THE STANDING SENATE COMMITTEE ON SOCIAL AFFAIRS, SCIENCE AND TECHNOLOGY
OTTAWA, Wednesday, May 16, 2012
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 4:15 p.m. to study prescription pharmaceuticals in Canada (topic: clinical trials).
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
The Chair: Honourable senators, I call the meeting to order.
Welcome to the Standing Senate Committee on Social Affairs, Science and Technology.
My name is Kelvin Ogilvie, chair of the committee. I will ask my colleagues to introduce themselves, starting on my left with the deputy chair.
Senator Eggleton: Art Eggleton, senator from Toronto, deputy chair.
Senator Hubley: Elizabeth Hubley, senator from Prince Edward Island.
Senator Campbell: Larry Campbell, senator from British Columbia.
Senator Cordy: I am Jane Cordy, a senator from Nova Scotia.
Senator Martin: Hello, Yonah Martin, also from British Columbia.
Senator Housakos: Leo Housakos from Quebec.
Senator Wallace: John Wallace from New Brunswick.
Senator Seidman: Judith Seidman from Montreal, Quebec.
The Chair: Thank you, colleagues. I guess I should have pointed out that I am from Nova Scotia.
We have two presenters with us today, and we are delighted to have you. I will identify you by name as I ask you to present. By our initial agreement, I am going to ask Dr. Miriam Shuchman, Chair of the Research Ethics Board of the Women's College Hospital in Toronto, to present first.
Dr. Miriam Shuchman, Chair, Research Ethics Board, Women's College Hospital, as an individual: Thank you. It is very nice to be here. I am here primarily because of my work as a health care journalist. I have been a national correspondent for the New England Journal of Medicine, I have been a freelance news correspondent for the Canadian Medical Association Journal and a number of other medical journals.
For those publications, I have written about the regulation of drugs and devices in clinical trials, and it is some of those articles that got me invited to present to you.
I do also work as an academic physician. I am a psychiatrist and I do chair a research ethics board at the Women's College Hospital in Toronto, but that is not what brings me here today, so I am going to speak about things I have written about as a journalist.
I will, therefore, speak about some fiascos or scandals, if you will, in this context of clinical trials. The reason is, as a journalist that is what you wind up writing about. You write about the things that get into the news, the things that went wrong. I just want to say at the outset that I am a clinician, I do spend one day a week in one of the busiest psychiatric emergency rooms in the country, and so I am well aware of the need for clinical trials, and I base my treatments on evidence from trials. Nonetheless, what I am going to present to you today are fiascos, problems that have arisen in trials.
One of the problems I will be identifying by doing that is the lack of information available to the public and to physicians and to the broader community to look at the sorts of issues I will be talking about.
The very first fiasco I will describe, which I think many of you will be familiar with, is probably the most serious adverse reaction in humans in the past decade. That was the TGN1412 situation in the U.K. This was a phase I clinical trial conducted by a very large contract research organization, Parexel, for a very small drug company in Germany. In this case there was a clinical fiasco, and five or six men wound up in intensive care, and some of them wound up losing digits or the tips of digits. It was a very serious situation.
I mention it here today because the U.K. spent a great deal of time investigating exactly what had happened. Germany did some investigation of what had happened, and there is a great deal available if you want to find out more.
My concern is if something like this happened here. When I was writing about this and I interviewed people, ethicists and scientists in Canada did not feel at the time we had a situation that was any safer than what was available in the U.K. Everyone has ramped up their safeguards since that time because of this situation, but I think we would know less and the world would know less because the limitations on information available in Canada are more stringent than in the U.K.
In the next situation I wrote about a man, John Dennis in Quebec. I have not interviewed John Dennis, could not find him, but his case wound up in the news because he threatened to sue a testing facility, Anapharm, because, in the course of participating in a phase I trial that he had volunteered for and was being paid for, he had to suddenly, due to some cardiac effect, be transferred from the testing facility to McGill's emergency room, and he felt subsequently that this was so unexpected for him that he would sue the company. He sued them for $95,000. We have no idea what happened, and when I was writing about this, I spoke with a lawyer for Fasken Martineau in Quebec who said that these cases almost never come to light. What little we knew about this we would almost never know. They are invariably handled as settlements outside of court with gag orders.
I put that out there to say: Are there serious adverse events in Canada? Of course there are. Will we hear about them? No. Now, the people running this trial would be obliged to report it. It is a phase I trial. It would be reported. The adverse event that happened to John Dennis would have been reported to Health Canada. It also would have been reported to the research ethics board that oversaw the trial, and there would necessarily be such a board. None of that information will be available to the public. REBs do not provide information to the public, and neither does Health Canada on adverse events.
Another case I will present was widely covered in the news. In 2006 a then-large testing facility, SFBC is what it was called then, was enrolling patients in a phase I trial in Quebec; and it turned out, as a reporter for Bloomberg news wrote, one of the men was in a room with someone who began to cough up blood. Many of you may have heard of this situation. Six or seven days later, the doctor running the clinical trial decided to shut it down. By that point, so many people had been exposed to this man who was coughing up blood because he, in fact, had tuberculosis that, according to a company report that I found posted as a PowerPoint on the web, 21 of the participants had been exposed. Many of the staff had been exposed. Several people, both participants and staff from the company, had to be treated prophylactically for tuberculosis.
This situation was investigated by Health Canada. The investigation was thorough and, in fact, led to a policy change. We know that because you can go on the web and find that, and I put that for you in my papers. It is titled “Update for Clinical Trial Sponsors: Requirements for Tuberculosis Screening of Healthy Volunteers in Phase I Clinical Trials.” They changed the requirements based on their investigation, but we as the public, as physicians, as patients entering trials, as companies looking to do these sorts of trials, can find out nothing about their investigation. I just cannot fathom why they would not make that available to the public. By contrast, when I was writing for the New England Journal of Medicine, I was largely writing in the U.S. I spent a great deal of my time at the FDA attending their advisory panels and hearings, and there is more transparency.
I want to talk about a very recent issue that has been in the news. You may know that just last week the FDA issued a warning about the Zamboni procedure for multiple sclerosis, so this is a situation where patients are very aware that there is a need for clinical trials. The perceived need is coming from the patients with MS, and they are going outside of trials to get this Zamboni procedure that I am sure you are all familiar with.
Last week the senior scientist in the device division of the FDA issued an alert. He said the FDA had two reports of serious adverse events with this procedure. One was a serious stroke and one was a death, and therefore, he wanted to make sure that people — patients and clinicians — were aware that this was a very risky procedure. You could have heard this on CBC; you could have read this in The Globe and Mail. If you then go on the website of the FDA to pull this up, in the warning from the FDA it mentions that there was a warning letter to a doctor carrying out this procedure in Albany, New York. That is relevant to us because, as you know, this procedure is not available in Canada, and Albany, New York is not very far from Ontario, so certainly our patients have gone there.
You can click on that letter, read it and see exactly what the doctor was doing that the FDA was concerned about. The FDA was concerned that the doctor was using stents. Therefore, he is using a device in what the FDA would consider an experimental procedure. Therefore, he cannot do that without FDA approval and without IRB, their research ethics board equivalent, approval, and he was, so that has been shut down. He has to meet their requirements before he can start up again, and any patient — or family member for that matter — who is interested could find that letter. As you know, this issue has been such a hot issue for anyone connected to someone with MS. Anyone could find that letter.
Health Canada has just issued another report on their inspections. We know they do these inspections. We know they do shut down trials. I have interviewed several different people at Health Canada who have talked about the trials they have shut down. Had that same situation happened here, we simply would not be able to find it. That is very concerning to me.
In response to the FDA alert, warning, our Minister of Health said — it was quite appropriate for her to respond, reporters were asking her — “I rely on advice from doctors and scientists who are continually monitoring the latest research.” However, whatever advice it is, and whatever led to it, we cannot find it.
I know the name of the senior scientist at the FDA who issued this alert because his name is on there. I know that I can call the press officers and ask to speak with him, and I have spoken to him in the past.
My argument is that all of us, patients, clinicians and the community, need to be more aware of these events and there should be something that we can do about it.
