Big Job, High Stakes
Big Job, High Stakes
Dr. Michael E. Shannon, chair of the CCSVI Coalition’s Scientific Advisory Board, talks about the coming Canadian clinical trials on CCSVI
A recognized expert in designing and running large clinical trials, Dr. Shannon answered questions about his interest in CCSVI and what it will take to make these trials a success.
Posted – November 6, 2011
In June 2011, the Federal Government announced plans to conduct a Phase I/II clinical trial for the purposes of evaluating the safety and efficacy of CCSVI treatment. Would you care to comment on this decision?
Well, I certainly applaud this decision, but I can’t help but question the need for an initial Phase I trial. As you may know, clinical trials are conducted in phases, each building on the previous one and intended to assist clinicians and scientists answer key questions regarding the safety and efficacy of a new drug, medical device or procedure as the development process proceeds. In a Phase 1 clinical trial, researchers must evaluate the safety, determine a safe dosage range, and identify side effects of an experimental treatment based on results from a small group of people (frequently healthy volunteers) exposed for the first time. In this case however, the therapeutic intervention is balloon angioplasty which is well established as a standard of care in North America and routinely used for many conditions. Angioplasty in arterial disease is widely used in carotids, renal arteries, mesenteric arteries and iliacs, and the risks of such interventions, with or without a stent, is much lower than the risk of open surgical intervention. As for the use of this procedure in venous disease, angioplasty is widely used to treat focal stenosis of the left iliac vein and carries with it a very low risk. Venous angioplasty is also used routinely to dilate stenotic arterio-venous fistula in patients requiring dialysis. In fact, it is used frequently and usually at the request of nephrology. So, in terms of the basic safety information for the procedure proposed in the treatment of CCSVI, much is already known. Now, if one looks south of the border for a minute, it should become very apparent that the FDA has accepted the basic safety information for balloon angioplasty since it has approved no less than three double blinded Phase II Clinical trials that are already being conducted in the United States. If the purpose of a Phase II trial is to evaluate the experimental treatment in a larger group of disease specific patients (usually between 100-300) to see if it is effective and further evaluate its safety, the FDA clearly considers that in a general sense, the procedure is safe and is focusing efforts directly on MS at a Phase II level.
It is my opinion, therefore, that there is no need for a phase I trial in this country. It will waste time and money and would provide nothing beyond what is already known world wide about this procedure.
Now let me say a few words about a Phase II trial in the context of MS and what might lie beyond. Although many issues which normally must be addressed by the pharmaceutical industry do not apply in this case, there nevertheless remains several key issues that will have to be addressed in any future Canadian trial involving CCSVI treatment before one can proceed to the more advanced Phase III trial. Having said this, there are very effective ways of meeting regulatory requirements for a phased research approach which I believe in this situation would be appropriate. More specifically, I am talking about what is known as an adaptive Phase II/III trial which would permit a very rapid and seamless transition from the Phase II trial, subject of course to interim assessments of safety and efficacy, to a full Phase III trial. This would still address all the regulatory requirements, answering all the key safety and efficacy questions, but save significant time and cost.
So my bottom line on this is, an adaptive Phase II/III clinical trial.
Posted – November 5, 2011
Why did you agree to join the Scientific Advisory Board of the CCSVI Coalition?
Approximately five months ago I was made aware of a rather unusual story involving a young man with MS and the challenges he faced in receiving a treatment that I was told was being recognized by a growing number of neurologists, particularly in Europe, as a novel and efficacious treatment for those suffering from this disease. The story took me to eastern Europe, a treatment provide at great expense, and what has been assessed by his family as an amelioration of symptoms which they attribute to this new treatment. So the obvious question in my mind was, “Why not in Canada?” And there was no satisfactory answer.
Further inquiry on my part and a convergence of people and ideas regarding CCSVI has captured my interest in an issue which – from a medical ethics perspective – needs attention. I’m not a neurologist and certainly not an expert in the field of neuro degenerative diseases such as MS. However, given my background and fascination with the process of converting good ideas into breakthrough applications in medicine, I felt that this situation was too compelling to walk away from.
