The silent treatment: How Canada has failed MS sufferers

Internal documents show why Canada has not kept its promise to accelerate contentious clinical trials for MS

<p>Dr. Daniel Simon points to the dye running through the jugular vein of Neelima Raval, 38, who has lived with multiple sclerosis for 13 years, and who is being tested for narrowed veins by Dr. Simon at the John F. Kennedy Medical Center in Edison, N.J., June, 8, 2010. Dr. Paolo Zamboni, a vascular surgeon from Italy, believes that the disease, which damages the nervous system, may be caused by narrowed veins in the neck and chest that block the drainage of blood from the brain, and has reported in medical journals that opening those veins with the kind of balloons used to treat blocked heart arteries can relieve symptoms. (Beatrice de Gea/The New York Times)</p>

Dr. Daniel Simon points to the dye running through the jugular vein of Neelima Raval, 38, who has lived with multiple sclerosis for 13 years, and who is being tested for narrowed veins by Dr. Simon at the John F. Kennedy Medical Center in Edison, N.J., June, 8, 2010. Dr. Paolo Zamboni, a vascular surgeon from Italy, believes that the disease, which damages the nervous system, may be caused by narrowed veins in the neck and chest that block the drainage of blood from the brain, and has reported in medical journals that opening those veins with the kind of balloons used to treat blocked heart arteries can relieve symptoms. (Beatrice de Gea/The New York Times)

Beatrice de Gea/The New York Times

On June 3, 2010, Peter Liu, a scientific director of the Canadian Institutes of Health Research (CIHR) in Ottawa, sent an internal email outlining his thoughts on a procedure causing medical and political schisms—and inciting patient activism. Liu, head of the Institute of Circulatory and Respiratory Health, was responding to CIHR executives’ request for his opinion about chronic cerebrospinal venous insufficiency, or CCSVI, a condition identified by Paolo Zamboni in 2008. Zamboni, director of vascular diseases at the University of Ferrara in Italy, made headlines in Canada in November 2009 with his hypothesis that multiple sclerosis, long viewed as a neurodegenerative condition, had vascular roots and was linked to blocked veins draining blood from the brain and the spinal cord. He found venous angioplasty—sending a balloon to open an obstructed blood vessel—alleviated, even arrested, symptoms.

Zamboni’s pilot study yielded amazing results but lacked scientific rigour: it was small and non-blinded; no one could duplicate its results, including Zamboni. Still, it stirred rare hope among the estimated 75,000 Canadians suffering from the incurable, degenerative condition. By June 2010, many were travelling out of country, paying upwards of $10,000 for CCSVI scanning and treatment unavailable to them at home. Some returned with YouTube testimonials, others with dashed hopes, others with complications. The issue had become a flashpoint. People with MS were mobilizing for treatment. CCSVI was up for debate in the House of Commons. The CIHR, which hands out just under $1 billion annually for scientific funding and reports to Parliament through the Ministry of Health, was under pressure to act. Canada has one of the highest per capita MS populations: three people are diagnosed every day. Eight provinces wanted to co-fund pan-Canadian trials, according to CIHR documents obtained by Maclean’s under an access to information (ATI) request.

Liu’s response to CIHR executives was cautiously optimistic as he called for clinical trials: “My own interpretation of the data is that CCSVI is likely a contributing factor in a restricted subset of MS patients,” he wrote. “We need a much larger multi-centre trial, including merging some of the ongoing trials, or developing patient selective criteria to narrow down to [a] group that will respond.”

Liu’s advice was ignored. Instead, as hundreds of pages of documents generated within the CIHR between June and September 2010 obtained under ATI reveal, the agency embarked on a process that was focused more on political optics than scientific results and, in hindsight, designed to reinforce the status quo.