I want to touch very briefly on a fiasco involving a contract research organization, and the reason I want to do that is that I have written about contract research organizations, and they represent almost a black box in the clinical trials enterprise. Very little is known about them. They are very reluctant to be interviewed, very reluctant to provide information to anyone reporting on them. I know that because my article gets cited a lot, even though it came out in 2007. There is just not a lot that can be written about them.
There was a situation with an antibiotic called Ketek that involved the CRO. This is not a bad news story about a CRO. In this case, the monitor for the contract research organization performed quite well. I just want you to realize what a vital role they play and how big a part of this industry they are so that you understand that you cannot do your work as a committee without seriously looking at the role of the contract research organization in 2012.
In the case of Ketek, which was later linked to liver failure, the company developing Ketek was what has become now Sanofi-Aventis, and that company contracted the trial out to a very large CRO called PPD, Pharmaceutical Product Development. A monitor with PPD got suspicious of fraud and then learned there was fraud at one of the trial sites, I think in Georgia. She let her superiors know. They, together, let the company know, Sanofi-Aventis, and when the FDA later investigated, the fraud was so extensive, and they found criminal intent, that the doctor running that trial site was put in jail for four or five years. This was very serious.
At the time, even though the monitor alerted the company, the company did not shut down the site. The company allowed that doctor to keep running that trial site, and the company did not remove that doctor's data from the submission to the FDA for approval of the drug. In retrospect, that was very bad since this drug was approved and was linked to very serious liver failure. We know a great deal about it because I think many of you will be familiar with Senator Charles Grassley, who has tried to do what you are doing south of the border. He called this young woman, the PPD monitor, to testify. I think because she was subpoenaed she said exactly what she had done. She and her superior had contacted the IRB, and the IRB said, “Well, we will just watch this. We cannot take any action.” The IRB later tried to say they do not have any record of that call. When the congressional investigators went in, they did find a record of that call.
With regard to that particular CRO, PPD was sold in October to private equity firms for $3.9 billion. It is by no means the largest CRO. Quintiles is the largest. I think it may be worth about $20 billion at this point. These are very big firms; you cannot at this point be doing large-scale clinical trials or many phase I small trials without involving contract research organizations. I just want you to be aware of that because there is not a lot known about them.
In closing, it is a great privilege for me to be here. I am a psychiatrist. This is the committee that sparked the commission on mental health and the strategy that we have all been hearing about these past few weeks, so I knew the name of this committee. It is quite a privilege to be here.
I am very glad that you are looking at the clinical trials enterprise. I wanted to leave you with a quote. When I was writing about some of the obstacles to doing clinical trials in Canada, and I know that is a major concern of yours, I was writing about the fact that people have to put a trial through 200 research ethics boards before they could get it going in Canada, so they might stop before it ever got off the ground. I spoke with Ray Saginur, who I think may come before your committee or already has. He is here in Ottawa involved in the Ontario Cancer Research Ethics Board. He said what is needed to resolve such problems and deficiencies is leadership at a national level, someone who will stand up and say we are going to do things better. That is my hope, that what this committee can do is inspire or provide this sort of leadership. Something needs to change with regard to what we know about clinical trials and how they take place.
The Chair: Thank you. I will now turn to Dr. Joel Lexchin, Professor, School of Health Policy and Management at York University.
Dr. Joel Lexchin, Professor, School of Health Policy and Management, York University, as an individual: Thank you very much for the opportunity to appear here. I will touch on some of the same issues as Dr. Shuchman did, but from a somewhat different perspective.
Just to give you a little bit more background about myself, like Dr. Shuchman, I am also a practising doctor. I work in an emergency department in downtown Toronto. I see people, prescribe drugs, and, like her, also recognize the importance of well-done clinical trials in determining what the best therapy is for the people that I see.
I have been looking at various aspects of pharmaceutical policy for about 30 years now, writing about this not as a journalist, though more as an academic. I want to share some of my perspectives with you.
One of the things that we have to recognize with respect to clinical trials is that a lot of the requirements around them are being governed by guidelines that have been established by something called the ICH or International Conference on Harmonization.
The ICH is an organization that represents the drug industry in three countries and regions — the United States, the European Union and Japan — and the regulatory agencies in each of those areas, so the FDA, the European Medicines Agency, and I am not sure what the Japanese equivalent is. Canada does have observer status at the ICH, which means that we participate but we do not vote.
Over the years, the ICH has released numerous guidelines around the conduct of clinical trials. Many of those guidelines have been adopted by Health Canada. There is controversy, however, around some of them. The ICH, for instance, has recommended shorter trials in animals with respect to whether or not potential drugs are carcinogenic. There is controversy around a number of these guidelines. The problem is that Health Canada adopts these guidelines without involving any kind of public debate. There may be a notice published in the Canada Gazette, but they do not ask for input into these from the medical community or from consumer groups. The adoption of these guidelines is done more or less behind closed doors.
I would like to move on now to talk about something that has happened more recently, which is the change in the fees, in the way that Canada is going to be collecting user fees from drug companies for evaluating the clinical trial information the companies bring forward.
As you probably know, every time a drug company wants to get a product on the market, it pays a certain amount of money, and these fees have recently been changed. This change in fees was also tied to a change in how quickly Health Canada has to review the data that the companies submit.
The fees now mean that standard drug reviews have to be conducted within 300 working days, and priority drug reviews have to be conducted within 180 days. Should Health Canada go over this limit by more than 10 per cent on average — in other words, take 30 more days for a standard review, 18 more working days for a priority review — the following year the amount of money that it can collect in fees will be decreased by the percentage that it went over its time limit.
There is evidence from the United States to show that when the FDA, which operates under somewhat the same rules, approaches the time limit, the FDA seems to speed up its reviews and ignore certain information that is in the data that the companies have submitted. As a result, these drugs that are approved close to the deadline in the United States — and the United States has the same timelines as we do — and if the drug is approved within two months of these deadlines, then these drugs turn out to have more safety problems than drugs that are not approved close to the deadline.
There is a concern that the same thing might happen in Canada. Health Canada may become concerned about its ability to collect user fees and, as a result, speed up approval if it looks like it will exceed the timelines, and those drugs may have more problems.
I will come back to this issue around timelines later on.
Dr. Shuchman mentioned REBs. There are several concerns around REBs. Clinical trials have to go through REBs. At this point Health Canada has not established any criteria for who should be on the REBs or really what kinds of procedures the REBs should undertake. These are up to the individual institutions where they are located.
Even more concerning, however, is that currently a lot of the clinical trials are being moved out of academic institutions where they were traditionally being done and they are now being done in the community, however you do not have REBs in the community. REBs are institutionally based, so in hospitals, medical schools, what have you.
In response to this, in all the provinces except in Alberta what have been set up are private, for-profit REBs. These are run as businesses and there is concern again, although this has not been studied enough to know whether or not these concerns are valid, that because the REBs, the for-profit ones, rely on money they get from the company that wants to conduct the trial, and if they turn down too many trials they may lose business and their profits will suffer. Therefore, the concern is that these for-profit REBs may be more lenient in terms of approving trials than the institutionally based REBs.
Health Canada has a system in place for monitoring clinical trials that are ongoing. I believe that the figure is that they monitor about 2 per cent of the clinical trials, but if you read information, and the latest information comes from the Auditor General's report that was released I think last fall, the criteria under which Health Canada decides which clinical trials to monitor are not well described. All Health Canada says is that they look at the trials where subjects are at the greatest risk, but how they decide which trials put subjects at the greatest risk is unknown.
I have received a comment to speed up. I will just jump down.
The Chair: Do not leave out anything essential.
Dr. Lexchin: I want to reinforce the point about what Dr. Shuchman said around secrecy of information, that all of the clinical trial data that Health Canada gets from the drug companies, all the information about safety and effectiveness, is deemed confidential by Health Canada. This is considered not clinical information but business information. As a result, even under access to information this data will not be released unless the companies agree to it.
There is the issue around what is called clinical trial registration. There is good evidence that companies in the past were burying clinical trials, never publishing ones that were negative. The system of registering clinical trials at their inception has been set up. Health Canada, back in June of 2005, started to study whether or not all clinical trials being done in Canada should be registered. As of today they are still studying this, so almost seven years later they have not reached a decision about this.
