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UNCORRECTED TRANSCRIPT OF ORAL EVIDENCE To be published as HC 42-ii House of COMMONS MINUTES OF EVIDENCE TAKEN BEFORE HEALTH COMMITTEE
THE INFLUENCE OF THE PHARMACEUTICAL INDUSTRY
Thursday 2 December 2004 SIR RICHARD SYKES, PROFESSOR PATRICK VALLANCE and SIR IAIN CHALMERS DR ROBERTO SOLARI, DR MALCOLM BOYCE and MR HARPAL KUMAR Evidence heard in Public Questions 407 - 515
USE OF THE TRANSCRIPT
Oral Evidence Taken before the Health Committee on Tuesday 7 December 2004 Members present Mr David Hinchliffe, in the Chair Mr David Amess John Austin Mr Keith Bradley Mr Simon Burns Mrs Patsy Calton Jim Dowd Siobhain McDonagh Dr Doug Naysmith Dr Richard Taylor ________________ Memoranda submitted by Imperial College London, University College London Examination of Witnesses:
Witnesses: Sir Richard Sykes Rector, Imperial College, London, Professor Patrick Vallance, Professor, Clinical Pharmacology and Head, Department of Medicine, University College London, and Sir Iain Chalmers, Editor, The James Lind Library, examined. Q407 Chairman: Colleagues, I welcome our witnesses to this morning's session. We are most grateful for your co-operation with our inquiry. I think you are aware that we have two separate sessions this morning, and we will try to keep each session to an hour each. We will keep our questions sharp and ask you for reasonably concise answers. Would you each like to introduce yourselves to the Committee? Sir Richard Sykes: I am Director of Imperial College. Professor Vallance: Patrick Vallance, Professor of Clinical Pharmacology and Head of the Department of Medicine at University College. Sir Iain Chalmers: I am Editor of James Lind Library and one of the co-conveners of the James Lind Alliance, which is a coalition of patients and clinicians trying to influence the research agenda. Q408 Chairman: Professor Vallance, I gather you have just got off a plane from America. We do appreciate you coming here in those circumstances. Sir Iain, you suggest in your evidence that the pharmaceutical industry has a perverse influence on the clinical research agenda, and you also criticise publication bias by industry. Could you expand on these observations and perhaps give us some examples of how you feel patient well-being is being affected by these concerns? Sir Iain Chalmers: If I could start with an example to make a general point, some researchers in Bristol a couple of years ago asked patients with osteo-arthritis of the knee and the people caring for them - physiotherapists, rheumatologists and general practitioners - what unanswered questions they would like to see addressed in research, and the answers that they came up with were things like better evaluations of surgical options, better evaluation of physiotherapy, and better evaluation of ways of coping with a chronic, painful condition. When the researchers compared the questions which these patients and professionals had given with what had been studied in osteo-arthritis they found that very few of those questions had been addressed, rather that yet more non-steroidal anti-inflammatory drugs, placebo-controlled trials were being done. All of the focus groups that they studied said, "we do not want any more studies of drugs, or pain-relieving drugs." That is just one example of the way in which research agendas can be distorted by the interests of industry. In fact, in this week's BMJ there is a report of acupuncture for osteo-arthritis of the knee, to give you an example of the sort of thing that industry has no interest in at all. First of all, there are inappropriate questions being addressed, or inappropriate from the point of view of patients and clinicians; and sometimes inappropriate comparators are used. Sometimes a placebo is being used as a comparator when there is already an effective treatment, and sometimes inappropriate outcome measures are being used. From the commercial point of view there may be reasons for doing these studies, but in fact they are not necessarily at all serving the interests of patients and clinicians rather than shareholders. There is also the problem of academic influences on the research agenda, which I regard as perverse. In this country, one of the most perverse influences is the research assessment exercise, which is done to decide how much of the science budget goes to support universities. For example, within that system there is no encouragement to review systematically what is already known from existing research, before ploughing ahead and doing new additional studies. There is discouragement of collaborative research, which is often necessary to get robust evidence about the effects of things. People in particular institutions competing for resources see collaborative research as a threat because it submerges the identity of the institutions, and does not give individuals in institutions the prominence which they think is required. That is very unsatisfactory because it means sometimes small-scale, often poorly-designed, studies, are encouraged because they do yield those sorts of results. The other thing is that increasingly there has been encouragement by academia to go for income-generating research. The way that that can manifest itself is - let us take a trial funded by the NHS R&D programme or the Medical Research Council. There may be a certain sum of money to support the recruitment of every patient in the trial, but sometimes industry can offer a bounty for each patient recruited of thousands of pounds. Clearly, people who are wanting to make income for their institutions or indeed their hospitals may find it difficult to go for a study that is looking at a more important question which is of no interest to industry that is funded by the MRC or NHS R&D programme, and they will go in the other direction. Those are the perverse incentives that I believe exist. You asked me about the problem of publication bias, which is a very serious problem, and one that I have been wittering on about for well over a decade. I am very glad that Sir Richard Sykes is here at the same session, because I want to give credit to those people in industry who, way back in the mid nineties, said that this was an unacceptable form of behaviour. Not only Richard Sykes and his colleagues within GlaxoWellcome did that, but also Mike Wallace, the Chief Executive of Sheering Healthcare did it too. It is quite unacceptable that people should be invited to participate in clinical trials, and then when the investigators or the sponsors do not like the results, their contribution is not made public, and it is a very, very serious problem. Q409 Chairman: Can I ask the other two witnesses whether they feel their institutions or research groups are influenced in similar ways by the industry in some respects; and, if so, how? Professor Vallance: I can answer from my own institution. We get a small percentage of our total research income from industry, and it is about 2 per cent in total of research income. Q410 Chairman: Where does the rest come from? Professor Vallance: From the Medical Research Council and major charities like the British Heart Foundation. Currently 2 per cent comes from industry. We are probably unusual in that in terms of having a very high percentage of peer-reviewed grant funding. But there is no question that what Iain Chalmers says is correct; that industry will of course pursue drug-related research over and above other kinds of research. The question is, to what extent that distorts the ability to undertake other types of research. One of the problems is that a rather small percentage of patients are involved in clinical trials and there is huge uncertainty in healthcare. There is capacity in the system, but it is not used. I remain concerned that we have not got the capacity issues right, or the infrastructure right to undertake more studies. It does not surprise me that industry will want to pursue studies of interest to itself. Sir Richard Sykes: Our research budget is £200 million a year; and £20 million of that will come from industry. That is the biggest industrial funding of any university in the UK. Most of that, of course, is in the physical sciences and engineering, not in medicine. However, we live in a knowledge-based economy. The knowledge base is university-based, and we want industry to work alongside universities. If we are going to be competitive in this country, then we have to use our knowledge, our creativity and innovative skills. Therefore, the universities have to play a very important role in that, and we have to have translation of research in healthcare or other areas because that is the fundamental basis now of being competitive. We have to use our knowledge base. Q411 Chairman: You do not feel that that relationship with industry has a bearing on the objectivity of the work that you do? Sir Richard Sykes: I think it has to some extent, but again ----- Q412 Chairman: In what way? Sir Richard Sykes: In the way that we have heard already, that industry will want to come in at the front end, doing clinical trials; they will also want to invest in certain types of research. Of course, the academics themselves will not get involved in that research if they do not believe it will benefit them at the end of the day, so how it manipulates is difficult to tell. Certainly, big clinical trials in patients related to the hospitals are certainly being done to generate money. We are being driven to generate money, otherwise we would not be competitive in the world. Q413 Dr Naysmith: This is really a question to Sir Richard. I agree with what Sir Iain said, and we are really pleased to have someone who has been at the top