands of potential drug candidates are narrowed down to a small number of compounds after early testing. Preclinical studies that meet the regulatory requirements, including the employment of Good Laboratory Practice (GLP), are also conducted to ensure that a drug is safe and to understand some aspects of how it works. Clinical trials are then conducted in humans in multiple phases. Once a drug developer has sufficient evidence, from preclinical and clinical trial data, that a drug is safe and efficacious, applications can be filed to both the FDA and Health Canada for drug approval. Finally, additional clinical trials may be conducted as part of post-market safety monitoring.
Barriers Beyond the Clinic
As you can see, the drug development process, including the clinical trials, is already a long and arduous journey. Thus it may be surprising to some that additional operational barriers are in place. Administrative issues, cost structures, contract negotiations, and diverse ethics reviews within and across provinces – all time-consuming and costly – make it very challenging for early-stage companies, which may have started in university labs, to even enter the clinical trial space. Furthermore, the time and effort required to jump through these hoops often discourages researchers and clinicians from participating in the clinical trial process. This may be especially an issue for Phase III clinical trials where it is challenging to recruit thousands of participants. These operational barriers have been called “bureaucratic, cumbersome, a liability to the drug and research industries, and even harmful to patients.” In fact, a change was so necessary that, on September 15, 2011, the Canadian Institutes of Health Research (CIHR), the Association of Canadian Academic Healthcare Organizations (ACAHO) and Innovative Medicines Canada (formerly Canada’s Research-Based Pharmaceutical Companies (Rx&D)) sponsored the first ever National Clinical Trials summit, “To Your Health and Prosperity – An Action Plan to Help Attract More Clinical Trials to Canada”. The goal was to devise an action plan that could unite us as a country and effect real changes across various sectors – academia, government, and industry – in how we conduct clinical trials in Canada. The lack of a centralized agency for clinical trials also leads to issues related to province-specific regulations and limits the geographical region from which participants can be recruited. The introduction of organizations to act as facilitators in this process, such as clinical research organizations (CROs), was meant to resolve some of these operational challenges; however, these organizations sometimes introduce their own problems since they engage third parties and can be under-sourced, leading to less than ideal coordination. In fact, some question whether the introduction of CROs provides any benefits to participants, clinicians, clinical trial sites, or companies.
Bringing It All Together
With so many challenges involved and so few drugs approved, is conducting clinical trials even worth it in the long run? Some argue no, claiming that clinical trials are conducted solely to bring a product to market and benefit drug companies. However, while that may be one aspect of clinical trials, there are many more beneficiaries beyond the obvious corporate interests. Clinical trials act as an essential interface between scientists, clinicians, healthcare organizations, and patients, bringing together science and application. Clinical trials help us – the scientists – study and understand diseases and treatments in a way that we normally wouldn’t at the bench, in a cell line or in animal models. They provide clinicians with access to cutting edge technologies that can be added to their knowledge base. They provide patients with rare opportunities for novel treatments that may be beneficial, with the expertise of leading clinicians that may otherwise be unavailable, and possibly with a sense of empowerment from understanding more about their own conditions and being part of something bigger. Finally, clinical trials provide healthcare organizations with an opportunity to support patients and clinicians, and to capture information related to the drug that may help refine and implement the product once it has been approved.
Furthermore, clinical trials stimulate the economy. Based on statistics provided by the National Clinical Trials Summit, “Canada’s academic healthcare organizations (research hospitals, academic regional health authorities, and their research institutes) attracted close to 300 million dollars of potential clinical trial revenue through new clinical trial contracts in 2007-2008.” While much of this amount goes to overhead costs, it also contributes to the growth of the research institutes where the trials are held. In fact, “the academic healthcare organizations within which Phase II and Phase III trials take place are overseen by some 1,500 clinician scientists whose research endeavours and budgets enable research opportunities for thousands more staff and students.” Many of these highly skilled trainees have the potential of landing well-paying jobs in the future, contributing to further economic growth.