Finally, I want to point out that clinical trials, while very useful, have a number of restrictions associated with them in terms of the range of patients who get studied. These people tend to be from a relatively homogeneous population. They do not represent the range of people who will be prescribed the drug once they are on the market. As a result, when drugs come on the market we may know how they will affect the 40- to 60-year-old men and women in these trials, but we do not know how they will affect the 85-year-old who is on five or six other drugs, or the 8-year-old child. It is crucial, because of these limitations in clinical trials, that we have an adequate system for monitoring the safety of drugs once they are on the market, but currently Health Canada puts three times the amount of money into reviewing new drug applications as it does into monitoring safety. There is three times the number of people involved in reviewing new drug applications as there are in monitoring the safety of drugs already on the market.
The last point that I will make goes back to this issue around timelines. I pointed out that new drugs that get standard drug reviews take 300 days. New drug applications that get priority reviews take 180 days. If you look at what happens to these drugs once they are on the market, what you find is that if a drug has a standard review about one drug in five will get a serious safety warning attached to it. However, if you look at priority review drugs, drugs reviewed in 180 days, that one in five figure drops to one in three.
Therefore, it seems that although Health Canada is supposed to be reviewing the data on priority drugs with equal rigour as it does with standard review drugs, that it is missing something because you go from one in five getting a serious safety warning to one in three getting a serious safety warning.
Thank you very much for taking the time to listen to me. I will be happy to answer any questions that you have.
Senator Eggleton: I will start with Dr. Lexchin in terms of clarifying a couple of points. You say that when Health Canada is going to post new regulations that it, in fact, goes to the Canada Gazette, puts it in there, which is the lawful way to do that, but what you are objecting to is they do not really bring in people who could advise them further on this. They just leave it up to them to take the initiative. Is that the point?
Dr. Lexchin: Yes, it is not that these regulations necessarily are bad or that they are good but, as with any changes, especially changes in clinical trials that are going to affect how the drugs are subsequently reviewed and how they are used if they get approved, that changes should be subject to debate. Strengths and weaknesses can be pointed out, and they should be pointed out, not just internally but by people working in the community or people who are going to have to take the products.
Senator Eggleton: This question of fees and the deadlines and the possible penalties if the department does not process the applications expeditiously, where does it come from? You mentioned the United States are doing it as well. Is it international in scope? Why are we doing it? I thought the point you were trying to make here is that to avoid the penalties or the loss of the fees, part of the fees, that it results in some speed-up of the process at the end that can be against the public interest.
Dr. Lexchin: First of all, the fees are not something just done here Canada. User fees are collected by virtually all of the regulatory agencies in the developed countries. Currently Canada is aiming for 50 per cent of the operating budget of the drugs part to be funded through user fees. In the European Union, I think it is 100 per cent. In the U.K., it is 100 per cent. In the U.S., it is 66 per cent.
In Canada, this was done in 1994 as part of Paul Martin's attempt to cut the deficit. They chopped money from Health Canada and parliamentary appropriations and, to make up for the difference, they instituted the user fees.
As far as I am aware, though, tying user fees to timelines for reviewing new drug applications is unique to Canada and the United States. At this point, these changes in Canada have only been in place for I believe a year, so we do not know how they will affect what Health Canada does. In the United States, there is some reasonably good evidence, as I said, that they do affect the reviews. If the review is coming up to this deadline, things get done too quickly to avoid losing money.
Senator Eggleton: Where do they come from? Was industry pressing for these?
Dr. Lexchin: No. The agency needs a certain amount of money to be able to operate, and you have to be able to plan for, in the future, how much money do you need, not just this year but next year and two years hence. If you figure that you will lose 10 per cent of your revenue next year by going over the timelines, then that becomes a concern.
Dr. Shuchman: I wanted to speak to the timeline issue. We are speaking about Health Canada, but there is the business end of the government that has done a great deal to try to recruit clinical trials, clinical trial companies and clinical trialists to Canada. You can go on line and see the pamphlets that are handed out at these meetings. They advertise the fact that we have shorter timelines, we will get your phase one trial approved within seven days and we will do this within 30 days, and that is part of how we bring this industry to Canada. When you hear about the complaints of losing it to China and Brazil and elsewhere, it is the feeling that things will happen more quickly. It is not simply a matter of saying, “Oh, we said we would get it done, so we had better get it done.” It is this sense on the agency that it is incumbent on them to meet the timelines they have advertised.
Senator Eggleton: Are we compromising safety with the objective of trying to get more clinical trials here?
Dr. Shuchman: I will not go that far, but I will say there is a tension. We do not want to lose clinical trials. In some arenas, certainly in chronic diseases, trials are important for our patients to have available to them. There is this tension between do you do it too quickly or do you lose them.
Dr. Lexchin: I would say that if the committee wants to make a recommendation, one of the recommendations should be to study the effects of tying user fees to timelines.
Senator Eggleton: That is helpful information.
How did we get into for-profit research ethics boards? I thought they were associated with hospitals and institutions.
Dr. Lexchin: They are.
Dr. Shuchman: I will try to speak to that. I think we have slightly different views.
Senator Eggleton: Who pays for them? Who sets them up?
Dr. Shuchman: Talking about private research ethics boards, the biggest one is called Western. Western is enormous. It is all over the world. It is also the private for-profit research ethics board that is primarily used by major universities in the U.S. I do not want you to think that this distinction is within academia and outside of academia. There are universities in the U.S. where the FDA has gone in, or HHS, the Department of Health and Human Services has gone in, and said this trial involved misconduct or this trial was improperly done. In terms of HHS, they can shut down all the research at the university. These patients were not consented properly, so there will be no research at this university until we know the human subjects are adequately protected. That has happened to Duke and at Boston University. These are major centres. Some of them, BU, for example, have said, “We are not playing around with volunteer academics chairing and running our REBs. We want professionals who do this for a living, who must do it well or they will not get paid.” They have gone to Western IRB. At least when I last checked two years ago, all of their human subject research that had any risk attached to it was done by a private REB, private for profit. I do not know of a private not-for-profit. These are all for-profit. Again, the tension is, on the one hand, they are private and not academic, and on the other hand that is all they are doing it, so they will argue they are doing it professionally.
Dr. Lexchin: Dr. Shuchman is right. Why do we have these? We have these because a lot of the drugs currently being studied are not drugs that necessarily have to be administered in hospital. Anything that is oral, you can run a clinical trial involving patients who are recruited through community-based physicians. If you want to run a trial on a new antibiotic for ear infections in children, you can recruit 100 or 200 pediatricians who work in the community to enrol their patients in these trials. REBs were set up as institutionally based. There is nothing not institutionally based except in Alberta, where I believe it is the College of Physicians and Surgeons in Alberta which has set up a not-for-profit REB that is in charge of doing the approvals for all of the non-institutional trials that take place in Alberta.
Senator Eggleton: What oversight mechanisms do these for-profit REBs have?
Dr. Shuchman: The same as regular REBs, which is not sufficient but it is that Health Canada can inspect any REB they want. They have a goal of inspecting far more REBs than they do, and I cannot tell you how many they have inspected that are private versus public, but that may be in their recent report. I think that is one piece of oversight. Another piece of oversight here is that you cannot have any REB, whether it is a for-profit company based in the U.S. or an academic REB here, that does not abide by the Tri-Council Policy Statement. As you know, there is an effort to ensure that is happening and there is nothing that ensures that is happening.
Senator Cordy: I am also interested in this, so if you have the for-profit who is paid for by the drug company who has their drug they want to get to market, I gather there is not a lot of information. Has any study been done to see the approval rates demonstrated by the for-profit REBs as compared to the not-for-profit? Is there any information related to that?
Dr. Shuchman: There is some. It is very interesting what there is, but it is limited. Let me just say, so you know, it is not as if the academic REBs do not charge. There is no drug company that can run a trial in an academic centre without paying, and the academic centres do want the money, so there is the conflict for them as well. They do not want to lose those companies and trials. For example, when the University of Toronto changed its regulations after the Nancy Olivieri affair, they did start to lose trials. There was an issue just in terms of the money.
