Dr. Peter Jüni’s Clinical Trials Module
Peter Jüni, MD, FESC
Canadian Research Chair, Clinical Epidemiology of Chronic Diseases
Director, Applied Health Research Centre, St. Michael’s Hospital
Professor, Department of Medicine, Institute of Health Policy, Management, and Evaluation, University of Toronto
By: Cricia Rinchon
Dr. Peter Jüni is internationally renowned for his methodological work and clinical research on the management of cardiovascular and musculoskeletal disorders. He also teaches the Institute of Medical Science (IMS) short course module on clinical trials. Over seven weeks, students in the module—myself included—were exposed to a broad overview of trial design, methodology, statistics, operations, and ethics.
Upon entering the first class, we were greeted by a presentation slide displaying the year of a clinical case in bold typeface: 1985. The next slide depicted an electrocardiogram of a patient experiencing ventricular tachycardia, a type of irregular heart rate. Dr. Jüni invited us to imagine ourselves as first-year residents in the Intensive Care Unit (ICU) of a small-scale hospital at two in the morning with no attending physician present. He urged that the fate of this patient was in our hands!
At this point in the roleplay, an experienced ICU nurse proposed using a newly FDA-approved drug (Drug X) for prophylactic therapy. The nurse anecdotally claimed to have seen many patients benefit from its use. With curious skepticism, we completed a literature search on Drug X and found reasonable animal studies explaining the drug’s mechanisms. Dr. Jüni then posed a question that instilled the theme for the rest of the lecture:
“Do you inject Drug X?”
Hesitant and skeptical, the class voted “no”. Over the course of an hour, we were presented with various stages of pre-clinical evidence: a case-control study, a preliminary pilot study, and then a randomized control trial (RCT). At each stage, the same question was posed, followed by a discussion on the strengths and weaknesses of each study. As the increasing hierarchy of information was progressively revealed, more of the class swayed towards “yes”.
This case study was a challenging activity that exercised critical thinking in a dynamic scenario. Those in the doctoral stream often undergo a similar decision-making process offline, as they critique scientific evidence at various stages: anecdotal observations, case-control studies, informally and formally reported pilot projects, and RCTs. Importantly, the module highlighted the ultimate goal of our work at the IMS: to have an impact on patients’ lives. Below, Dr. Jüni kindly lends his insight into the past, present, and future of RCTs, and provides personal advice for students navigating academia.
What have we learned since 1985 and how has the development of RCTs improved?
Since the mid-80’s, change could not be more dramatic. The average size of major trials was a few hundred patients or less with a very limited capacity and limited statistical precision to detect relevant signals, either for benefit or harm. Since then, our understanding of what constitutes a valid trial has exploded. Since the mid-90’s, initiatives like CONSORT (Consolidated Standards of Reporting Trials) have helped us find a way to move forward as a community to do large scale trials and appropriately report them. In osteoarthritis research, for example, before 2000, drug trials just looked at pain as an outcome in a maximum of 200-250 patients, and nobody could estimate the risks of gastrointestinal bleedings or myocardial infarctions associated with different painkillers. From 2000 onwards, the first trials in several thousand patients were published and provided us with a better understanding of the safety of painkillers.
Now looking towards the future, what are you worried about? What are you excited about?
Many of us are worried about pivotal trials costing up to several hundred million CAD—which would make it not possible to address certain medical conditions because the potential economic gain of a new intervention for a rare condition is just too small to justify the cost. We need novel, pragmatic models, also for drug approval, to be able again to perform randomized trials at a reasonable cost. Canada, and especially Ontario, has a huge advantage with the possibility of accessing a considerable part of the routine healthcare through institutions such as the Institute of Clinical Evaluative Sciences here in Toronto. This allows us to combine traditional aspects of a clinical trial with pragmatic approaches and could reduce trial costs by a factor of five to ten.
When did you decide to make the switch from practicing medicine to clinical research?
In 1993, when I studied medicine in Bern, I went to the student bookshop and found the book Clinical Epidemiology by David L. Sackett and colleagues. It was at a time when the Swiss-German setting was very hierarchical, and professors were rather authoritarian without really being questioned. When I tried to dig deeper, many of the answers I got were superficial and merely based on opinion. Then this book, authored by Canadians, said, “Use your own brain! The one single basis for clinical medicine is randomized trials, forget expert opinions if there is no evidence to support them.” This was revolutionary at the time for me as a medical student from a continental European university, and I was immediately hooked. I just knew I was to become a clinical epidemiologist—to me, every other professional idea became secondary.
Globalization has made international collaboration more seamless, but what are the most noticeable differences between Bern and Toronto after moving here a little more than a year ago?
I think that the most striking difference is how we all live together, coming from more than 160 different nations. Toronto is a melting pot, culturally and ethnically. People live together here in a constructive, peaceful, and open way. Everybody is from somewhere else, so no one is really a foreigner and everyone is at home here. The speed and extent of integration here is much more pronounced than what I’m accustomed to from Europe. My office happens to be in the middle of the Eaton Centre, and even as I walk through it on my way home, I see this diversity with any step I take, and the beauty that happens when cultures meet. I find this extraordinary. Immigration also means that we have an amazing influx of brainpower, and that people haven’t forgotten that it is actually a privilege to live here and not a right. People don’t take everything for granted, and try to work with what they have.
What advice would you give the students of the IMS?
Beware of intellectual dishonesty in academic settings. Roger Federer could never go to a tennis court and just pretend to be a good tennis player, he actually is one. Unlike in sports, you can get quite far in academia by just pretending. I believe institutions are most functional when people are just honest: first of all with themselves, but also with others. They dare to admit that they don’t know, and acknowledge their own mistakes. As a mentor, I try to encourage this attitude with my younger colleagues. It helps tremendously to pause and ask: “Hey, wait a minute, I just haven’t understood it quite yet, could you please re-explain?” If you allow yourself to admit what you don’t know at any given moment, it enriches your reality tremendously.