FIGHTING FOR CLINICAL TRIALS IN CANADA: UNTANGLING SCIENCE AND POLITICS

1. FIGHTING FOR CLINICAL TRIALS IN CANADA:UNTANGLING SCIENCE AND POLITICS Kirsty Duncan PhD MP

3. WILLFUL BLINDNESS There are things we could know, should know, but somehow manage not to know -Alice Stewart -Barry Marshall and Robin Warren Human capacity to ignore what is in front of us is staggering -invisible gorilla In order to see more clearly, we must challenge our biases, encourage debate, and not back away from complicated problems

13. CANADA REQUIRES EVIDENCE-BASED MEDICINE In order to undertake diagnosis and treatment of CCSVI in Canada, clinical trials must be undertaken Based on the evidence presented at the first CCSVI conference, I decided to bring the fight for clinical trials to Parliament Unfortunately, a highly polarized debate regarding whether or not CCSVI causes MS, and whether or not liberation was a cure for MS, dominated academia and the media--rather than the fundamental question, regarding whether or not MS patients improve following the procedure On the one side, there were the neurologists "I think there are going to be millions of dollars spent now to follow a hoax.... If I thought for one instant there was substance to this, I'd be all over it (Freedman)” On the other side, there were the people living with MS

14. FIGHT FOR CLINICAL TRIALS IN PARLIAMENT In May, 2010, my colleague, Dr. Bennett, and I wrote an open letter to the Health Minister asking for clinical trials for CCSVI and a registry in Canada In May, I asked for an emergency debate in Parliament -a four-hour take-note debate on CCSVI was granted in June The neurological subcommittee I founded held four meetings on CCSVI -we heard from Drs. Zamboni, Simka, Haacke, and McDonald -all said clinical trials were needed In the summer, when I questioned a top-ranking health official, why we could not have a registry, he explained because ‘we don’t know what is being done overseas’

15. POLITICAL PROCESS Eventually, the Government put in place a political process to decide whether or not to go ahead with clinical trials; in August, the Canadian Institutes of Health Research, in collaboration with the Multiple Sclerosis Society of Canada, convened a ‘meeting of top researchers’, ’with a special emphasis on neurovascular issues including the recently proposed condition called CCSVI’ Sadly, it was an expert group with no experts in the imaging/treatment of CCSVI -leaders, such as Dr. Sandy McDonald, were not consulted, and there was no inclusion of international experts in CCSVI treatment No data were presented from international scientific conferences, no site visits were made to labs and operating theatres -just blind acceptance of a handful of studies, including two which had been published in an astounding six weeks This seems a cursory review at best by ‘top researchers’, particularly when: -55,000-75,000 Canadians suffer with MS; two major conferences had taken place by August, 2010; over 1500 procedures had been performed worldwide by the time of the meeting, with encouraging results in patients with relapsing and progressive forms of the disease; and a large body of research examining the role of abnormal venous vasculature in MS was completely ignored

16. RESEARCH IGNORED The first observations related to abnormal vasculature in MS appeared in Cruveilhier in 1839, followed by researchers including, Rindfleisch, in 1863, and Putnam in 1937 There is extensive literature examining such areas as: -venous stenosis -cerebral hydrodynamics and venous hypertension -hypoxia -inflammation and cerebral plaques -vascular damage to nerves -reduced perfusion -loss of small medullary vein visibility in MS

17. AFTER THE AUGUST, 2010 MEETING After the meeting, we were told that CCSVI experts were not included for fear of biasing the discussion -yet researchers, who had vehemently spoken out against the procedure, were included in the group On September 13th-14th, 2010, the Federal-Provincial-Territorial Ministers of Health met in St. John's, Newfoundland -what was the agenda, who was present, what presentations and arguments were made regarding CCSVI, and were all sides of the issue presented? And most important, why, in some cases, did provinces change their positions?