of scientific research and one of the country's major companies. We suspect that you will be able to give us quite an insight into what goes on if we can discover the right questions to ask. One of the most important questions facing this Committee in producing the report is to try and find the right balance, if there is one, between business and trading and health priorities and between marketing and evidence-based clinical practice. I am sure you would agree that that is something we all want to do. As I have just said, you have experienced both sides. What do you think of this conflict? How do we get the right balance? You have partly touched on it, but as a more global thing? Sir Richard Sykes: I think we have carried a lot of baggage from the past, and somehow we have to recognise that those days have gone, or at least they are going away. We have to look forward. If we are going to deal with some of the big problems in healthcare today, it has to be a partnership between the academic face, the research base, the industry, the NHS. We have to work together to solve some of these big problems. I believe that this has got to be a collaboration today, not a group here, a group here and a group here, and it is all "them and us". That method will not work. Q414 Dr Naysmith: How do you get rid of this conflict between trade and health, and how do you make sure that they work together? Sir Richard Sykes: I think you need a lot of transparency. As Iain said, you need to be transparent, and you need to make sure what everybody is doing, and that the information is there so that we can all share with it and deal with it, rather than having things hidden - "if we do not like the result we put it away and do not tell anybody", which is totally inappropriate. Transparency is particularly important. Q415 Chairman: Do you see there is any way of squaring up that transparency with a market system where there is this obvious emphasis on the need to create profits and business incentives; and on the other side the health policy? Do you see that can in any way actually be balanced out so that you can have transparency and also a commercial market operating, which is what the companies clearly want? Sir Richard Sykes: I do not think there is any conflict at all. If you produce good medicines, whether they are diagnostics, whether they are treatments, whether they are palliatives, curatives, preventatives, whatever they are - if they benefit somebody in society, we should all be very happy. That is the objective at the end of the day. Q416 Dr Taylor: The phrase "commercial confidentiality" is thrown at us all the time. How do you square that with transparency? Sir Richard Sykes: There are certain areas where, at the beginning of the research process, there has got to be a degree of confidentiality in terms of intellectual property. Once that intellectual property has been achieved the whole point about intellectual property is to make it available to everybody so that everybody can see what you are doing. Q417 Dr Taylor: How early in the process should that be done? Sir Richard Sykes: As soon as you have got the intellectual property file. Q418 Dr Naysmith: How do you resolve the conflict that Sir Iain referred to, where you have the situation where people who are suffering from an arthritic condition would much more benefit from physiotherapy or something like that than from another painkiller and another anti-inflammatory, and the companies just put the money into that? Sir Richard Sykes: If the doctors continue to prescribe analgesics for treating these diseases, so that the market - I do not know what it is today, but it must be billions of dollars for these kinds of drugs - then what do you expect the market to do? They respond to it. That is what I am saying: people have to work together. If you are talking about osteo-arthritis, the first thing you need is a diagnostic, because it is a nightmare to decide whether somebody has osteo-arthritis or not. Q419 Dr Naysmith: Where does the transparency come in, then, because you were just following down that because it is the job of companies to generate profits as well as to generate ----- Sir Richard Sykes: They cannot generate profits if nobody sells the drug. The companies do not sell the drug to the patient; it is the doctor - the gatekeeper. Q420 Dr Naysmith: We will come to some questions later on about the role of the industry and marketing the product. Professor Vallance: Can I make a comment on this? It seems to me that the job of saying which of the trials are missing and what the patients want that are not drug-related trials is a matter for the NHS to set the agenda and to say, "where are the gaps and what should we be addressing in a clinical trial?" It is unrealistic to expect industry to go out and want to do that. Q421 Dr Naysmith: I think we will come to interesting questions later on related to what the role of the Department of Health should be versus the Department of Trade and Industry and whether it should operate through the Department of Health. I want to move on to something else. I have been very impressed in this inquiry by witnesses who have been able to tell us about the practice of ghost writing, someone else writing papers, sticking their names on a paper that they know very little about. I am sure that Richard, as a scientist, will not think that is a very good idea, but does it happen widely in the industry? I am really talking about clinical trials rather than original research. Sir Richard Sykes: I am sure it happens because academics are very, very busy people, and they prefer to do research than spend a lot of time writing papers. If the industry puts forward a method of relieving them of that chore, then I am sure that that does happen throughout the industry. That would be true generally. Is it a good idea? I think it can be, as long as everybody is in agreement with what is written at the end of the day, the results and what they are. Q422 Dr Naysmith: You would never have done it as a scientist, would you? Sir Richard Sykes: It would never have been within anything that I did as a scientist to do that. I am not a clinical researcher, so I was never informed of that situation. Q423 Dr Naysmith: How much will the chief executive of a big British pharmaceutical company know about the details of the sort of things we are talking about now, and the kind of research that is being pursued? Is it seen in terms of one, two or three new drugs progressing, or would you be interested in things like incentives and disincentives for sales representatives and the pressures they face to meet targets; or would you be really interested in producing a drug that benefits humanity? Sir Richard Sykes: I must make it clear to everyone here that people go to work in the pharmaceutical industry generally - and particularly the researchers - because they really have a mission. They want to discover and develop something that is really going to benefit people, and the young people that go into industry today go with that desire. I have met very few people who did not want to achieve that end. The people working in industry work very closely with academia in the big companies, and they all have one objective at the end of the day. In my opinion, these are not people that are driven by greed, money or avarice; they are driven by the desire to be successful and to do something that is going to benefit people. When you get higher up in the organisation, those objectives change to some extent, but not the people doing the work. As a scientist and a chief executive, I obviously took a lot of interest in what was going on, because that was my desire as well; to make sure that we could develop things that really benefited people. Sir Iain Chalmers: May I add something on ghost writing and publication practices? One of the developments under Sir Richard Sykes's regime at GlaxoWellcome was that there was a publications unit headed by Dr Elizabeth Wager, which worked with some people in other companies developing good publication practices - one of the things that came up with ghost writing and gift authorship and so on. They developed good publication practices guidelines for the pharmaceutical industry; they are on the Web. When I wrote to the successor of Sir Richard Sykes, Jean-Pierre Garnier, congratulating him on supporting the successor company GSK after he came into office, not only did I not get a reply but Dr Elizabeth Wager and her team were sacked. They still have the good publication practice guidelines and they are on a website. They have only been signed up, the last time I looked, to about six companies world-wide. I think it is a very, very serious situation. In other words, if companies are really genuine about wishing to adopt the sort of publication practices that you were touching on, then they should sign up to that guideline. Q424 Mr Amess: Gentlemen, the Committee would be very interested in hearing what you think of the idea of setting up a public register of all clinical trials. If you think it is a good idea, can you tell us at what point trials should be registered? Should this register be operated by an independent authority, if there is such a thing as an independent authority - Richard over there calls himself an independent, but he is up to his neck in the grubby world of politics; but if you could find an independent authority why do you think it could be operated by the pharmaceutical industry? Sir Iain Chalmers: I have already said that I have been wittering on about this for nearly two decades. Q425 Mr Amess: I am sorry if I am repeating things which you have answered already. Some of us are trying to stick