What do we know about the private for-profit REBs? There was a wonderful study done by the general accounting office in the U.S. Have you heard of this study?
Senator Cordy: No.
Dr. Shuchman: They did a sting. They realized that these private for-profit REBs were cropping up all over the place, and there were so many of them that it was hard to keep track of them. They decided they would do a sting operation. They looked for the three that looked like they might be bad, and they did that by looking at the websites and seeing what they advertised, “We will get it done really quick, 10 times as fast.” They came up with a fictitious and very harmful device. It was completely fictitious. It did not exist. Had it existed, because of the way it was described, it could have been very harmful. I think it was being tested on women with breast cancer or something.
They then sent this protocol to the three REBs on which they were doing this sting operation. Not only was the device fictitious, but everything about it was. The company had a fictitious address. It was supposedly registered with the FDA, and it was not. If anybody had done the checking that should be done when you get one of these protocols, something would have turned up.
Of the three, one completely rejected it immediately. The second one rejected it pretty soon. The third one approved it. That REB was hauled before Congress and fairly quickly went bankrupt.
This study has been used to say what Dr. Lexchin is saying, which is that there may be a real problem out there. We need data. However, as far as I know, we do not have data. What we have is just this one sting operation.
Dr. Lexchin: Yes, the information is anecdotal. Again, that would be an area that this committee could look at; namely, recommending that there be serious research done, looking at the types of trials that are submitted to not-for-profit versus for-profit REBs, and looking at approval rates or changes that are required before the trials are able to proceed.
As Dr. Shuchman said, you cannot get this data at this point.
Senator Cordy: Does the government monitor 2 per cent of clinical trials? Is that what you said?
Dr. Lexchin: Health Canada has a goal of inspecting 2 per cent of clinical trials that are being done annually in Canada. The Auditor General's report, I believe, said that they do not meet that goal because they do not have the resources at this point.
Dr. Shuchman: Right, and they have just released a more recent inspection report, but I do not think they met that goal in that report, either.
Senator Cordy: So they do not give us any information, either?
Dr. Lexchin: They give us some information. They will say how many of the trials that they have inspected had “serious” and “not serious” deficiencies — I believe they divide them into those categories. However, they do not see what those deficiencies were.
Dr. Shuchman: I would like to contrast that. South of the border, yes, the FDA can inspect an IRB, but so can the Department of Health and Human Services' Office for Human Research Protections, the OHRP. I spoke with someone there who is international, and she often comes to Canada. She said she never comes to Canada without someone at some institution she visits grabbing her and saying, “You guys have to come inspect this IRB” at whatever institution it is at. She said she always has to say, “We cannot. We do not have any power.” It is not like the FDA can go inspect if they have a clinical trial going on. This is a U.S. agency. They cannot come in and inspect an REB here. However, there is a sense that there is not enough going on.
Senator Cordy: Health Canada will sometimes fast-track a drug. Could you tell me what the criteria are for fast-tracking and how is it done. I look at MS patients, as an example. You mentioned the FDA report where two people have received stents and have died. That is good public knowledge to have.
However, we have Tysabri, which has affected 232 people with infections of the brain. It has killed 49 people. That was fast-tracked by the Canadian federal government. Gilenya, which is for MS patients, has killed 11 people and is currently under review. What does “under review” mean?
I guess it is sort of three-pronged. First, how and why does a drug get fast-tracked? Second, Gilenya has killed 11 people and is under review by Health Canada; what does “under review” mean? Third, do we get any information if it is under review? You have MS patients who are caught between a rock and a hard place: Do they get venous angioplasty, which has killed two people, or do they take Tysabri or Gilenya, which is killing far more people?
Dr. Lexchin: The criteria currently for priority reviews or fast-tracks are supposed to be that the drug offers a significant therapeutic advantage over existing treatments for serious diseases. For instance, you would not get a new antibiotic for ear infections fast-tracked, but you probably could get a new drug for, say, pancreatic cancer fast-tracked since pancreatic cancer is a pretty bad disease. Those are the criteria that Health Canada uses.
How they are applied in practice, though, is difficult to understand sometimes. If you compare, for instance, Health Canada to the FDA, Health Canada is more restricted in its use; about one third of the drugs that it considers are given priority reviews. In the United States, half the drugs that it considers are given priority reviews.
Why do they make these distinctions? That is an interesting question because there are no data to answer that.
What does “under review” mean? Again, we do not really know. What criteria does Health Canada use to decide on whether drugs are unsafe and whether there should be a safety warning issued about drugs? The answer is that these are decisions that are done internally, and no data is released.
You have instances where one of the products pulled from the market was gatifloxacin, an antibiotic. It was pulled from the market within a month after a safety warning was released. What happened in the space of a month that it goes from “you should be worried about prescribing this drug because of these things” to “this drug is so unsafe that it cannot be kept on the market,” and we do not know. There are drugs pulled from the market without any previous safety warnings. What happened there? Was Health Canada unaware that there were safety issues? Did they not consider the safety issues?
The Chair: We will deal with post-approval issues as a whole separate study, so I will interrupt you there.
I allowed part of it because you were dealing with new fast-track information. However, I have a full list here, and the answers are taking quite a long time. I would like to make certain that we get all of the questions on the table.
Senator Seth: I have two questions for Dr. Lexchin. You mentioned in your presentation that drugs undergo a standard 300-day review by Health Canada and have a one-in-five chance of being pulled out from the market because of the safety problems. You also mentioned the priority drugs that undergo a 180-day review period and have a one-in-three chance of developing similar problems.
How long should Health Canada and its branches review new drugs and new priority drugs to decrease this very high percentage of safety problems?
Dr. Lexchin: I do not think it is a question of how long they should take. It is a question of how in-depth the review should be. The conclusion from the statistics that I gave is that the 180-day review may not be done in-depth enough to discover potential flags around safety problems that these drugs can develop once they are on the market. It is reasonable that if you have serious illnesses and inadequate treatment for them to get these drugs on the market quickly. However, at the same time, when you are looking at the data, you have to apply the same rigour as you do with standard review drugs.
Senator Seth: Do you not think that one-in-five is really too dangerous to get into the market? It is prescribing the patients with such a high risk.
Dr. Lexchin: Again, this comes down to the issue around who is studied in clinical trials. Drug companies want to be able to show that their drugs work, and the easiest way to show that your drugs work is by removing as much what you can call “noise” as possible. You want people who have clearly diagnosed diseases. You do not want people taking other medications. You do not want really young people or really old people because they have physiological differences, so you narrow the number of people or you narrow the range of people who are going to be enrolled. Estimates are that perhaps 1 in 100 people who have a disease will actually get into a clinical trial, and then the drugs go on the market. Once they are on the market, there are no restrictions on what patient doctors can use these drugs on. If there is a new drug that hits the market, I could prescribe it for my — if I had one — 95-year-old grandmother, but she was not part of those trials. Therefore, having safety issues turn up is inevitable.
Dr. Shuchman: I want to add something. We have no patients here, but Dr. Lexchin mentioned pancreatic cancer, and if you had a family member with pancreatic cancer —
Senator Seth: You would try anything.
Dr. Shuchman: It is not risk by itself. It is the risk of the drug versus the risk of the disease. The disease will kill you; the drug might.
The Chair: I will interject here. I think Dr. Lexchin is referring to the issue of the spectrum of people that are involved in a clinical trial and the issue of the subsets, and we have covered that very thoroughly. You are making the point that that may well be part of the issue with regard to post-approval problems. We will examine that in detail, and I think you have made that very clear, and we have heard it a number of times, so that is well on our record in that area.
Senator Seth: You mentioned that Health Canada is not obliged to release how it analyzes the efficacy and safety data it receives from pharmaceutical companies because it considers the information commercially confidential. Even under the Access to Information Act, how can such important guidelines be kept from the people who use and study these products? What step can be taken to improve transparency in this area?
Dr. Shuchman: What I will say about that is when I interviewed Agnes Klein of Health Canada, she pointed out our laws are different. They feel restricted by the laws, and it might take a legal team to look at what options we have within our laws. I will say that making the information available is crucial. Where it is available south of the border, it has been crucial.