18. LISTENING Over the past year, I am personally in touch with over 1,000 MS patients across Canada -of these, over 350 have now been treated; many suffer PPMS and SPMS I receive three and four personal notes each week and innumerable phone calls detailing their progress -their changes: improved circulation; changes in the color and temperature in their face, hands, and feet; reduction in the searing nerve pain and the constrictive pain; reduction in brain fuzziness; and improvements in motor function, vision and hearing ‘I did not wait for Canada and had my procedure done 3 months ago today in Albany, New York. It took me 5 weeks to feel better - new blood supply in an old body - but I am now reaping new rewards on an almost daily basis. Some of my improvements are: better 3D vision, things no longer look flat, less glare from the sun or snow, amazing night vision. My left foot woke up, no longer numb. My balance has improved on my left side. I think however the greatest gift has been sleep. Now I can sleep deeper, wake up and go to work (part time) and I do not need to nap in the day. I am really enjoying these "placebo" effects!!!!’ ‘I'm busting at the seams to let everyone know, I have just returned from where I had the CCSVI procedure (venoplasty)...I spent a lot of time researching this and decided I wanted to go to one of the best out there, it took two hours I had five balloons 2 ...the benefits are phenomenal, my numbness on left side disappeared immediately, vision has improved tenfold, I will now be able to read books again ( used to be one of my favourite pastimes), drop foot gone, fatigue gone. I walked the furthest I have walked in over two years 2 days after the procedure, balance is greatly improved but will work on this with physio as well as muscle mass repair. ... benefits are PRICELESS:-)’

19. FIGHT FOR CLINICAL TRIALS IN CANADA I have asked hundreds of written questions of the Government, attended six international conferences on CCSVI -no Government official has ever attended one I take every opportunity to speak on CCSVI in Parliament -thankfully, Canada’s extraordinary MS patients send me petition after petition so I can deliver these in the House of Commons I was thrilled that Drs Haccke, Hubbard and McDonald joined me on Parliament Hill in February -they came at their own cost to speak to Members of Parliament and Senators to ask for follow-up care, clinical trials and a registry We asked the Minister of Finance to fund clinical trials and a registry

20. POLITICAL PROCESS FAILED MS PATIENTS FOR A YEAR New ‘Scientific Expert Working Group’ -sadly, it has the same flaws as the initial group—namely, no experts, no experience, and conflicts of interests that went undeclared The new group is to analyze interim and final results from seven Canadian and US MS Societies-funded studies, for which we already have answers -namely, that Bulgaria, Canada, Italy, Kuwait, Poland, and the United States report that 87 to 90% of MS patients show one or more venous abnormalities (by MRI/ultrasound by a trained operator), and 97% when angiography is done Canadian MS patients deserve science; they deserve evidence-based medical practices -sadly MS patients couldn’t have evidence-based practices if their Government refused to collect any evidence--either through clinical trials or a registry Canadian patients, who have been travelling overseas since January 2010, have not had their results tracked -one Canadian neurologist, who had had the CCSVI procedure, said to me, ‘if we had collected the evidence in a registry for the last many months, would we still be calling these anecdotal stories?’

22. LAST WEEK OF JUNE, 2011 June 20th: welcomed Tim Donovan, and the New Hope for MS tour to Parliament Hill -called on the Government for clinical trials, and announced that Senator Cordy and I would enter Bills into both the House of Commons and the Senate calling for clinical trials for CCSVI June 27th: Senator Cordy tabled CCSVI bill June 28th: CIHR’s Scientific Expert Working Group met June 29th: the Health Minister reversed her position, and announced clinical trials

24. SCIENCE LARGELY IGNORED 12,500 procedures had been undertaken in over 50 countries worldwide (March 2011) Eight international CCSVI conferences -Dr. Petrov reported that 62% of his 461 patients showed a functional improvement -Dr. Mehta studied 150 consecutive MS patients, who showed more than a 25% increase in quality of life scores (one year after angioplasty) as measured by physiatrists unaware that the surgical procedure had taken place -Dr. Gilhooly reported that of his 125 patients, they show the following improvements: fatigue (60%); mobility (48%); vision (20%); sensory (60%); brain fuzziness (almost 60%); and bladder (over 40%) Reports from returning Canadian MS patients, treated outside Canada Recommendations by the Ontario Association of Neurologists, the Canadian Society of Radiologists, the Canadian Society of Vascular Surgery, and the American Society of Interventional Radiology