to our scripts, you see! Sir Iain Chalmers: I promise you that I have not given a detailed answer on this. Registering trials at inception is one of the steps needed to tackle this problem of publication bias. It has been proposed at least since 1986 as a way of addressing this problem. Very good progress has been made in some respects. For example, the trials that are funded by the NHS or by the MRC are now all registered on the meta register of controlled trials set up by the publishing company, which has done an extremely good job. In addition there is a need to uniquely identify trials, in the way that books are identified. There was an ISBN scheme, which was introduced initially by two publishers, and then it became part of the International Standards Institute. WHO has recently assumed responsibility for developing the International Standards SRCPN. It is a very important initiative which has now got international backing from WHO and from the International Committee of the Medical Journal Editors and so on. In terms of which trial should be added to that register, and indeed for which it should be required, there should be registration. I think it is reasonable for industry to say that in the early days of drug development there are issues of confidential commerciality that they will want to keep under wraps. However, at the time when studies start to be likely to influence patient care, those are the studies that really do need to be registered prospectively and reported fully. Q426 Mr Amess: Who would judge that? Sir Iain Chalmers: One way of judging it is to see if the study was randomised, because that way people are really taking a serious interest in making sure that they are not misled by bias. I would say randomisation would be a good trigger, although it has to be said, unfortunately, that drugs are still being licensed on the basis of rather inadequate evidence, looked at from my perspective anyway of uncontrolled case series, particularly in cancer. Q427 Mr Amess: You mentioned the need for registration of trials at inception. Can you explain to the Committee why you feel that is so important? Sir Iain Chalmers: Yes, if you wanted to address a question about uncertainties about some treatment or other. Clearly if you want to look at all of the evidence that has been generated, and not just a sample of it, and certainly not a biased sample, until you identify at inception the studies that are addressing a particular question, you cannot know that you have identified all of the relevant evidence. There are examples of people being harmed, and certainly resources being wasted because disappointing studies have not been published. To try and identify those in retrospect - in the mid eighties we wrote to over 40,000 clinicians around the world to try and flush out unpublished studies, and it does not work. You need proper registration of these studies so that you have a handle on it right from the beginning of their life. Q428 Mr Amess: Gentlemen, do you have anything to add to your colleague's remarks? Professor Vallance: I agree with what Iain said. The cut-off point in a sense is when a trial is trying to establish a therapeutic end-point, then that should be in the public domain and should be registered. I think that is true for academic and industrial-sponsored trials. Sir Richard Sykes: I agree. Q429 Mr Amess: Gentlemen, do you think the current draft regulatory system is adequate? If it is not, what do you think is wrong with it? Might the MHRA take a greater role in addressing the problems of adverse drug events or post marketing clinical trials or, again, do you think it would be better to be handled by some sort of independent authority, if you can think of such an independent authority? Professor Vallance: There are a number of problems. MHRA, when it licenses a drug, is looking for the effect of that drug over and above placebo very often. I understand why that happens as a regulatory process, and that is in harmony with other places in the world, but it is not a question you want answered in terms of whether you want the drug available in the NHS. That is where NICE comes in. There are some boundary issues that need to be explored, and whether NICE has said in advance the criteria it wants to put in place to say something is a true advance over existing therapies. Q430 Mr Amess: What is your view of how it operates at the moment? Professor Vallance: NICE has done a lot of very good things, and in many ways it has worked tremendously well. It is often on the back foot when a trial shows in advance, because it is then left with asking how big an advance it is and whether it means something. The problem is that very often it does not mean very much, but they are always seen as denying ----- Q431 Mr Amess: So this links up; it is all written up. Professor Vallance: Yes, there is an expectation by patients and doctors and others. I would prefer to see at least as a pilot NICE looking at the idea of setting criteria as to what is an advance in a given therapeutic area. Q432 John Austin: In your evidence you have suggested there is a lot of information on the effects of drugs which is collected in the routine of clinical care. Could that be used as a base for evaluation? Professor Vallance: There is an immensely valuable database called the GP Research Database, which is routine clinical data collected on 5 million patients through computerised systems, and that will increase in the NHS. It is an under-utilised resource for looking at drug safety. There is good evidence it is under-utilised, and one of the reasons is that it has been incredibly expensive to access, and just about the only groups that have accessed it in the past have been in hospitals. UK data of direct relevance to safety in this country has been used mainly by groups in hospitals. That database is now owned by the MRHA and it extremely valuable for drug safety, and there will be more of that coming along as NHS computer systems get put into place in hospitals. Q433 John Austin: What is the barrier now? Professor Vallance: Cost and to some extent expertise. Q434 Mr Amess: I do not think you addressed the point about the drugs. Professor Vallance: The database is the way to get that. You can get a lot of safety information and you can monitor safety much more accurately. I suspect that some of the issues around cost might have been picked up using that database. Sir Richard Sykes: I think you have to recognise that you can never win at this game. The MHRA or any regulatory agency gets a set of data. Usually you do this through clinical trials with from anywhere between 3,000 and 10,000 patients. If an adverse event is one in 20,000 or 30,000 or 50,000, you are never going to see it. There has got to be a process of making sure you have enough information to give an approval to have the drug into the clinic, but then there have got to be very clear monitoring processes for seeing that drug operate in a true market place, where now you are not selecting the patient who receives the drug but patients of a great genetic diversity are now receiving that drug. That, by definition, will produce adverse events. Remember that these drugs, at the end of the day, must be poisons, otherwise they would not be working. The body is a very complicated organism. It is all connected. If you inhibit one bit, you are going to inhibit something else somewhere else, and that is an adverse event, and that is the risk/benefit relationship at the end of the day. The more information we can get about this, the more we understand about the underlying mechanisms of disease and how those mechanisms are connected to other mechanisms. This will change over the next 20 years absolutely dramatically. That is where we have to make sure agencies like the MHRA are tied in to this modern technology so they can get better, more valuable information, to make better decisions. Q435 Mr Amess: You think they are the appropriate body. Sir Richard Sykes: As long as they change and develop with progress, then they should be fine. Q436 Dr Naysmith: Why should it be better in the future because it has not been all that good in the past? I know it will change with the different scenarios, but you are still going to have to regulate. Sir Iain Chalmers: I have a slightly different take on your question. It seems to me that unless you establish that a new treatment is either better or cheaper than what is already available, then worrying about side effects is displacement activity. In other words, if we had better information, complete information on the effects of the treatment and the benefits, and in addition to that we had some better idea about what difference these drugs were going to make about outcomes that matter to patients - which is very important because often they are evaluated in terms of outcomes that are completely meaningless to patients. If we had evidence that a drug is beneficial, having taken a control for publication bias and taken into account that we are interested in outcomes that matter for patients, then that drug becomes interesting in terms of trying to make sure it does not have any unexpected side effects. The initial problem is the worst one; that we do not yet have good mechanisms for identifying drugs that are useful to patients, partly because of publication bias, but partly because the outcomes are either not sufficiently important to them. I was listening to the Chair of the Psoriasis Association speaking yesterday, who is a lay person. He was saying that the studies of psoriasis do not measure the things that he and other sufferers of psoriasis rate as important, such as itchiness and pain. There are those