I will give you one example. I think the drug is muraglitazar. This drug was nearly approved. The FDA policy is, when there is an advisory panel that is considering a product, all of the information about that product that is available to the panel is also available online to anyone who wants to look at it two days before the panel meets. Two days before the panel met about that drug, people who knew a great deal about it, leading cardiologists, pulled that data down and analyzed it very quickly. The panel met and subsequently recommended approval. Within three weeks of the data being available, the cardiologists who had looked at it had their analysis published in JAMA showing that this was going to be a risky drug because of its effects on the heart. They had reanalyzed the same data that the FDA had looked at, because it was available to them, and that drug was not approved.
The Chair: The point you are making is that getting the information available is critical.
Dr. Shuchman: Yes.
The Chair: And required publication of trials is critical.
Dr. Shuchman: No, this was not publication. This was data the company submitted to the agency in order for the drug to be approved. Once the FDA is going to meet, it is all available, but it is not a study that has been published.
The Chair: However, making that available is critical, right?
Dr. Lexchin: Yes. Making that kind of data available is critical, and to give you one other example very quickly, this has to do with the use of the selective serotonin reuptake inhibitors for depression in children and adolescents. It was never approved by either the FDA or Health Canada. If you looked at the published data, then what you would conclude was that these drugs probably had a small benefit and were not terribly risky. If you got the unpublished data, in other words the studies that were in the drawers of the FDA or Health Canada, and you included those in your analysis, the conclusion changes dramatically, and the conclusion is these drugs do not work and they have a risk of harm.
The Chair: The point is it is not only the information that goes forward with regard to the support. The issue is any information developed during the trial process should be made publicly available? Is that what we hear you saying?
Dr. Shuchman: That is right.
Dr. Lexchin: Yes, except for things that would violate privacy issues, things like that.
The Chair: Of course.
Senator Seth: This is while the trial is going on?
Dr. Lexchin: No, once the trial has been completed and the information is then sent to Health Canada, that information should be made public so everyone can access it.
Senator Hubley: Dr. Lexchin, my question concerns recruiting doctors for trials. I am interested in how that happens. Who does the recruiting? Are doctors sufficiently informed about the trial to make that very important decision of submitting some of their patients to that trial?
Is there a liability issue here for doctors if the trial does not go favourably? Have there been incidents where patients are able to come back on the doctors?
Dr. Lexchin: I cannot answer the second question. I do not think that there is any data in Canada about that.
How doctors are recruited depends on where the trial is being done. If it is being done in an academic institution on cancer drugs, then you will go to the oncologists who treat that particular form of cancer. You will present the protocol to them — who can be included, who can be excluded — and you will ask them to talk to their patients. There is usually a trial nurse available so that once the patient says, “Yes, I will consider it,” the trial nurse comes in and goes through the various risks associated with the trial, explains you can drop out at any time, should you choose, that kind of stuff.
The community trials are largely, these days, being done by the contract research organizations that Dr. Shuchman was referring to, and it is the contract research organizations that will then find the doctors. These doctors are not really investigators. They are merely people who say, “Yes, you could be in the trial,” and they identify patients.
Senator Hubley: They are paid for that service?
Dr. Lexchin: They are paid for that service. The amount of money is variable, and I do not know that anybody has actually looked at how much doctors can receive from that. All the information is anecdotal.
Senator Wallace: Dr. Shuchman, the graphic examples you gave, as you referred to them the fiascos that occurred, for the patients in phase I testing brings to my mind what standards there are and how stringent the standards are that apply, I suppose it would apply to all phases, but beginning with phase I, to the phase I approval process. Do you have any comments to make about the standards that apply so that the patient who agrees that they will be part of the phase I trial will have comfort that appropriate standards are being applied to the approval of that phase I trial testing?
Dr. Shuchman: I can say that after the awful tragedy in England, here and in the U.S. and in the U.K. and in Europe, a great deal of time was spent on looking at the design of that trial, what went wrong. The particular design would never be used again in a brand new drug, and that became widely known within the field of clinical trials. I think many people will be familiar with what the design was and why it could never be used again. In that way, standards are developed, and they are applied. I do not know if that answers your question.
Senator Wallace: Is it just a series of one-offs? It depends on the particular product? Generally, is there sort of an overall standard that has to be met that you can fit each of these individual standards into?
Dr. Shuchman: I do not know that we on our own can give you that expertise. Again, I am more familiar with what is available south of the border, but there is something called the Clinical Trials Transformation Initiative. I do not know if anyone from there is speaking to you. Rob Califf runs that. That is a Duke FDA partnership, and they are trying to look at exactly these questions. They are trying to ask empirical questions about how we should be doing clinical trials. It has a great deal of FDA funding in order to do that.
Likewise, there is a very recent April Institute of Medicine report on how should we transform the clinical trials enterprise, again, asking precisely these questions — what are the standards we should be applying both to the investigators in the community and academic investigators and to trials, per se.
These are questions where many more bright minds than you have before us have sat. Dr. Lexchin has done a lot of the writing they are looking at. A lot of people have thought about these, and you can look at some of those things.
Dr. Lexchin: The only point that I would add to what Dr. Shuchman had to say is that phase one trials are different from phase two and three. Phase one trials typically involve volunteers who are being paid. These are small trials looking basically at things like dosage. Since people are paid to enter them, again, there is a concern that some people may volunteer for these trials who really should not be part of them. They also recruit college students because college students need money, but you get people who may go into them for the money and may lie about their health conditions because they need the money. How often that occurs, nobody knows.
Senator Wallace: With that in mind, I am sure that all patients would be required to sign a waiver before they agree to take part in the trial.
Dr. Lexchin: Yes.
Senator Wallace: Do we have any standards in Canada as to basic information — not just basic, but very specific information that has to be provided to these patients so the waiver is an informed waiver?
Dr. Shuchman: Those standards in Canada are in the Tri-Council Policy Statement, and you know they have just put out a second edition. They felt that that was a great deal of what they were focusing on, exactly what information has to be given to patients, who should be giving it to them to make sure that there is no bias when they receive it, how long should they have to consider it, those sorts of things the TCPS is focused on.
Dr. Lexchin: Again, the only caveat to that is that what the tri-council is doing is necessary, but if you actually talk to people after they have signed a form and they have been informed about what they are signing, a lot of people still do not understand what they have just signed.
Senator Wallace: Right, exactly.
I have one final question, Dr. Shuchman. You refer to the lack of information that is provided to the public about the trials and the results and so on that flow from that. After a patient has agreed to become part of a phase one and then perhaps beyond that in subsequent phases, do we have requirements in Canada that the patients be provided with information that comes up subsequent to their testing? If they heard about some of the results, they may want out at that point, but if they do not know some of the adverse consequences that are coming up, they just continue on. Do we have anything in Canada that requires that information to be provided to them?
Dr. Shuchman: This is an evolving area of ethics. It comes under the heading “return of results,” the notion that patients who volunteer to take the risk of being in a trial should have the right to know what the results were. However, as far as I know, all that is required is the research ethics boards need to know what is your plan for returning results. For most investigators, it will be to publish, to disseminate the information by publishing your findings. There is a sense that we need to know how you will get these results to people.
Senator Wallace: Would both of you agree that, on an ongoing basis, patients should be provided with that new information as it arises from the tests?
Dr. Shuchman: Can you say what you mean?
Senator Wallace: Yes. As a result of the testing that is occurring and the data that is available to the pharmaceutical company, if there is something that comes from that that would be of concern or be relevant to particular patients, that that be provided to them, rather than waiting until the entire test is done. Tell them perhaps at an earlier stage, and perhaps they wish to leave the test at that point.
Dr. Shuchman: One of the issues in terms of what you are saying is that you may not know anything. What does a scientist mean when they say, “I know this?” They may not actually know something until the trial is done, so there may not be anything you can return that is of interest.
Where this question is arising a great deal, and I know Dr. Lexchin may have something to add, is with genetic research, because there you are asking people to give samples. You are then keeping those samples, and there is a great deal of interest in what are you going to do if five, seven or nine years from now you actually do discover some genetic link. How will you get that back to people? There is no answer, but it is a very hot area.