I certainly have no preconceived notions about the utility of CCSVI angioplasty and I do not subscribe to any particular religion related to the pathogenesis of MS. So I have no bias. What is important to me is good science and well thought out clinical trials which might, in time, offer definitive answers to very complex questions. That is to say, if the studies and trials are designed properly, the clear answers should fall out. And these answers might translate into improved health care.
Given my background and relative neutrality in this field, I was asked by members of the CCSVI Coalition to join their newly formed Scientific Advisory Board and consider assuming a role as its Chair.
I think that the decision to conduct a Government sponsored clinical trial to clarify the efficacy and safety of CCSVI treatment offers all MS patients in this country an opportunity for change and hope for a brighter future. So my decision to join the SAB was an easy one as I feel very strongly in this case that it is incumbent upon our scientific and medical community to provide as much support as possible for what CIHR is initiating. As odd as this might sound, I consider my involvement in this process to be a moral imperative. This and only this is why I am involved.
So from your perspective, your newness to the field of MS therapy may be an advantage, coming into an area where different interests are competing?
Historically, great advances in medical science have been realized as a result of professional controversy. I think that the challenge here is to try to harness the intellectual energy of the various opinion leaders to achieve and sustain a forward momentum. I think that we all see ourselves on the side of the patients but they are best served through more consideration of new ideas.
Since I am not a neurologist and have no personal connection with someone suffering from MS, I am and will remain totally neutral on subject of CCSVI. I have actually been in similar situations in the past when my neutrality proved to be of value as we struggled through various intellectual minefields. The bottom line for me is the need for objectivity, cooperation and continuous focus on research excellence. I believe that senior management within the CIHR feels the same way and these shared values are bound to yield great results.
As it turns out, I know one of the pioneers in this country for CCSVI treatment, whom I hold in the highest regard, Dr. Sandy McDonald. When I heard that Sandy had gone to Europe to study the diagnostic techniques and subsequently the therapeutic interventions that were considered by international authorities to be highly efficacious, I knew immediately that this warranted my further attention. For Dr McDonald to travel halfway around the world to study with some of the most experienced clinicians in this field was, for me, very telling. This notwithstanding, I am and will remain absolutely neutral and this may indeed be an advantage.
So in a way, the announcement of plans for a Phase I and II clinical trial on CCSVI treatment posed a scientific challenge you couldn’t resist?
It was once said that good fortune occurs at the intersection between opportunity and preparation. We are certainly faced with an enormous opportunity to possibly change the lives of thousands and so I cannot resist getting involved. But there remains the challenge of preparation, which will demand the involvement of many very talented people for long periods of time to develop a protocol, have it approved and then execute it with speed and precision. The good fortune is what may be realized through the efforts of many for those in great need, those suffering from MS.
Who’s going to benefit from this clinical trial?
The MS patient is going to benefit either way. If CCSVI treatment turns out to be efficacious –that is to say, the risk/benefit ratio is in favour of this treatment – the MS patient is going to benefit. It may not be in terms of a cure but it may be quite significant in terms of its impact on quality of life. If it doesn’t work out, I would suggest that the MS patient would still benefit since there would no longer be justification for spending inordinate sums of money on something that has little or no therapeutic benefit and may in fact, cause harm. So either way, if the trial is designed and executed in a proper manner, the MS patient will benefit.
You have been involved in numerous clinical trials at a high level. What does it take to run a successful clinical trial?
In my opinion, a clinical trial becomes successful because of the people involved, their expertise and their effort. Contrary to what some might believe, a clinical trial is not a loose affiliation of Principal Investigators who pull together as many patients as they can, administer an experimental treatment and then observe the outcome. A successful trial requires expertise, commitment, hard work and a common purpose, all operating within a research framework or protocol that reflects up-to-date science and is rigidly adhered to.