fundamental earlier problems that we need to address. Q437 Mr Amess: To help the Committee in reaching its findings, can you think of a good mechanism? Sir Iain Chalmers: I do not know how radical this is, but I would propose that there should be a provisional licence given to drugs on the basis of the kind of outcome measures and the type of follow-up that has been done in studies submitted to the MHRA, and that a decision about whether this new drug represented good value for the NHS should await until there is more evidence about whether or not it affected outcomes that matter to patients. Q438 Chairman: Is that a model that applies anywhere else in the world? Sir Iain Chalmers: I do not know. Q439 Mr Burns: In parallel with your criticism of the industry you have said "denial of access to information held by the MHRA puts the interests of the pharmaceutical industry ahead of those of patients and prescribers", and you categorise it as "deplorable". Can you explain to the Committee what exactly you mean by "deplorable"? Sir Iain Chalmers: Let me give you two examples, both of them relating to pharmaceutical products. One relates to a treatment that has been used every since the Japanese attack on Pearl Harbour for treating people who were severely burned or otherwise critically ill, which was to give them a transfusion of human albumen solution. Ever since that time, until very recently, there has been no adequate assessment of whether the claim that this was a way of reducing the chances of those individuals dying was in fact substantiated in good evidence. The human albumen solution has been repeatedly used in this country. It was re-licensed in 1993 for use in this country, yet a systematic review of all of the studies that gave any information about death at all that was done in the mid 90s showed no evidence that it was helpful, and some evidence was that it might be harmful. There are mechanisms for thinking about how this harmful effect might be mediated. The reaction in those days of the Medicines Control Agency to this news was to slightly modify their labelling, but to keep confidential the evidence upon which the drug had been re-licensed in 1993. It was not considered in the public interest to allow that to be made public, which I think is indefensible. If you have a question about a widely-used product, which has been used for decades, you need to know what criteria the licensing authority, which is meant to be looking after our interests, has used to decide that the product was safe and effective. Subsequently, there was a lot of fuss about it in this country, and a controlled trial has been done in Australia and New Zealand, which failed to detect any advantage of this product, human albumen solution, compared to salt water. As you can imagine, salt water is a good deal cheaper! There is some evidence that in a certain sub-group of patients it may be harmful, but the worry from the systematic review was not substantiated. However, we have been paying millions and millions of pounds for a way of resuscitating patients which is no better than salt water. That is one example. Another example is so-called evening primrose oil for eczema. This was given a drug licence. The Department commissioned a systematic review of the evidence relating to the effects of this drug in eczema. The reviewers did an extremely good job, in which they included both unpublished data provided by industry and published data that was available. They were unable to find any evidence that the drug was useful in eczema, except in doctor-assessed itch - not patient-assessed itch, which raises an interesting question! The drug continued to be sold to the NHS, which was about £7 million a year at the time that the study was done. Industry put pressure on the Department not to release the results of the systematic review. Two years ago the MCA withdrew the licence on the grounds of lack of efficacy, but did not make available the evidence that had led it first of all to license the drug and then to withdraw it. Those are examples of the sort of secrecy that those outside the system have to put up with. That secrecy is not in the interests of the public. Q440 Mr Burns: Do you think there are ever cases where it might be in the interests of the public to deny access to publication? Sir Iain Chalmers: I cannot think of examples, but that is not to say that there may not be some. Clearly, one of the problems that epidemiologists face is if they find an association between let us say coffee drinking and pancreas cancer, which was found at some time. Do they report that association and stop a lot of people drinking coffee who enjoy it but who might worry they will get pancreas cancer? There is an issue about not causing unnecessary alarm, but when it relates to licensed products that have been given the go-ahead for marketing in our country to our population, I just do not think it is consistent with 21st century values of the public that that information should remain secret. Professor Vallance: I will go one stage further. I do not understand how you can use a drug if you cannot act on information to see if it works. Sir Richard Sykes: If you really wanted a system that works more effectively you would have a regulatory body in terms of approval; then you would have the body that is determining whether you have efficacy and safety; but NICE can only make those decisions once the drug has been on the market for quite some time. Then you can ask those questions. Therefore the data has to be transparent because there is no way you can make the decisions. If they say there is no benefit to be gained from the drug, and the NHS stopped supporting that drug immediately, that would be a better system at the end of the day, but you can just imagine the arguments as to whether there was real efficacy. If you set up NICE correctly, you would be able to do that. Q441 John Austin: The evidence we have had both from the United States and Australia has suggested that only a minority of drug innovations offer any significant therapeutic advance. Would you say that is also the situation in the UK; and do you think the industry does concentrate too much on the so-called "me too" products? Sir Richard Sykes: If you look at the whole history of drug development - and really it started as an industry in this country in the sixties, and the first range of drugs - if you think about beta-blockers for treating hypertension - obviously people recognised that there was a mechanism here to attack high blood pressure, so lots of people get involved in that research because they see the patterns. Once you are down that track and you have invested a certain amount of money, you are going to continue. Again, if you can show safety and efficacy, those drugs get approved. Let us say there are 15 beta-blockers on the market: doctors will put patients on the drug that tends to work for them best, so you are actually doing a genetic analysis on that group of patients by having 15 drugs available to you. Each one of those drugs has a benefit to a certain class of patients, worked out by pure random testing, I suspect. That has been the tradition going forward, so if you go back to the sixties and seventies, we have gone through that period where drugs come out and they are followed by other drugs, because safety and efficacy has been proven in the market place and therefore you know if you go into that area you are going to end up with hopefully a safer and more efficacious drug. This is where I said earlier that the world is now changing. That model will not work any more, and this is why we have seen this paradigm shift in the drug industry and why we read that drugs are not coming out as fast as they used to, and there are no new molecules, because it is going back to basics. It is now trying to understand the underlying mechanisms, and to deal with that right at the fundamental issue, rather than serendipitously moving along the track and then everybody following that track. This is the change that is taking place, and my view is that over the next 20 years we will start to see drugs that will offer real benefit to patients. You will not get a lot of "me too-isms" I suspect. Q442 John Austin: You said earlier that the industry manufactures the drugs and the doctors prescribe them. You have gone through a period of asking why doctors prescribe a particular drug. Professor Vallance, in his evidence, has pointed out that in order to gain a licence a drug does not have to prove it is more effective than existing treatment; it just has to prove that it is more effective than the placebo. Professor Vallance says that not a lot of doctors know that. Sir Richard Sykes: It is not true in the United States of course. The FDA will tend to eject drugs that do not show benefit over existing drugs. Q443 John Austin: That is not the case in the UK. Sir Richard Sykes: It is up to the regulatory agency to make that decision. They have the right to make that decision. Of course, we then have the body called NICE, which is another regulatory agency. Even if the MHRA has approved a drug, NICE could say "this adds no real benefit to what is already there and therefore we will not support it." You have to remember that with the exception of the infectious diseases, we do not cure disease but we treat the symptoms. Hypertension and high lipid levels are not diseases at all. We are treating something that is a symptom or hopefully it will prevent something by treating that symptom. We are moving into an area that will change quite significantly. Most of the drugs are palliatives. Q444 Dr Naysmith: You have used the phrase, Sir Richard, quite a lot, "safety