Dr. Lexchin: I do not have any comments on that particular issue, but one of the points that Dr. Shuchman raised was around the results of the trials becoming known through publication. The problem here, or one of the problems, is that while trials are ongoing, drug company priorities can change. There is a merger, and that results in a reorientation of the research initiatives that the company is undergoing. There have been a number of instances where clinical trials, while they are ongoing, have been shut down because of changes in priorities, which means that nobody knows whether or not the product that was being studied was safe or effective just because the data was not gathered. The patients who participated, and these people are doing it on a voluntary basis, are in the dark because there cannot be enough data generated to know, and the clinicians who are undertaking the trial have essentially wasted their time because they do not know what the results are.
Senator Campbell: This is extremely interesting. How many trials are there per year in Canada?
Dr. Shuchman: The data that I had in one of my articles is old. This field is moving so quickly. I think that was a 2008 or 2009 article. I do not know.
Senator Campbell: Ballpark?
The Chair: The committee has the information, and it has been provided with it over a period of time, changes by category and by industry. We will get a copy to the senator.
Senator Campbell: The reason I asked that is that I am not permanently on this committee, but it astounds me that we would accept one in five as a problem. It astounds me that we would have one in five, and it goes out there and the public are using it. I understand your pancreatic cancer. I totally understand that, and quite frankly I am prepared to take a risk on anything, but many of these drugs are not in that genre. They could be for various and sundry illnesses. Am I being theatrical?
Dr. Shuchman: I was going to say you cannot run a clinical trial and not expect adverse events. It sounds like you are looking at a post-marketing issue. The issue that you typically hear is that what you are saying is not known when the drug is being tested pre-marketing. It is after it is on the market that you find so much out.
Senator Campbell: Once it hits the mass market.
Dr. Shuchman: That is my impression.
The Chair: I think the critical issues here that they have identified are ones we had identified in launching this study as areas to pursue. The reasons for the one in five are somewhat complex, and we get into the issues that they have touched on. We will analyze those in real detail in a focused study, because it comes down to a lot of factors, including how drugs are prescribed. It is a complicated area, and we are going to attempt to move that forward by looking at specifically the post-approval monitoring issues, adverse drug reactions and the off-label uses as clearly focused areas. You are touching on an exceedingly important area, but we will study those with focused approaches.
Senator Campbell: I will not belabour into orphan drugs and drugs on shelves that I would like to see what is going on. One of the difficulties is that do not know what we have. We have people run trials for, let us say depression, and it does not work. We do not know that it may have worked for some other disease, and this is one of my interests.
Senator Housakos: Dr. Lexchin, as a point of clarification, earlier in the discussion, in responding to Senator Cordy's questions, I think I heard you say that that only 2 per cent of clinical trials are validated, reviewed and inspected by Health Canada. Is that accurate?
Dr. Lexchin: Two per cent are inspected by Health Canada. I believe that is Health Canada's target figure. What they say in their public documents is that they want to inspect the trials that put patients at the highest risk, but they do not outline the criteria for how they decide which trials those are.
Senator Housakos: How would that compare to the United States or Britain?
Dr. Shuchman: To Britain, I am not sure. The U.S. was meeting a higher standard and, in addition, the U.S. has inspectors outside of the U.S., because there are trials being run on drugs where these trials will be submitted to the FDA but they are not happening in North America. The U.S. has inspectors in China and Brazil. We have no inspectors outside of Canada.
Senator Housakos: What would be the percentage in the U.S. vis-à-vis the 2 per cent here?
Dr. Shuchman: I do not know the number, but Health Canada was not meeting its 2 per cent goal. When I was writing about it, they were just above 1 per cent, and I think they have improved but I do not know how much. The United States was considerably higher than that.
Senator Housakos: Are Health Canada's inspections random? Are there criteria they use?
Dr. Lexchin: Again, there are supposed to be criteria, but Health Canada does not publicly outline them, except to say trials that put patients at the highest risk. You could ask Health Canada what that means.
Dr. Shuchman: Just so you know in terms of numbers, Health Canada is not the only agency inspecting trials in Canada, because there are FDA-sanctioned trials and the FDA comes to Canada. I do not think there is a hospital in Toronto that has not had an FDA inspection.
The Chair: We need to understand that this is a random inspection of trials that are based on protocols that have been supposedly worked out. These are not the only way in which trials are approved to go forward. It is like checking up on the processes in place. Again, it is a bit complicated but the issue they put forward to us is one we need to pay attention to.
Senator Seidman: Dr. Shuchman and Dr. Lexchin, both of you have talked about CROs. Could we explore that in a little more detail, please? There is an increased trend toward the use, as you already said. I would like know if that has an impact on the quality and safety of clinical trials from your point of view.
Dr. Shuchman: As we said, there is virtually no data. When I was writing about this for the New England Journal of Medicine, I spoke with economists, including one who had done quite a number of interviews, so he had qualitative data, and the concerns were that as compared to the pharmaceutical companies, before they had contract research organizations to contract this out to, they did it themselves. One of the big differences that came out was that the people who were doing this in the pharmaceutical company had worked there a long time, worked on the same product, and often were with the product for the life of that product. The people working for the CROs are typically young people. They have not been at that CRO very long and they will not be. The turnover on a given clinical trial could be 100 per cent easily, within the time of the trial, and the turnover within the time of the lifespan of the drug development was massive. One of the differences was just the history, having the history of what went forward.
One of the economists spoke about it as the de-skilling of the pharmaceutical enterprise, because you had people who had been with a drug company for 20 years and had a great deal of expertise in a given area, versus young people right out of university who were moving on to something else very soon. You had a less skilled workforce. No one provided any evidence of safety concerns. There were concerns of just what we heard about, the private research ethics boards, that the contract research organizations, because they are very large for-profit companies and want these trials, will take trials that are poorly designed, whereas the academics, because they do not want to be publishing a poorly designed trial that will look worse for them, might be more prone to argue.
One of the people who spoke with me about this may be coming here. That was Muhammad Mamdani. He worked for Eli Lilly in the United States for a while before coming back to St. Michael's, and he felt there was a significant difference in the situation of dealing with the CEOs there. I do not know if that helps at all.
Dr. Lexchin: The only point I would add is that in terms of the interest in publishing data, the CROs, the people who work for them are employees, not academics, and they do not care whether or not the data they have generated gets published in medical journals or other academic settings, whereas the academics do care because it is part of their job to do it, to get information out publicly. It also contributes to promotion, ability to get research grants, et cetera, so another concern with the CROs is that they may decrease the incentive to publish.
Senator Seidman: Should there be some kind of oversight of CROs or some kind of regulations?
Dr. Shuchman: There may at this point be that I am not aware of. I know that when I was writing about this the FDA was very concerned about the fact that this was one element of the system that had not been tied in. They did not have inspections. They did not have a clear way of oversight. At this point there may be, at least south of the border, some oversight, but I am not aware of any.
For all that I am concerned, and I am especially concerned because we know so little. At the same time, they have the incentive to train their people. They will bring in these people just out of university and send them through lots of training because they want things done and want them done quickly. You just cannot make that happen in academia. What you have are academic contract research organizations. It is not that you do not have CROs. If you take a major player in this country or south of the border, they will have their academic version of a contract research organization.
Senator Seidman: Do we know what proportion of clinical trials is operated by CROs in Canada?
Dr. Lexchin: The numbers I have are that about two thirds of all of the clinical trials being done in Canada are being done in the community. Virtually all of those would be run by CROs.
The Chair: I think we have heard the number 80 per cent versus 20 per cent. The thing that needs to come into play here is that if the 80 per cent group uses a hospital or facilities governed by CIHR researchers, they are required to meet the same standard as those. When we are saying these things, we need to be careful about what we are talking about.
Dr. Lexchin: Before you talk about regulation, you need better data to know whether or not you should be worried about regulating.
Senator Seidman: I was going to ask the question about the CIHR and the differences we see in the research that they sponsor.
Dr. Lexchin: CIHR research is peer reviewed. You cannot get CIHR funding without being peer reviewed. Drug company or CRO-run trials are not peer reviewed. You are not competing for money.