The initial call for CCSVI research was showy. In November 2009, Yves Savoie, CEO of the Multiple Sclerosis Society of Canada, invited proposals. In May 2010, the society committed $700,000 to a US$2.4-million, two-year project with its U.S. counterpart: seven studies looking at the relationship between vein anatomy and MS. Treatment studies would await results. Savoie also called on the feds to invest $10 million: “It is obvious that the relationship between CCSVI and MS requires further investigation,” he said.

The feds appeared willing. On June 15, 2010, CIHR’s president and CEO Alain Beaudet spoke before a parliamentary subcommittee looking at CCSVI; he boasted of the CIHR’s “patient-based research” and “urged” researchers to apply for targeted grants. “Research into clinical treatment has to be accelerated,” he said, noting an August meeting at the CIHR would review “how best to accelerate research and innovation in MS.”

But research wasn’t accelerated; it was stalled. No grant proposals met the CIHR’s criteria. The August meeting ended with a decision not to fund clinical trials. There wasn’t enough “evidence to proceed,” according to a press release. Not mentioned was the fact the CIHR didn’t have the money to fund clinical trials; it was overcommitted by $10 million for the year. Only in June 2011, a week after Liberal MP Kirsty Duncan announced plans to table a bill calling for a “national CCSVI strategy” that threatened to turn the issue into a political football, did the CIHR find evidence to justify trials. Five months later, it called for proposals. On April 18, 2012, Health Minister Leona Aglukkaq announced one had been selected. The researcher’s identity will be revealed “if and when ethics approval is granted,” a CIHR press release offered cryptically.

Meanwhile, an estimated 25,000 CCSVI treatments have been performed worldwide; how many on Canadians is unknown. A registry announced by the CIHR in March 2011 will be running by the end of the year. Three deaths have been reported—two Canadians and one American—along with complications and reports of the dangers of using stents to keep veins open, contrary to Zamboni’s protocol. The situation is at a crisis point—with desperate patients travelling for treatment that may or may not benefit them, and the MS Society advising people with MS not to be “examined or treated for CCSVI outside an established research protocol,” which doesn’t exist in Canada.

Fed up with federal inaction, provinces are going rogue. Earlier this month, Newfoundland and Labrador announced results from a one-year, non-controlled observational study that found “no measurable, objective benefit” among 30 patients who themselves reported short-term “physical and psychological well-being.” The province said it won’t insure the procedure until more research is in. Saskatchewan has just begun sending 86 MS patients to a clinical trial in Albany, N.Y. Many residents have already taken matters into their own hands, among them Michelle Walsh of Beechy, Sask. Walsh, 38, was diagnosed with MS at age 18. Her condition was deteriorating when she travelled to Bulgaria for treatment in July 2010. She’d just been fitted for a wheelchair. “I had nothing to lose and everything to gain,” Walsh says. Improvements were instant, she reports. Six months later, given advances in the procedure, she travelled to California for another treatment. Earlier this year, feeling her fatigue returning, she believed her veins were closing, or re-stenosing. Also experiencing chest pain, her GP referred her to Saskatoon cardiologist Ruben Rajakumar, who treated her for venous hypertension. Soon after, the province’s College of Physicians and Surgeons instructed Rajakumar not to treat MS patients; any CCSVI procedure complications had to be referred to the local MS clinic, a situation Walsh compares to “being sent to a dermatologist for back pain.” She returned to California for a third procedure. All three totalled $33,000, though fundraisers defrayed costs. The expense was worth it, Walsh says: her quality of life has improved—no more chronic fatigue or headaches, clearer eyesight, renewed sensation. CCSVI treatment isn’t a cure, she says: “But it’s the only thing that has given me hope, or relief of a lot of symptoms.” MRIs show her brain lesions are not active. She has stopped taking MS drugs. She needs a cane to walk, “but the wheelchair sits in my garage collecting dust.”