and efficacy" and "approved by the market place". How long would you give for the market place to bring something both safe and efficacious if you were still in charge of a company? Sir Richard Sykes: I do not think it is a time issue; it is a quantitative issue. You could put a drug on the market like a Cox-2 inhibitor, and in one year you have millions of patients on that drug. If you were treating small-cell lung cancer, you would only have perhaps a few thousand. You have to somehow contain that period on numbers of people treated. Q445 John Austin: Lots of people take RSAs, and some of the predecessors have been pretty toxic and have been marketed very heavily and sold in their millions. When are we going to recognise that? Sir Richard Sykes: If you started from square one now and did that, I would say now within a period of three years you would have a pretty good idea of whether those drugs are safe and efficacious. Remember, it is always a risk/benefit ratio. There has to be a risk. There is a risk with every possible drug. Q446 Dr Naysmith: I think what the industry is play down the risk and play up the benefits. Sir Richard Sykes: Yes. Q447 Dr Naysmith: You said there were 13 beta-blockers. Sir Richard Sykes: I used an example, but there are probably more. Q448 Dr Naysmith: It will take a very long time until a doctor finds the right one for the right patient, if he is having three months at a time. Sir Richard Sykes: Until you get the genome sequence for every individual patient and you can use that information to the best advantage to determine which drug ----- Q449 Dr Naysmith: That is not there yet, is it? Sir Richard Sykes: We are not there yet. Dr Taylor: For clarification, a doctor does not use all 13. Dr Naysmith: No, but he was talking about finding the right one for a patient. Q450 Dr Taylor: I wanted to go back to Sir Iain. You have touched on the final recommendation in your paper. The recommendation was that selected promising but inadequately evaluated drugs should be used in the NHS only within in the context of controlled evaluative studies until enough is known to judge their cost-effectiveness. Cox-2 inhibitors probably had some real benefits. If Viox for example had only been released on a controlled trial basis to start with, would that have allowed it to be restricted in its prescribing, and then when it was eventually released would that have just delayed the discovery of the side effects? Can you comment on that? Sir Iain Chalmers: I would like to comment on two issues. People embarking on new studies and reporting new studies do not do a systematic review of what is already available in terms of evidence, and when they have new data set the new data in the context of an updated systematic review. We know now from evidence published in the Lancet a couple of weeks ago that had such a process been in operation for Viox, then the adverse effects might have been identified as long as four years ago. The first thing to do is to take notice of all the current evidence. At the moment, that is impossible because of this problem of publication bias and because of the fact that academia does not value the process of finding out what is known already, using scientifically defensible methods. That is academia's problem; it really is. It is their fault. In terms of allowing a drug, if you like, a provisional licence, there may be some drugs that have been given a licence on the basis that they seem to have an encouraging effect with an outcome patients that may not value, but which is seen as relevant in the process. In those circumstances, if you want to find out whether it holds value for the patients, those are the sort of circumstances in which the drug should be released in the context of a further evaluation. For example, the Class 1 anti-arrhythmic drugs were given to people who had heart attacks to try and prevent arrhythmias because they were a risk marker for subsequent premature death. These drugs were very good at suppressing arrhythmia, but they were also pretty good at suppressing life; they killed people. They were licensed on the basis of a surrogate outcome, which patients would not have been worried about, and they came into widespread use. An estimate has been made that during every year in the United States at the peak of their use in the late 1980s they were killing more people than Americans who had been killed in the whole of the Vietnam war. That shows an example of the kind of circumstance where it would be important to release - not just a drug; it might be a device or a surgical operation, in the context only of a randomised trial, until we knew more about its worth to the NHS and the patients who use the NHS. Q451 Dr Taylor: In the case of Viox, if everything has been available beforehand we would not have got into this problem. Sir Iain Chalmers: That is the evidence that was published in the Lancet about three weeks ago, that four years ago we could have known there was a real problem. Q452 Dr Taylor: Can I go on to picking up side effects after marketing, when there is not that bank of information before. The yellow card system, as we have heard so many times, is not really working effectively. It was Professor Vallance who talked about the GP database. How will that help? Professor Vallance: That, and increasing numbers of databases, as the NHS becomes computerised, will allow you to collect data from everyday practice, for dealing with the issue that Sir Richard raised - the variability once a drug is out there in the real world away from the rather tight setting of a clinical trial. Q453 Dr Taylor: So one will be able to tie up side effects with drugs. Professor Vallance: Yes. You can on that system already. You can interrogate it. Of course, it is not randomised and not very good at having efficacy, but it is quite good for picking up safety signals, and once a drug is out there in practice it is very difficult to get efficacy data unless you have randomised controlled trials; it is much easier to pick up safety signals. Q454 Mr Bradley: Do you think the Department of Health is the right sponsoring Government department for the pharmaceutical industry as opposed to the DTI? Sir Richard Sykes: My view has always been that it should be the DTI. The pharmaceutical industry in this country is a global business, not a national business. The DTI is a global business, but the DoH is not global. Therefore, the DTI should be the sponsor. The only reason that the DoH is the sponsor of the pharmaceutical industry is so that the fox would not eat the chickens! Professor Vallance: Sir Richard knows far more about this than I do, and I think there is some sense in that, but it is not an area I know about. Sir Iain Chalmers: I was only introduced to this possibility quite recently, and it does seem very sensible. Clearly, the pharmaceutical industry in this country is a very important part of our manufacturing economy, but I do not see that we should subsidise that industry by buying useless treatments for the NHS, just because they are being manufactured in this country. There is a tussle, and I can see that there is a real debate to be had there, presumably at Treasury level, but the NHS ought to be giving the best possible treatment to patients who use it. Professor Vallance: Sir Richard will comment on it more, but the percentage of the market involved ----- Sir Richard Sykes: It is 4 per cent of the world market. Q455 Dr Taylor: By pure chance we started this inquiry at the stage when Viox and SRI's problems were coming out, so the inquiry was greeted by the press with a huge welcome; but here we are, we are going to expose all the iniquities of this desperate industry. Is this just prejudice, and would you make a comment on this, because we have this terribly difficult problem of writing this report and getting it right and not blaming an iniquitous industry, if it is iniquitous, and blaming it if it is? Do you have any comments? Sir Richard Sykes: It is not an iniquitous industry. I think it adds great value, first of all to the UK, the industry in this country. It has been one of the great success stories. It has spun off a lot of bioscience activity in this country, which is still some of the best in the world, and that has been very important because it has been a base for many pharmaceutical companies' research and development, which is critically important for the economy. Like all businesses, they are private businesses and they have shareholders. They have to provide returns. The industry itself has always been highly regarded, particularly in times of recession. Everybody is sick and the industry has always been a good place in terms of investment. Obviously, like anything else in the world today, it becomes very competitive and once people become highly competitive they are driven to do strange things, so I think that today the industry has got a very bad name. That is very unfortunate for an industry that we should look up to and believe in, and that we should be supporting. I think there have to be some big changes. The industry has got to get back on track and get rid of its bad image by being much more transparent in some of the things we have been talking about, by working closer with other bodies, and being much more interactive with the public. We need this industry; it is critically important. We need it to work with other people, with academia and with industry. I think we have a great opportunity in this country to continue to be leaders in this area of research. Q456 Dr Taylor: You are almost in a unique position to comment from both sides of the argument, so it is very valuable. Professor Vallance: My experience