Making a Better Model
It is clear that conducting clinical trials in Canada has enormous benefits for multiple stakeholders and the economy at large. So how do we ensure that we stay competitive at a global scale? How can we simplify the clinical trial process and speed up drug approval without compromising the safety of the patients or our understanding of the product? Unfortunately, there is no simple answer. However, we can start by looking at how clinical trials are designed. The current method of design focuses on a specific study plan called a protocol. Before a clinical trial begins, researchers review information available about the drug to develop research questions, objectives, and readouts. Important considerations include selection criteria, the number of participants, the duration of the study, the control groups, the delivery and dose of drugs, data to be collected, and the way data are analyzed and reviewed. This is how a standard (or traditional) clinical trial is initiated – all the design elements are locked down prior to the initiation of the trial.
As with traditional clinical trials, it is critical that the implementation of adaptive designs is scientific, ethical, and unbiased.”
Increasingly though, researchers are exploring the use of a more adaptive clinical trial design with greater flexibility. Instead of pre-determining all the design elements, sometimes based on very preliminary knowledge that may evolve over time, an adaptive clinical trial allows researchers to use knowledge accumulated during the trial to constantly improve on the design as they learn about how the drug works. Adaptive trial design is applicable to both exploratory and confirmatory clinical trials. For exploratory clinical trials, the goal is to find the safe and efficacious doses or dose-response modelling. Using adaptive design here would help assign a larger percentage of the participants to treatment groups that are performing well and allow for the exploration of a larger dose range than can be done with traditional design. To accomplish this, knowledge of key biomarkers, relevant models and simulations, and advanced statistical methods are all used to establish dose selection that will have the best chance of success in the confirmatory phase.
For confirmatory trials, adaptive trial design can be used to implement well-planned changes in the future course of an ongoing trial based on the data accumulated throughout the trial. As in the exploratory stage, these changes would need to be implemented using well-known statistical and modelling tools to ensure that they do not undermine the statistical validity of the trial’s overall conclusions. To this end, statistical tools and models are applied on a larger scale, with the goal of identifying the target patient population in which the drug is efficacious. This requires additional knowledge of the drug including the optimal dose and dosing regimen. Successful implementation of this adaptive design could improve patient selection, selection of dose and dosing regimen, the time required to complete the trial, and the overall likelihood of success.
It should come as no surprise that regulatory agencies (like Health Canada or the FDA) scrutinize this type of integrated trial design more so than the traditional design, especially ones not blinded. Despite the flexibility in their design, adaptive clinical trials still need to have “a clear design rationale, demonstration of statistical validity, simulation-based operating characteristics, and a comprehensive charter for the data and safety monitoring committee that addresses both the interim decision rules and the manner in which operational bias will be prevented.” As with traditional clinical trials, it is critical that the implementation of adaptive designs is scientific, ethical, and unbiased.
What Lies Ahead
Although still a relatively new concept, especially for clinical trials in Canada, the future of adaptive clinical trial design is bright. Two back-to-back reports in the New England Journal of Medicine in July 2016 reported the successful implementation of the adaptive design in clinical trials that investigated breast cancer treatment. In Canada, the CIHR has recently initiated a new funding program for clinical trials as part of Canada’s Strategy for Patient-Oriented Research (SPOR) – a collaborative funding initiative with the objective of “foster[ing] evidence-informed health care by bringing innovative diagnostic and therapeutic approaches to the point of care, so as to ensure greater quality, accountability, and accessibility of care.” To accomplish this objective, SPOR provides funding opportunities specifically aimed at overcoming the current operational and financial challenges that face researchers or small companies hoping to start a clinical trial. The initiative actively looks for investigators to develop and test alternative/innovative clinical trial design in Canada, such as adaptive trials, trials using Bayesian methods, and small sample biologically-based trials (e.g. personalized medicine trial). It also encourages the involvement of existing SPOR-funded entities, such as SUPPORT and CCTCC, to strengthen collaboration and join up researchers with the available resources. Lastly, SPOR encourages patient engagement so that it is ultimately the patients who “influence and accelerate decision making, translation and uptake of new practices, leading to improvements in patient experience with the health system and health outcomes.” With all of these changes to clinical trials underway – the push for simplified operational structure, the adaptive trial design, and new funding initiatives in Canada – it seems likely that we will get to see more translational research being brought to the clinics in the near future. And that would be truly exciting.
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