So let’s talk about that framework or protocol for a moment. Putting together the protocol is probably the most critical process for any trial and requires highly experienced, well informed subject matter experts working collaboratively with clinical trial design specialists, statisticians and regulatory experts. Together they produce a document that defines in great detail every aspect of the trial, from patient selection to data analysis. Issues such as the number and type of patients are central to success. Determining what will be measured as an outcome must be carefully thought out with full agreement from all stakeholders. The determination of primary, secondary and tertiary outcome measures is essential if the real benefits of a treatment are to be fully appreciated. Finally, the actual therapeutic intervention must be made clear and in many cases, investigators need to be trained on the experimental procedure to ensure standardization. The intervention for CCSVI can be no exception.
Can patients who enter the trial feel confident for their safety?
One of the primary responsibilities of the Canadian Regulator within Health Canada is safety. Therefore, to be approved, this trial must be designed in such a manner that all information related to adverse and severe adverse events will be collected in real time and reviewed at arm’s length by a Safety Review Board. This board must be in place from the outset, comprised of medical professionals and ethicists whose sole responsibility is SAFETY. All members of this board are completely unblinded. They know exactly which patients belong in which arms of the trial, and they know real time what’s happening to these patients. They are responsible for analysing all adverse advents, day by day, to ensure that some problem is not developing which, if serious enough, might create grounds for stopping the trial.
Putting together a clinical trial on CCSVI is evidently a huge undertaking. Who should do it?
Such a trial must be developed and ultimately managed by people who not only have the necessary experience and expertise in the diagnosis and treatment of MS, but by people with a strong background in statistics, clinical trial management and regulatory affairs. I should clarify here that the Canadian Regulator within Health Canada cannot participate in the development of this trial. They must at all times remain at arm’s length. Their role is to approve the protocol.
What are the potential pitfalls most likely to throw off a clinical trial?
The first potential pitfall I should mention involves developing a protocol without embracing the full domain of medical and scientific opinion regarding issues such as diagnostic procedures for CCSVI and the most effective therapeutic intervention. Issues such as who should be included and who should be excluded from the trial are also critically important and, in my opinion, should be based on the most up-to-date information available. That means involving clinicians with broad, hands-on experience in this field.
Another pitfall relates to a lack of trial discipline. If there is a failure to adhere to the protocol, whether it involves patient selection, patient treatment, data collection or data analysis, the trial findings can be compromised, which would be tragic.
These are a couple of examples of problems which, if not recognized and planned for in advance, would have profound if not catastrophic effects on this or any trial.
What’s at stake with a clinical trial on CCSVI?
I suppose that this question could be answered in many different ways, depending on one’s perspective. As I see it, what is at stake with this trial is the possibility of being able to change the quality of life for potentially thousands of Canadians suffering from MS. I am not saying that the CCSVI intervention being proposed will definitely improve the lives of all MS patients. We may determine that there is absolutely no benefit for anyone. But our final decision on this needs to be evidence based. To this end, we must do everything possible to ensure that the proposed CCSVI trial results in clear, definitive findings.
Do you see this particular clinical trial as posing more than the usual challenges?
Yes I do. There are controversies regarding the most appropriate diagnostic approach. There is also a problem with the level of experience among Canadian investigators, which can only be resolved through proper training. But if we have no depth in this country, who will provide the training? It is noteworthy in this regard that many members of the CCSVI Coalition’s Scientific Advisory Board have had a great deal of experience with both the diagnosis and treatment of CCSVI. Most are very familiar with the treatment procedure and many routinely train other professionals.
Studies involving CCSVI intervention have proven very complex to interpret and the treatment presents some interesting challenges from a “blinding” perspective. Ideally, clinical trials should be double blinded, that is to say, neither the patient nor the investigator knows whether the actual treatment was received. Although both of these can be addressed using the concept of primary and secondary investigators, it will be a challenge to control.
Finally, I am somewhat concerned that the controversies regarding the role CCSVI may play in the pathogenesis of MS and the therapeutic merit of CCSVI treatment may have extended beyond the boundaries of healthy scientific debate. I think that everyone needs to humble themselves a little in the interest of good science and ultimately to realize the best possible outcome for our MS patients.
Interview by Caroline Connell.