of research from the industry is that they want to make innovative drugs and often in areas where there is a need, which is sometimes not recognised by doctors but by patients, such as incontinence and other areas. I think within the research side that is what they want to do. From the marketing side they have a different job, which is to sell whatever they have. It seems to me that part of the response to that is to be much more robust about what we are prepared to buy and pay for, and have our own criteria for what works and is an advantage. Q457 Jim Dowd: You say industry wants to make innovative drugs. We received evidence, certainly when we were in Australia and elsewhere, that the vast majority of intellectual effort in drug companies is now going into maximising patents, not in developing new drugs.. Professor Vallance: I think the research side of industry wants to create new drugs. If you ask anyone in research, that is what their aim is. The marketing and other side of industry may have other objectives which are about patent extension. Within industry there is exactly that tension that you are exploring here. Most people want to make innovative medicines. Q458 Jim Dowd: Clinical practitioners are all clear-eyed optimists ----- Professor Vallance: No. The basic scientists in industry are striving very hard. They recognise that the real money comes from the innovative blockbuster that beats everything else. That is what their focus and energy is on in terms of drug discovery. Another end of industry is all about making the most money you can from what you already have, and that is where patent extension comes in. That is why we need to be much more robust about what we need and what we do not need, and why we need it. Sir Iain Chalmers: I would like to separate these two things. One is the influence of industry on scientific record, which at the moment is indefensible, and previously we are agreed on that. There needs to be a great deal more transparency. The other is the influence of industry on the way that drugs are used. Basically, you are in a market place then, and it is up to organisations like NICE to make sure that the NHS gets good value for money. All sorts of tricks will be used, as marketeers will always use to get people to use their products. There is however such a distortion now in that the things that do get studied, because of the economic power of industry and its influence not just on individual academics, but the whole academic institutions, that some important questions are not being addressed. That is a great shame. If one takes of some of the recent innovations that have come not from industry but from looking at old drugs like aspirin and magnesium sulphate - Epsom salts for the treatment of convulsions of women during pregnancy and devices to help people who are having subarachnoid haemorrhage, which are nothing to do with the drug industry - there are all sorts of important questions like those that are very relevant to patients using the NHS and which are in some instances getting squeezed out because of this increasingly close partnership between industry and academia. I do not think that is a good trend. Q459 Mrs Calton: What do you advise your colleagues and students about the influence of the pharmaceutical industry on prescribing patterns? Professor Vallance: We have a pretty robust course for students, which illustrates very clearly the influences on prescribing. We have a system which we introduced for the students which I was explaining to Iain beforehand, which was rather unpopular when I first introduced it, which is a simple evaluation sheet that they carry around on their ward rounds, and when they see anything being prescribed they go away and ask whether it was a reasonable or unreasonable decision, and what was behind it. That was unpopular. The idea of students challenging consultants about the evidence generated a very interesting culture amongst students. Q460 Jim Dowd: Was there a high mortality rate? Professor Vallance: At student level, those are the things we have done. I think it has changed perceptions of students as to how you evaluate evidence. There is an ongoing problem with many doctors that perhaps they are not trained in evaluation skills, and also, coming back to the point about marketeers, sometimes data is presented in a way that is complex to disentangle, and people find that awkward. I do not think many doctors are well equipped to undertake those analyses. Q461 Mrs Calton: Would you say the sort of practice that you now have when teaching students is widespread, or is it isolated? Professor Vallance: It is patchy. It is becoming more common. I think it could be developed further. Q462 Mrs Calton: What assessment have you made that the teaching is effective in influencing outcomes? Professor Vallance: The evidence we have relates to the questions we set in exams and assessments. I do not have prescribing data to show it is valuable; but there are anecdotal examples of individuals which clearly have been influenced by them, and which link with the work that the unit is doing and the James Lind Alliance. Q463 Mrs Calton: It would be helpful if we had more evidence that this was a useful activity. Certainly the information we received in Australia was that the influence of the pharmaceutical industry on prescribers was extreme, and that those prescribers were not always aware of the influences. Professor Vallance: I think that some prescribers are poorly equipped to evaluate the evidence before them. The way evidence is presented is sometimes extremely complicated, with composite end-points wrapped up as though they all meant the same thing, and relative risk being presented when actually it is absolute risk. Simple things could be done, for example, for every medicine trying to evaluate as best you can - although it is not always easy to do it - the numbers you need to treat to gain a beneficial effect and the numbers you need to treat to get a harmful effect. Those two standardised numbers could be quite helpful if everyone were to "buy in" presenting in that way. Sir Iain Chalmers: When the evidence is strong and you know that it is strong, you can change practice very fast indeed. For example, I referred a moment ago to treating women with Epsom salts rather than far more expensive drugs when they have eclampsia, because the cheaper drugs are better. That evidence was generated completely outside this country in Latin America, Africa and India, and it changed British obstetric practice overnight. Similarly, a study that was done recently, which raised questions about the use of steroids given to people with acute brain injury, was recently published in the Lancet. It shows that this practice, which has been going on for about three decades, has been killing tens of thousands of patients. I am very clear that that will stop pretty dramatically now. The essence of the issue is that if there is strong evidence, patients and clinicians will take notice. Q464 Dr Naysmith: I would like to ask a peripheral question to Sir Richard. Going back to Dr Taylor's question, when you talked about the importance of the pharmaceutical industry to the country and the research that was done and so on. During that you mentioned the importance of university research. I have heard you say in the past that academics in this country, particularly scientists, are very poorly paid, and this is one of the things that - not just pay but conditions of service - which reflects on it. People used to come to this country - firms - to do their research, partly because of what was happening, and it still happens now - I am getting to the punch line! You have been managing director of one of our really important university science orientated universities for a couple of years: have you managed to do anything about that? Do you still think the conditions for young scientists in this country could be improved, particularly if you want a pharmaceutical industry, and have you managed to do anything about it? Sir Richard Sykes: There has certainly been a big change with this Government. We can go back now to the late 90s. This Government has recognised that there are a significant number of issues within universities in terms of teaching and research, and they have changed that quite significantly. There has been a lot of money put into infrastructure so that you build better laboratories and facilities. There has been more money for paying people better salaries. You can always argue that you need more, but I would say today that the top universities are in a much better condition than they were 5-10 years ago. That is improving all the time, and I know the Chancellor will probably say something else about it again today. There is a recognition that we have to put money into these places if we are going to drive the economy. It is critically important. To me, this is a very, very big issue. We must keep tracking inward investment on the basis that we do have a very big industry. Q465 Dr Naysmith: You think there has been an improvement and things are getting better. Sir Richard Sykes: Yes, there is no question about that. The NHS has stood outside this whole biosciences process, and that is totally unacceptable. This is a jewel in the crown. If we could bring all this together, no other country can do this because they do not have this system. If we could bring all these parts together during a period when there will be some dramatic developments in those areas, then I think the UK becomes a very attractive place for businesses to come and operate. Q466 Chairman: Do any of the witnesses have anything further to add? Is there anything within