The Chair: Based on some of the reaction around the table, it is important to understand that the CIHR guidelines deal with the nature of the openness of the trial. We are not talking about CIHR actually running those trials, but rather that they must meet the same standards of openness and so on with regard to that if they use a facility where researchers actually get research funding from CIHR.
Dr. Shuchman: I also do not want you to think that because CIHR funds that there is not a CRO involved. If CIHR is funding a trial that is cross country with 300 sites, there is likely a large CRO involved.
Senator Martin: We are discussing so many intriguing things. I want to ask a little bit more about the CROs, and I understand we need to have better data in order to look at how to regulate.
Can American or foreign-owned CROs conduct research in Canada? We have clinical trials outside of Canada, but are there CROs from around the world here in Canada?
Dr. Shuchman: Absolutely.
Senator Martin: I am interested in these CROs, but I think we will save that for another time.
Dr. Lexchin, regarding the Canada Gazette, when you talk about the adoption of the guidelines that are published through the ICH — that would be notices posted in the Canada Gazette — it seems to be done behind closed doors, but once the Canada Gazette is published, it is available to the public. Regarding the medical practitioners and the industry, do you feel there is a disconnect in the information that is available and that they are not going to it? Is the process in itself too limiting? Should it be engaging of those other stakeholders?
Dr. Lexchin: Publishing it in the Canada Gazette is good, but all that says is here is what we will do, and it does not ask people to contribute to the discussion about whether or not what you will do is the best thing.
You should publish it, but you should also invite commentary from the interested parts of the community into what you are planning on doing. Most of the people will not be interested because a lot of these are very highly technical documents, but there may be researchers out there who have views about the standards that will be changed, and they should be heard, I think.
Senator Martin: In terms of the process, is this something that has been appealed to Health Canada to engage more of the community or the researchers rather than just publishing it in the Canada Gazette? Have there been attempts for it to be more engaging?
Dr. Lexchin: My honest answer is I do not know, but I do not believe so.
Senator Martin: Maybe this is one area that we can either examine more closely or recommend that this process should involve researchers and physicians in order to ensure that whatever we are implementing in Canada is indeed what is best for the whole system. It is very complex, I understand, but I thought with Canada Gazette that between the first and the second there is an opportunity for public input and whatnot.
Dr. Lexchin: I do not believe Health Canada asks for public input when it is going to adopt ICH guidelines.
Let me clear that harmonization internationally of the way clinical trials are done is not a bad thing. It means that everybody is operating to the same standards, but it is just a question that sometimes the standards should be debated so that we are not doing things that may turn out to be problematic in the future.
The Chair: Is it not the case that when an issue is published in Canada Gazette, there is a 75-day period for input?
Dr. Lexchin: I believe there is, but I do not know whether Health Canada takes into consideration what the input is.
The Chair: That is another question. My point is with regard to the senator's question as to whether there is an opportunity for input. The reality is there is a 75-day period. What people do with input is a separate question.
Dr. Lexchin: Okay.
Senator Martin: This has been discussed at length, namely, the under-represented groups in the clinical trials. You talked about various examples of a fiasco and whatnot. Do you have insights from particularly down in the U.S. and other places that may be helpful to Canada in increasing the representation or things that could be done to help that?
Dr. Shuchman: I think it is a crucial issue. I do think some attention has been paid to it in Canada. When I think of the vulnerable groups where we clearly need more data, I know you have heard about the pediatric groups and I think you have also heard about pregnant women. In my field in particular, psychiatry, we have data on birth defects, but we do not have any data on women because we just do not have trials with pregnant women. There are vulnerable groups where we do need data and we do not have it.
I think your question is how we bring these people into trials, ensure that they are in trials and do it safely so they are not put at too high a risk. There are ways to do it. Part of it is, as you have heard, incentivizing both your companies and your researchers to do so. Through the regulations, you can use carrots and sticks to ensure that you get the data that you need. It is a big issue.
Dr. Lexchin: Health Canada, relatively recently, issued guidelines around the inclusion of women in clinical trials. It could go further. When a drug is being considered, and it is going to enter into clinical trials, you have, based on the disease that it will be treating, a reasonable idea of the population that will actually end up getting the drug once it is on the market. You could issue guidelines to say, for instance, that we expect that most of the people using this drug will be 65 and over, and, therefore, if you do not include this kind of a population in your trial, it is not likely that you will get a favourable review from us. Health Canada could issue further guidelines with respect to who is expected to be included in the trial.
Senator Martin: That is a new point.
The Chair: I will pursue this one a little bit. We have had a lot of testimony on this, as you would expect. There have been recommendations that all trials should include some of the highly identified subgroups, if you like, those physiologically different, young people, for example, pregnant women, and women increasingly, and the elderly.
There has also been the suggestion that the data collected should be presented in a manner that shows the results in those subgroups separately from the amalgamated result of the trial. In other words, the data is collected over all, and this is the overall result for the total population involved in the clinical trial. If, within that clinical trial, there is a certain number of youth, women, elderly, should the data be presented both in the overall result and in the result for those specific subgroups? Would that be something you would recommend?
Dr. Shuchman: One of the questions I would ask is you may have a statistician or methodologist available to your committee. I am not a statistician or methodologist, yet that is a question where you will hear people in academic settings debating that vigorously because what you are talking about is called subgroup analysis. In the subgroup there are fewer people, and therefore the strength of your conclusion is much weaker, and the weaker it gets the less people are willing to trust it.
That is a non-statistician's view of the problem but, beyond that, you have to be looking at a very specific study and say that in this study there are enough people over 65 that the subgroup analysis would be useful. Or what the agencies can do, and they will do, just as Dr. Lexchin was saying, is say we want another trial.
The Chair: I think I was putting a proposal where the suggestion is you deliberately include enough of those subgroups to make them statistically viable. That is obvious; the results have to be useful.
What I am asking is this: If that is the case, would you support the idea that that information should be made available per subgroup?
Dr. Shuchman: I want to speak to the practical realities. The single most pressing thing that keeps a trial from succeeding, and many trials that are started never complete and do not succeed, is that they cannot recruit enough patients. That is the single biggest problem facing a trialist. To bring in enough women or children can be very hard.
The Chair: Dr. Shuchman, I understand. I am asking you a theoretical question.
I will turn to Dr. Lexchin. We have heard a great deal with regard to subgroups, and under the assumption that a large enough trial could be conducted with significant enough numbers of the specific subgroups, would you consider that publishing of the data per subgroup, in addition to the overall trial, would be valuable?
Dr. Lexchin: The bottom line is yes. If you are going to the trouble of telling the companies that they have to recruit, then you want the data. The data will give doctors an idea of who should or should not get the drug, and it will also give patients an idea of whether or not they should be taking the product.
The Chair: Dr. Lexchin, I also want to come to the issue of research ethics boards because a lot has been said here today and I would like to get our committee to understand what is involved. For example, a research ethics board has a very significant role to play in deciding whether a trial will be conducted at a given site for which that research ethics board operates. Is that correct?
Dr. Lexchin: Yes.
The Chair: Is one of the items that the research ethics board deals with the document that is given to the patients who will be involved in terms of the degree of explanation of what they will encounter?
Dr. Lexchin: Yes. You have to submit this to the research ethics board to ensure that it is acceptable to them.
The Chair: The individual research ethics board attempts to determine, within a given site, let us take for example an academic institution, that the elements that they consider suitable to a fully ethically viable trial have been met by the trial that will be conducted in their site?
Dr. Lexchin: Yes.
The Chair: One of you has made a number of comments about the viability of these ethics boards in terms of the overall outcomes of the trial. We have heard about the issue of multiple ethics boards being involved in a given trial, and that is one of the issues that can slow down the movement toward a trial getting under way.
You have also referred to the issue of concern about a trial when it is conducted and the implication that perhaps certain standards were not sufficient within the trial. Would you consider that if there was a standard, highly published requirement for ethics boards, that is, take a province for example, where we know even within the provinces there are multiple sites and multiple ethics boards. The suggestion has been made to us that it would be really helpful to have a standard requirement for ethics boards. That is, that the ethics boards would have a standard requirement for what the person proposing the trial must meet in terms of having that trial conducted within the province, let us just say, to keep it focused on one locale.
