Coming only seven months after an expert panel chaired by Canadian Institutes of Health Research (CIHR) president, Dr. Alain Beaudet, recommended against a federally-funded CCSVI trial, last week’s sudden reversal of that decision caught the public (including yours truly) by surprise.
Standing at the side of Canada’s health minister, Leona Aglukkaq, Dr. Beaudet explained to reporters that he had met the previous day with his panel to discuss ongoing studies of chronic cerebrospinal venous insufficiency (CCSVI). A review of their findings (the group met last November and again on June 28th) suggested "a trend to an association between the greater prevalence of CCSVI in patients with MS than in healthy controls."
Elaborating on Dr. Beaudet’s comments, Ms. Aglukkaq stated: “At [the June 28] meeting, experts discussed the seven ongoing studies looking at CCSVI and linkages to MS, and reviewed scientific reports that are presently available. Based on this information, Dr. Beaudet has advised me that there is unanimous agreement that a clinical trial should proceed at the Phase I/II level.”
Taking these comments at face value, one is left with the strong impression that, just 12 months after it began, the $2.4 million Multiple Sclerosis Society (MSS)-funded research, on which the CIHR is banking so heavily, is pointing to a positive association between venous anomalies and MS.
Those who tended to be highly suspicious and critical of the motives of the MSS in limiting its initial funding to a series of “vein anatomy studies”, should take note: the organization deserves credit for doing exactly what it promised at the outset. When announcing the seven awards in June of last year, the MSS pledged, “As part of our commitment to keeping people with MS and the public informed of progress, researchers will be asked to provide 6-month interim updates to the National MS Society on their grant progress.”
“The newly funded studies should bring clarity to the debate, and we should know very soon what this phenomenon means in MS and what the next steps should be,” Dr. Aaron Miller, Professor of Neurology and Medical Director of the MS Center at New York City’s Mount Sinai Medical Center, commented at the time the grants were awarded in June, 2010.
Now, by letting science, rather than emotion, carry the day, we have learned in less than one year what, to paraphrase Dr. Miller’s words, the next step will be.
But co-mingled with this good news is the disquieting fact that it is much easier to announce a clinical trial of CCSVI than to actually carry it out.
As an example, one need look no further than Saskatchewan. In announcing $5 million for a provincially-funded clinical trial last year, Premier Brad Wall was optimistic that the first patient would be enrolled in an approved study by mid-2011. So far, it hasn’t happened.
"The understanding I have is that it [the clinical trial proposal] didn't meet some of the protocols that were set out by the [province’s] expert panel. In other words, there are some pieces lacking within the research proposal," explained Saskatchewan’s health minister, Don McMorris.
Although not ruling out a Saskatchewan trial, the minister couldn't say when it might start. Now, with Ms. Aglukkaq on board, Mr. McMorris is interested in working with the federal government on a plan. And what are the prospects for an early start to a federally-funded trial? While the CIHR is hoping for “early in 2012”, it conceded that the process could take much longer.
In contrast to that gloomy forecast, I believe that Canada’s first CCSVI clinical trial can get off the ground within 6 months, and finish in 18 months, if the study conforms to “the phase I/II level” specified by Dr. Beaudet and the minister.
As one who has spent decades designing and participating in clinical cancer trials, I know the importance of starting small and building on what is learned. Trying to cross the finish line with an ambitious phase 3 trial at the outset is almost always impossible. Perhaps that approach to CCSVI is what derailed the effort in Saskatchewan.
Rather, the first step in the clinical assessment of any new treatment (such as venoplasty in CCSVI) is much more modest, consisting of an “exploratory” or, as it is sometimes called, a “proof of concept” study…in technical terms, the combined phase 1/2 trial alluded to by Dr. Beaudet and the minister.
The purpose of such a study is to test a new therapy for (1) safety and (2) preliminary signs of efficacy. It is usually a small, uncontrolled, non-blinded trial, typically involving 50 to 100 patients with advanced disease, for whom there is no proven conventional treatment.
With that as background, I recommend that 50 patients with recently-diagnosed primary- or secondary-progressive MS, for which there is no effective therapy, be selected for an initial exploratory CCSVI treatment study that employs the following simple, straightforward design:
After a comprehensive neurological assessment and brain MRI, patients undergo venous imaging (Doppler ultrasound by the Zamboni technique, followed by selective catheter venography). Any patient found to have significant venous (jugular and/or azygous) anomalies during venography has a dilating procedure (venoplasty) performed at the same time.
Whether or not they have narrowed or obstructed veins requiring a venoplasty, all 50 patients are then tested by neurologists for the presence or absence of neurological improvement (including fatigue) every month for 1 year, with repeat brain MRIs at 6 and 12 months.
The results are tabulated and assessed by an independent data monitoring and safety board (DMSB) every 6 months. A final report is issued at the end of the study and the outcome determines the next step.
While such a study cannot give a definitive answer, it will likely provide reasonably accurate preliminary data as to the safety, effectiveness and durability of venoplasty in a small, but defined, group of MS patients. It may also raise new questions, while generating a knowledge base on which to build new studies.
While the pressure of time felt by patients battling MS is greatly appreciated, a small first trial, such as the one I have described, is often the best way to quickly test the waters and kick-start the process.
In medicine, as in life, sometimes less is more. Let us hope that those who design Canada’s first federally-funded clinical study of CCSVI get that message.
http://healthblog.ctv.ca/post/CCSVI-clinical-trials-Announcing-them-is-the-easy-part.aspx