The CIHR taking on CCSVI, a political and medical land mine, was new territory for the federal agency. Approving new or off-label procedures is the purview of provinces, and often happens without clinical trials—arterial angioplasty being a classic example. But Zamboni’s theory challenged the entrenched, though unproven, autoimmune model of MS, one that underlies a mindset and a US$13-billion industry of symptom-modifying drugs. It also unleashed the spectre of patients demanding an unproven procedure.

Neurologists, the go-to MS specialists, were quick to denounce the CCSVI hypothesis. “There is not a shred of real evidence anywhere that messing around with these veins does anything to help MS patients,” Paul O’Connor, director of the MS clinic at Toronto’s St. Michael’s Hospital, told the National Post in early 2010. O’Connor was then a researcher on clinical trials for fingolimod, much-touted as the first oral MS drug (Health Canada approved it as Gilenya in March 2011).

Doctors wanting to research CCSVI faced a Catch-22. Venous scanning and angioplasty are insured under the Canada Health Act, but not for treating MS. Sandy McDonald, a Barrie, Ont., vascular surgeon, travelled to Italy in early 2010 to study Zamboni’s protocols. He returned to oversee treatments of six MS patients; four had “significant symptom improvement,” McDonald says. His plans for a larger trial were quashed at the hospital level because he wasn’t part of a national trial. But no national trials had been approved; his application for a CIHR grant was rejected.

ATI documents reveal CCSVI was a priority at the CIHR in the months before the August 2010 meeting to “accelerate research.” The agency clearly felt the urgency: “Pressure for us to target funds and ensure no [neurologists] review the applications as they are biased,” read a June 15 internal email.

Working closely with the MS Society, the CIHR assembled an “expert” panel to assess the radical new procedure, itself a paradox. An email called for “the real stars” in neurological issues, with the proviso they’d had research funded by CIHR or the U.S. National Institutes of Health, which meant they were professionally invested in the autoimmune theory. A few vascular specialists were also contacted. One, Barry Rubin, medical director of Toronto’s Peter Munk Cardiac Centre, was surprised, he told Maclean’s: “I’d never seen an MS patient in my life.” He agreed “partly because I thought there was a need for a vascular expert and partly because I was indebted to CIHR for funding my research for 15 years.”

Oddly, anyone experienced with Zamboni’s imaging or treatment protocols was excluded. The CIHR’s Beaudet, a neuroscientist himself who openly questions the CCSVI theory, wanted to “avoid controversy and bias,” he told Maclean’s in August 2010, though CCSVI critics, including O’Connor, made the cut. Zamboni wasn’t contacted. Instead, CIHR executive director Christine Fitzgerald asked the MS Society for the name of a “credible researcher abroad familiar with Zamboni’s protocol” in a bid to “head off criticisms.” She coached Beaudet in answering questions about Zamboni’s absence: “Inviting Dr. Z would be highly inappropriate. The scientists will be discussing how one could best evaluate his work.”

Communication within the CIHR was often tinged with a Yes, Minister-style concern with optics and “consistent messaging” with the MS Society. Staff monitored “CCSVI” on Google Alerts, separating media reports mentioning “CIHR” from those that did not—even plotting bar charts and graphs with the data. Gauging public temperature was vital: the federal-territories-provincial health ministers were meeting in St. John’s on Sept. 13, with CCSVI on the agenda. The CIHR was keen to keep political distance: “Don’t want to be pulled into ftp politics,” Fitzgerald wrote Beaudet in June 2010.

The agency was in constant contact with the Ministry of Health. One exchange indicated CCSVI was on drug companies’ radars; the ministry wanted input after being approached for a meeting by an official for Merck Serono, the company behind another oral MS drug in clinical trials. He wanted “to discuss CCSVI treatment and a new oral MS drug treatment,” though a further CIHR email clarified: “There is no linkage between this drug and CCSVI.”