Do you see any benefit to the patient, down the road, if there was the situation where there is an ethics board approval process standardized in a given province as long as that approval requirement is a highly public process or document?
To put it differently, do you see any danger in going to a single ethics board standard within a province?
Dr. Shuchman: I see no danger in it. One of the articles I read recently said there are about 60 articles now looking at the data on research ethics boards and showing what I think you have all heard, which is that they disagree, each want different changes on the consent form and having many of them, even though each one is trying to do a good job, makes the process slower.
I think what you are suggesting is an attempt to harmonize them so they would each function the same way. As chair of one, I have to say that you have the individuals on the board. It would be worth a try. I do think it would be better than what we have now, but I think that the Ontario Cancer Research Ethics Board model, the model of having one central board, again staffed by experts, with volunteers but not only volunteers, is, in my view, the best model in terms of both getting the expertise you need around the table and making it move more quickly.
Politically you may not be able to get there, and politically you might at least be able to start with the standards. I absolutely think it is worth a try. It would be better than what we have.
Dr. Lexchin: I believe that in some of the Scandinavian countries, from trials conducted in multiple sites there is a single ethics review so that you do not deal with 20 different sites demanding 20 different changes.
The Chair: That is very helpful. The Ontario Cancer Research Ethics Board will be appearing before us.
I want to pursue some of your earlier testimony. I got a little confused about the clarity and openness with regard to information. It seemed to me that I could interpret what you were saying along these lines: the greater the degree of transparency the better with regard to clinical trials.
That is to say that if all aspects of the trial and the results of the trial are required to be published quickly and made available, that might enhance the assurance that trials will ultimately better benefit the population. I do not want to put words in your mouth. I want to go to the idea of transparency and see where you are on that issue.
Dr. Shuchman: I absolutely believe that the greater the transparency, the more information that is out there, it will be lapped up by the experts in that area, either in that clinical field or in that sort of trial. We will know more than we would have known if it just stayed in-house at a given agency or a given research ethics board.
Dr. Lexchin: Along those lines, from the U.S., where you can get access to the unpublished data, there is sufficient evidence to show that if trials are published depending on their results, sometimes the results are different in the publication from the results that are presented to the FDA. Negative trials presented to the FDA become positive trials; if the trial presented to the FDA was negative, it is more likely not to be published than if the trial presented to the FDA was positive, which means that, for clinicians like us, when we look at the evidentiary basis to make a decision on how we will use this drug or whether or not we will use it, we may only be seeing a subset of what is actually out there.
The Chair: If I interpreted your comments correctly, even trials that are truncated, you would see importance in having the information on that trial to that point made available? Perhaps I misinterpreted what you said.
Dr. Shuchman: I think it was something Dr. Lexchin was saying, but I do think yes, and it goes to the point the senator here was making that here we have these tests on trials and yet they are sitting on the shelf, and something has been done, and it would be useful to us to know that. Yes, I would want that data available.
I was going to add one thing, which is another aspect of transparency. We have talked about the patients. I think there is a push within the clinical trials field to involve patients more and earlier so that they are actually involved in the process of trial design. There are community members on research ethics boards, but by that point the protocol is set, and I think another way of making things slightly more transparent is bringing patients into the process sooner.
Dr. Lexchin: Let me just add that it is important to have the data made public, not just for the drugs that are approved but also for the drugs that are not approved, because the drug that is not approved may be similar to a product that is already on the market. If the new product is not approved, what does that say about the drug that is already available? Similarly, companies may come back in two or three years and want to re-submit and the drug may be approved, so what changed? What kind of new data was there that went from “no, the drug should not be on the market” to “yes, the drug should be on the market”? Unless you have data about drugs that were denied, you do not know the answer to these questions.
Senator Eggleton: I want to talk about competition for clinical trials because a few witnesses have raised this issue. They say we are losing ground; we do not have as many; some statistics have been cited. I wonder a couple of things we talked about earlier with the fees and the penalties. The fees are lower in Canada, from what you are saying, than they are in some other countries, and there is this penalty aspect, which also comes into it here and in the United States, so I am wondering how that all plays into this. I guess what I am looking for is, if we get into promoting clinical trials here, what is the good and what is the bad of that? Will safety or efficacy suffer here somewhere if we try to make ourselves so attractive for these things? Tell me about the good and the bad of getting into this kind of a competition.
Dr. Lexchin: Let me just clarify. The fees are Merck wants to get a new drug on the market. It submits its data to Health Canada and has to pay Health Canada I think it is $350,000 to review the data. That is what the fees are. That has nothing to do with clinical trials, whether they are done in Canada or not.
The answer to your question is it depends. There are benefits. There are problems with trying to attract more trials. Some of the benefits are that we have paid lots of money to train Canadian scientists and doctors. We do not want them to leave the country, and if they are not able to do what they see as their job, maybe they will go to the United States or go the U.K. or somewhere else and we will lose them and we will lose the money that we have invested in them. We want to keep people in Canada because that is part of how we build the society and how we improve on the medical care.
On the other hand, do I really care whether or not we attract a clinical trial on the tenth ACE-inhibitor, a drug for hypertension? The answer to that is no, I do not, because we already have nine of them and we do not need a tenth. The tenth is just there because the drug company thinks it will make money. If we are going to attract trials, we want to attract high-quality trials, trials for products that really make a difference or potentially can make a difference in the way that Canadians will be treated and really use the brainpower of the people that we have trained.
If it is a question of doing a trial or not doing a trial, these people may do a trial on the tenth ACE-inhibitor, but really that does not appeal to them. It is a way of keeping their lab going, but it is not something that they really want to do.
Dr. Shuchman: We often refer to those as marketing trials, and you may have heard that term. They are really done just to get the clinician exposed to that drug, and they are not adding important information. At the same time, there are certain illnesses in my field, psychosis, in other fields, cancer, where you would never want to be treating those illnesses in a setting without access to clinical trials because the existing treatments just are not that good.
Senator Eggleton: Tell me about the downside. I think you have said that it is a good idea to keep good, well-trained people here, but what is the downside? Do you see a downside?
Dr. Lexchin: The downside is wasting people's time. If there are clinical trials just for the sake of clinical trials, then a lot of those trials will not be very meaningful. The drug companies, for legitimate reasons, develop products where they think that they can make the most money, but that is not necessarily the products that are most necessary to be introduced.
Let me just make one other point about competing for clinical trials. While we have a number of definite advantages here in Canada in terms of the training of the scientists, in terms of the medical facilities, there are certain things that make it more difficult, which is just sheer numbers.
India has 1.2 billion people; China has 1.5 billion people. If you are a drug company looking to do a trial, you want to recruit large numbers of people and you want to do it quickly. Where will you get it done? Well, you will get it done faster in India or China than you can in Canada, and the costs will be considerably less. An article was published that said a first-rate centre in India cost the company about one-fifth the amount that a second-rate centre in the United States would cost.
The Chair: Dr. Lexchin, you have again gotten into a complex area there, your comment about not doing me-too kind of trials.
Some of the evidence we have heard or has been presented to us in documents is the issue that the number of clinical trials could fall below a kind of critical mass. There actually is an infrastructure that physicians have to maintain in order to ensure that they can do quality clinical trial work, and so me-too trials may help ensure that they can keep these highly trained researchers on staff over a period of time in order to be able to do the new drug that comes along. That is another aspect. Is that not the case?
Dr. Lexchin: Yes, it is. Not every drug will be a breakthrough or a major therapeutic advance, so yes, people will take clinical trials that are for me-too drugs just to keep their labs open, but you want to try and keep that number down by encouraging trials for products that have the potential for being useful.
The Chair: Thank you very much. You have given us a lot of useful information, and if you think of particular aspects or examples with regard to transparency after you leave that are in addition to those things you referred to, we would welcome those. A number of the things that you have identified we do have as part of our evidence or will have before we are done. However, if you think of particular examples, we would welcome those. With that, on behalf of my colleagues, I want to thank you very much for appearing before us today and being very frank with us. I hereby declare the meeting adjourned.
(The committee adjourned.)