25. MARCH 16th 2011 LETTER Ìt is a theory based on the results of a small, uncontrolled study from a single site in Italy by Dr. Zamboni. To date, several other research groups conducting carefully controlled studies have failed to reproduce the observation that CCSVI is associated with MS.` No mention of studies presented at the Venous Endovascular Forum in Poland or from the International Society of Neurovascular Disease conference in Italy, and its press release dated March 15th

26. SEVEN CORRELATIONAL STUDIES Why was virtually no information released about these seven studies on June 29th, 2011? Are there any preliminary findings in terms of the seven studies and the literature review? What is the prevalence of CCSVI in MS patients across the seven studies? How do these results compare with those reported from around the world? And most importantly, are there unannounced preliminary findings which are sufficiently compelling that a failure to conduct clinical trials would now be considered unethical?

27. CLINICAL TRIALS: UNANSWERED QUESTIONS Will this be a multi-centre clinical trial? Have "power" calculations been conducted to determine an adequate number of patients to be included in a clinical trial to demonstrate clinical efficacy at the 0.05 level of significance? How many patients can reasonably be expected to be included in the trial? What will be the exclusion/inclusion criteria? What funding will be provided for the clinical trial, and when will funding be available? Will the number of patients participating in the clinical trial simply reflect the amount of money being made available by the Government (i.e. a backward calculation) or will it be based on meaningful statistical requirements?

28. POSSIBLE ACTION PLAN Ensure proper health care is not refused to a patient on the ground that the patient has chosen to seek, or has obtained, the CCSVI procedure outside Canada Establish an Advisory Panel, composed of experts who have been actively engaged in imaging or treating patients with CCSVI, and patient representatives, who have been treated, to advise on the procedure Provide funding for an ‘Adaptive Phase II/III trial’(i.e. clinical trials for the CCSVI procedure in multiple centres across Canada)

29. NATURE OF SCIENCE ‘Science is like building a building. You can’t just say you want a 50-story building and then start building the 50th floor first. It doesn’t work that way. Your goal is to get to that 50th story, but you have to build brick by brick. Then others can come along and start building on top of that brick. That’s how science works.’ The more and more independent investigators obtain the same results, the evidence becomes stronger, and science progresses, and becomes an organized body of knowledge--including both (1) ideas that have stood the test of time as well as attacks by fellow scientists, and (2) ideas that have failed those tests and ‘fallen by the wayside’

30. THE KEY QUESTION Do MS patients’ quality of life improve following treatment for CCSVI? -must endure the rigour of the scientific process, just like any other new hypothesis, but it must not be subject to new or modified rules: -namely, opinion over evidence -single studies that ‘disprove’ theory -failure to collect relevant data -wilful ignorance of any qualitative and quantitative data

31. 100 RESEARCH QUESTIONS Venous system Venous system and MS CCSVI and MS CCSVI diagnosis CCSVI treatment Determining the best CCSVI treatment Possible impacts of CCSVI treatment on MS Patients CCSVI re-stenosis and diagnosis Secondary procedures for CCSV Prevention of CCSVI in the next generation

32. MS PATIENTS WANT AN INVESTIGATION How emerging science and experts were willfully ignored? How special interests co-opted science? How an organization that was supposed to steadfastly advocate for MS patients flip-flopped on its position? How process was used not to do science? How conflicts of interests went undeclared? How a pioneering surgeon had to risk his reputation? How MS patients were forced to fight the system? How the Minister repeatedly failed to advocate on behalf of suffering Canadians, particularly with regard to follow-up care--especially when we began raising the issue in July with officials? Who was responsible for repeatedly failing to take leadership, and who must be held accountable for the abject abdication of responsibility?

33. THANK YOU Thank you to the doctors for your science, your compassion, and your courage to be pioneers Thank you for standing strong in the face of adversity—for doing science, and hoping that eventually evidence over egos, politics, and the various Government lobbies will prevail Thank you to those living with MS for your courage, your tireless efforts to help bring clinical trials to Canada... you inspire me every day