Canada’s largest scientific research agency didn’t always do its homework. Some invited scientists declined due to lack of expertise: “I don’t work at all in the area of multiple sclerosis currently,” one responded in an email. The agency also didn’t appear to research vascular links to MS following a June 15 email from its VP of government and institute affairs: “According to a Hamilton researcher, this idea of blood drainage to the brain has been linked to MS on and off for 100 years.”

Students gathered the CCSVI studies reviewed at the meeting—19 readily available on, though accessing some journals proved difficult. Research supporting the status quo was highlighted: “Here are three of the most recent publications on MS and CCSVI . . . that do not support Zamboni’s theory,” a CIHR staffer wrote.

Two days before the meeting, the office of the deputy minister of health asked whether the CIHR even had the money to fund CCSVI clinical trials. It didn’t, Fitzgerald said: “[Beaudet] would have to redirect money for this, so could find some but definitely not all.” In a recent interview, Beaudet confirmed a $10-million shortfall. “We hadn’t seen the crisis coming,” he says. But it wasn’t a problem, he asserts; by the time a trial was approved, “we’d be in the next fiscal [year].”

The Aug. 26 meeting of 23 participants, including 14 neuroscientists and two vascular specialists, was held in private. Nine studies were reviewed; two, about stent risks, didn’t even refer to CCSVI. The first “discussion point” of the meeting set the tone: “It is premature to conduct a clinical trial on something that isn’t known to exist.” An Aug. 31, 2010, press release announced a unanimous decision: “an overwhelming lack of scientific evidence on the safety and efficacy” of CCSVI treatment made it “unethical to study the procedure further beyond the [MS societies-funded] studies.” They would await more research to see if research was warranted. The release was meticulously vetted. In an internal email, Beaudet complained he found an early draft “a little too focused on the term CCSVI when in fact we don’t even know whether such an entity exists.” He proposed “venous malformations” or “abnormal venous drainage” instead. Previous vascular links to MS were overlooked: “There do not appear to be other references to this proposed condition in the medical literature.” The release announced a “scientific expert working group” had been formed to monitor CCSVI research—and it would become the de facto authority on the subject. Many in the group were investigators on the MS societies’ ongoing studies. (In a recent interview with Maclean’s, Beaudet says scientists reviewing their own work isn’t a conflict here, even though he’d excluded Zamboni for that reason: “It’s good science to ensure coherence of the seven studies.”)

On Sept. 12, 2010, the eve of the ministers’ meeting, Newfoundland Health Minister Jerome Kennedy vented his frustration in an email to the federal health minister: “I have been concerned about the CIHR’s apparent dismissal of observational research methods and the slowness of the critical path,” he wrote. He said his province would launch a small observational CCSVI trial. An ad hoc provincial response was emerging; Saskatchewan pledged to fund clinical trials, New Brunswick set up a $500,000 fund for residents to be treated offshore, B.C. contributed to a provincial registry. (Within the CIHR, a newspaper column criticizing the provinces for “micro-managing” MS research was circulated and praised.)

The CIHR stayed on the file. In February 2011, it awarded an “expedited knowledge synthesis grant” to yet another group of scientists to conduct a “meta-study” of CCSVI literature. The lead, Andreas Laupacis, a Toronto epidemiologist, had criticized the composition of the CIHR’s panel in a December 2010 article. He had no experience with MS, he says, but had been paid to sit on a safety review panel for Gilenya.

On June 20, 2011, days before the CIHR’s CCSVI panel was to meet again, MP Kirsty Duncan made her call for a national CCSVI strategy—accelerated clinical trials, a national patient registry and access to aftercare. (The bill was quashed by six votes in February 2012.) Duncan, a vocal proponent of CCSVI research, says she was fed up: “The CIHR put a political process in place instead of a scientific process. Evidence was being wilfully ignored from the literature, from scientific conferences and from returning Canadians treated for CCSVI.” On June 28, the CIHR reviewed the CCSVI literature “meta-study”—eight reports, four that were available in August 2010. A June 29 press release announced the government would fund a phase I/phase II CCSVI clinical trial.

In May 2012, nearly two years after his call for “accelerated” research, Beaudet told Maclean’s he’s pleased with the progress, even though research has yet to begin: “We were entirely validated,” he says of the wait, citing mounting positive anecdotal evidence from patients after CCSVI treatment, the meta-analysis, and science now linking CCSVI with other neurovascular conditions. “My bet is that it is not causal,” he says of the relationship between CCSVI and MS. He floats another theory: “It’s possible that some of the symptomatology is linked to vascular abnormalities it is acting upon; that’s one of the hypotheses we’re going to launch the trial on.”

Results from the MS societies-funded studies won’t be in for months. In the interim, patients’ needs have been forgotten as scientific conversation focused on whether CCSVI causes MS, not if treatment might offer symptom relief for some—per Liu’s June 3, 2010, email. As Marc Stecker, a person with MS in New York City who blogs on the much-read, puts it: “The marketing of CCSVI seems to have far outdistanced the science.” CCSVI advocates say the phase I/II trial, which will cost at least $1 million and take 18 months, is a waste of time and money. Eight safety trials, assessing over 1,300 procedures, show no serious complications. Beaudet himself calls venoplasty a “low-risk” procedure: “The biggest risk is re-stenosis.” Laupacis says the trial is too small to draw valid conclusions: “We’ll have to look to international work.” Michael Shannon, a former deputy surgeon general of Canada and chair of the scientific advisory board for advocacy group CCSVI Coalition, has called for fast-tracked phase II/III trials, moving directly into assessing treatment. Shannon, the former co-chair of the FPT Steering Committee on Blood Governance, draws parallels between the government’s inaction on the CCSVI file and the stonewalling by Health Canada and the Red Cross that lead to the tainted-blood scandal of the ’80s: “Have we learned nothing from the past in terms of delaying for so-called scientific due diligence when there is potentially considerable benefit to be had from the treatment once you understand the risk-benefit equation?”

Barry Rubin, who sits on the CIHR’s “scientific expert working group,” remains skeptical of the procedure, indicated in a damning article he co-authored in the May 2012 Journal of the American College of Radiology. “The ‘Liberation procedure’ for multiple sclerosis: Sacrificing science at the altar of consumer demand” compares CCSVI treatment to laetrile and “faith healing” before claiming that funding clinical trials of a procedure “that has minimal basis in rational, empirical knowledge seems questionable.” The lead author, Michael Brant-Zawadzki, made a complaint to the U.S. Food and Drug Administration, which led to an FDA CCSVI “safety alert” in May, citing complications and three deaths.

Other, more subtle, pullback is evident. On May 1, before a federal health committee, Deanna Groetzinger of the MS Society said they were revising a $1-million pledge to CCSVI trials made in September 2010: they’ll invest $500,000, then another $500,000, “if the phase one and two are successful.” Echoing Beaudet, Groetzinger praised the process: CCSVI research in Canada is moving at “lightning speed.” That’s not how Warren Ruttle sees it. “The time the government is taking to approve a simple procedure is astounding,” says the 36-year-old Regina resident who was diagnosed with MS in 2007. Ruttle hasn’t travelled for the CCSVI procedure due to uncertainties, cost and lack of aftercare: “I can’t afford to travel to get basic follow-up care.” He applied to Saskatchewan’s out-of-country trial but was ineligible; he’s allergic to imaging dye. Now he’s applying for government disability, having stopped working as a chef in February 2011.

Ruttle’s plight signals how, for people with MS, months can be life-changing. And why, in a scientific vacuum, Canadians with MS will continue to be medical refugees. Only hard, unbiased science, if and when it comes, will alter that equation.

These excerpts from documents obtained under an Access to Information request outline the Canadian Institutes of  Health Research’s (CIHR) response to public and political pressure to research chronic cerebrospinal venous insufficiency, a new condition proposed by Italian doctor Paolo Zamboni.

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