our terms of reference that you feel we ought to have covered which we have not covered within this session? Sir Iain Chalmers: There has not been enough disagreement in this session between your witnesses, and I just want to introduce one note of disagreement! It has been estimated that between a third and a half of the increase in life expectancy during the last 50 years, and the increase of 5 years of life free of morbidity, has been achieved by what has gone on in healthcare. That is a fantastic record. The promise of post genome medicine that is going to do better than that is, so far, not shown to be delivering. We ought to take a little bit with a pinch of salt some of the promissory notes that we have had from Sir Richard. I also want to make the point that the smaller the thing you study in academia, the higher your status. Those that are interested in clinical research are way down the bottom of the pile! Q467 Chairman: I think I should give Sir Richard the right of reply, especially as he is a Yorkshireman! Sir Richard Sykes: I think we expect too much. We sequenced the genome a few years ago, and we now have 300 genomes; but what we need is a thousand human genome sequences. That will happen because the technology is changing dramatically. Until we get that information and until we start to collate it and understand what is going on, we are competing against hundreds of millions of years of evolution. We cannot do it in five years. It takes time and it will take 10-20 years to see the benefit of those, but it will come. Q468 Chairman: Professor Vallance, have you anything to add, or are you happy to sit and let them get on with it? Professor Vallance: There are things coming through. I agree with Iain about healthcare, but things like treating heart attacks with block-busting drugs - there has been a huge change in practice, and a vaccine against cervical cancer viruses holds out huge promises for the future, so I am slightly more optimistic. Chairman: Thank you for your evidence. It has been a very interesting session. Memorandum submitted by Cancer Research Technology
Examination of Witnesses:
Witnesses: Dr Roberto Solari, Chief Executive Officer, MRC Technology, Medical Research Council, Dr Malcolm Boyce, Chair, Association for Human Pharmacology in the Pharmaceutical Industry, and Mr Harpal Kumar, Chief Executive Officer, Cancer Research Technology, examined. Q469 Chairman: Welcome to our second set of witnesses this morning. Once again, can I express our thanks for your co-operation with our inquiry. Would you briefly introduce yourselves? Dr Boyce: I am a physician, a clinical pharmacologist, and I manage a contract research organisation called Hammersmith Medicines Research, which is based at the Central Middlesex Hospital, an NHS hospital. It is a bit unusual for the private sector to be embedded in the public sector. I largely undertake evaluation of potential new medicines for the pharmaceutical industry. Dr Solari: I am Roberto Solari, Chief Executive of Medical Research Council Technology, the technology transfer arm in medical research. Mr Kumar: I am Harpal Kumar, Chief Operating Officer of Cancer Research UK and Chief Executive of the Cancer research and development arm. Q470 Chairman: Can I ask you all to speak up; it is not particularly easy to hear in this room and we want to be sure of what you are saying. The MRC stated that it shares a desire to maintain public trust in the governance and practice of medical research. How do you feel this trust can be best achieved? Dr Solari: In matters of trust you need, as speakers this morning have said, transparency. People have to feel they know what is going on and have access to the information. They have to build this trust with all stakeholders in industry, and the public. Q471 Chairman: Do you think that genuine transparency is achievable within a situation where you have this tension in terms of competition and companies obviously wanting to succeed with their products? Is it something we could achieve in the way that you are suggesting you would like? Dr Solari: You have to look at the drug discovery process and the drug development process, and clinical trials as a very long and complex series of events, which can take anywhere from 15 years from early discovery right through to the product reaching the market. There are periods during that 150-year process where you have to keep things secret in order to protect your advantage over the competition, because this is a business. In the early stages, where you may have discovered a new compound or chemical entity that has some activity, there is still an awful lot of work to do before that early discovery becomes a product. You want to keep that secret, like any business would keep trade secrets to themselves. Coming to a certain point you do make disclosures and find patents, and patents are published. There is a period where just for the functioning of the industry you need to keep certain things secret, but later on in the process when it is appropriate and possible, that information becomes open and transparent. You have to look at the whole process. Dr Boyce: Can I emphasise something that did not come out clearly in the previous evidence? It is very important to separate the stages of drug development, which can broadly be described as early and late. Early clinical development is essentially part of research, whereas late clinical development once a product begins to emerge tends to be influenced much more by the marketing group. The early group, the research - in my years of experience of working within the industry, as a pharmaceutical physician working within the NHS doing clinical trials, setting them up around the world - the commitment and sense of altruism amongst researchers, whether they are voluntary researchers or in the clinics, is absolutely the same as it is for academia. Indeed, it is probably more transparent because there are those who work - certainly in my experience of trying to liaise with those in academia - they want the money and they want the funding, but they do not necessarily want to recognise the association, so it is a much more insidious relationship. The transparency is there in early drug development. I certainly have no problems whatsoever in recognising that. Occasionally, the industry is less than open about publication of results but we have to remember that the attrition rate is very high in early drug development, some would say as high as 80 per cent, certainly the majority of molecules. Incidentally, I wanted the opportunity to comment on "me too" and your experience in Australia. Our unit works almost exclusively on new molecules. There are abundant new molecules coming through. If you think all the drugs coming through are patent extensions, you should come out and see our unit because that is not our experience. I could give a spirited defence of "me too" products because there is plenty of evidence that, when there are lots of "me too" products, the one that come on early to the market drop out and the ones that are developed as "me too" often are the ones that succeed. To get back to the publication, I have certainly run into difficulties with publishing work when I was based in the industry and in my current practice. I have had problems in recent years persuading companies to publish the work. They do not want to publish it because it is negative. They do not think it merits publishing, or they do not want their competitors to know that they are in a particular area of research. I battle against that. Often they are short sighted. You have to understand the pharmaceutical industry is a large organisation. They do not always have clear policies. You will get a decision from one person and a different one from another. Although the ethos may be towards publication in practice it does not always work out. One has to battle to get publications done but I have always succeeded in doing that and there are ways in which you could make that a bit more transparent. Ethics committees are burdened with lots of unnecessary things but one condition of ethical approval is that the results are published. That is a gateway and it would be very easy to control all the clinical trials like that. Secondly, the European Clinical Trials Directive requires all clinical trials in investigation of medicinal products to be registered, to get a new drug number. That is going to be a marvellous way of monitoring the trials done within Europe and following them up to see how many of them get published. It will be owned by the Commission and I do not think necessarily by the individual regulatory authorities but I do not know enough about that to comment. Q472 Dr Naysmith: You said that you tried slightly to justify not publishing negative results. Do you not think that not publishing negative results is dishonest? It is cheating, certainly. Dr Boyce: Or they are not interesting enough. Q473 Dr Naysmith: I am distinguishing between publishing an academic journal and a firm saying, "These are negative results." Dr Boyce: If it merits publication, it should be published. There are sometimes differences of opinion about whether something merits publication, even amongst academics. Q474 Dr Naysmith: I am not talking about something meriting publication in the sense of being a scientific paper that lots of people will consult. If you have a drug company doing research and it gets negative results, not to publish them, even if they have to publish them at your expense rather than through a journal, is dishonest. Dr Boyce: I would not say it is dishonest. It is not sensible. It is not in the interests of medicine in general. Mr Kumar: You have asked two questions, one about trust and one about transparency. With regard to the question of trust, our own experience in Cancer Research UK where we raise around £350 million every year from the British public is a testimony to the fact that the British public does have trust in medical research carried out in this country. On the general principle of is there trust in medical research, I would say yes. Clearly some of the disclosures or allegations that have been made over the last several weeks with regard to some of the practices in the pharmaceutical industry might affect that but I think it is unlikely to affect the generality of medical research. It is more about some specific practices. With regard to can we achieve transparency, I would argue that we could achieve sufficient transparency. We, as you know, have argued for a register of all clinical trials so that every clinical trial should be required to be registered centrally; and secondly for publication of all clinical trial results. There are probably ways in which the concerns of the pharmaceutical industry can be mitigated with regard to early phase studies but ultimately all trial results should be published and if that were done I think we would have sufficient transparency. Q475 Jim Dowd: You said there is general trust in medical research in this country. Is it not the case though that it depends who is carrying it out? I am sure that is true of Cancer Research UK, the British Heart Foundation and others, where they are seen to be a charity or at least not for profit, when they are doing it but when any of the large pharmaceutical companies do it is there not a higher degree of scepticism? Mr Kumar: The surveys we have seen ask the general question about medical research as opposed to the question about who is carrying it out. You see numbers around the 70s and 80s in terms of general support for the carrying out of medical research, so that is the basis upon which I make my statement. Q476 Dr Naysmith: Do people know it is being carried out by Cancer Research? Mr Kumar: The surveys I am talking about are just generally about medical research without saying that we are commissioning the survey. Q477 Dr Naysmith: Dr Solari, in the written evidence you say that industry representatives contribute to the development of MRC policy and funding decisions at strategic and practical levels. How does this happen? Is there an equal, reciprocal arrangement? In other words, does the MRC attempt to shape drug firms' research policy or policy in other areas? Dr Solari: The MRC is governed by a council and there is one industry representative member of council which is a ministerial appointment. It is publicly advertised. That is one person out of about 20. I do not believe there is an undue influence but industry is one of the important partners for the MRC. The MRC has a number of partners. It has the Department of Health; it has universities, other research funders, medical charities and the UK public. What the MRC tries to do is to make sure that on all of its bodies, governance bodies and boards, there are representatives of all of our stakeholders. I think that is one of the great strengths of the MRC, that it is an independent body but that it interacts effectively with all of the bodies with whom it needs to interact. It is part of our remit to have representatives on our council and on our various boards, but I do not believe there is inappropriate influence. Do we influence them? I hope we do. The MRC is one of the greatest supporters of high quality medical research in the world, with 23 Nobel prizes so far awarded to MRC scientists or scientists supported by the MRC. The track record of the MRC is outstanding. I believe we have shaped, biomedical research in a global sense, so yes, I would be surprised if we have not influenced industry. Q478 Dr Naysmith: Does the Medical Research Council decide that maybe something is needed, a treatment or something, and look around to try and influence the pharmaceutical industry to provide that kind of research that will answer the problem that they are talking about? Dr Solari: I believe the sorts of clinical trials that the MRC does and supports are different to the clinical trials that the pharmaceutical industry does so we do not do trials on new drugs. You heard about some of them earlier - the Epsom salts for pre-eclampsia; the use of steroids for brain inflammation following head trauma. They were trials supported by the MRC. Q479 Dr Naysmith: Does the MRC initiate any of these? Do you have anyone looking around and saying, "There is this gap that needs to be filled and nobody is filling it. Can we help?"? Dr Solari: Yes, I believe we do. For example, prophylactic treatment of AIDS patients and young children with antibiotics. That was a gap that was seen by the MRC and the MRC supported that trial and showed that there was a real advantage to prophylactic use of contramoxicil. Yes, I think the MRC does identify those needs. Sometimes they involve a drug that is made by a drug company and so we would ask the drug company to supply that drug for the trial. They are very willing to do that. The large, prospective use of statins to reduce heart attacks and stroke was such a study. It was done in partnership with a pharmaceutical company but it was to answer a very broad, unmet medical need or question for society. Q480 Dr Naysmith: Do you think there are any adverse effects of this not terribly close but close-ish relationship between the MRC and the drug companies, or some drug companies? Dr Solari: Potentially. We have to be aware that they are businesses and they are run along business lines. We are here to serve the public good. We have to make sure that our partnership does not stray into areas where they are driving our agenda. We need the pharmaceutical industry and they need us to deliver improved health care. We have checks and balances. We make sure that there is no undue pressure by the pharmaceutical industry on the activities of the MRC but it is potentially a concern and we watch for it very carefully. Mr Kumar: For Cancer Research UK, I would answer the question in a very similar way to the way that Roberto did. We tend to do two types of clinical trials. We develop new drugs that arise out of the research that Cancer Research UK funds, whether in its own institutes or universities around the country. Sometimes those give rise to new drug possibilities and we will carry out internally the early phase studies on those drugs prior to partnering them with a biotech or a pharmaceutical company. In those cases, all of our studies are entirely controlled by us with no influence from pharmaceutical companies at all. We also do a number of later phase studies and those span every possible type of study you might think of, from the types of things that Roberto was talking about to does broccoli help you avoid bowel cancer, to new studies on drugs either prior to or post registration. In the cases where we are looking at those types of trials, we will always insist that we control the protocol and the study design. To the extent that a pharmaceutical company is involved at all, it would only be to give a sum of money in the form of an educational grant which would simply be for funding data monitors or the supply of a drug. It would not be to have any control over the trial at all. Dr Boyce: We contract a lot of trials for the industry but I cannot name a single instance where they have tried to influence the procedures and the results. They might argue about the interpretation but that is not unusual even amongst academics. If there is a breakdown of trust between the pharmaceutical industry and society, that surely must stem from the breakdown of trust about science rather than the industry alone. I do not think the industry has a patent on lack of trust. That largely stems from the lack of grasp of understanding of the general public. At least that is the way I see it. We can produce evidence that something is not useful but it does not prevent people going on doing it. I wonder how many people in this room took their vitamins this morning. All the evidence is that they are not useful but if you believe published data there will be several people in this room who have taken vitamins. A well informed public is not taking any notice of scientific facts. The trust surely has to start with education rather than the pharmaceutical industry. I think it is a bit unfair to blame the pharmaceutical industry for lack of trust over science. Q481 Dr Naysmith: Sir Richard Sykes was giving the answer to your vitamin thing. There may be a tiny proportion of the population who will benefit but Sir Richard Sykes was saying that very shortly you will be able to identify the relatively small number who want a particular vitamin and make sure they have it. That will be the end of the vitamin industry. Dr Boyce: That is a lovely concept but I fear that Sir Richard is incorrect. Q482 Dr Naysmith: Have you come across ghost writing of papers? Dr Boyce: I have in the pharmaceutical industry, yes. Once or twice I have been asked to do it but they have been multicentre studies throughout the world that I have organised and set up. Q483 Dr Naysmith: You must have lots of people who ---- Dr Boyce: The problem with academics is, despite the fact that they need publication for their success within academia, they are not always good at writing up the publications and they do not always write well. Q484 Dr Naysmith: Do you write for them? Dr Boyce: No, I have never done it, but I have known individuals within a pharmaceutical company write up a publication in which the company was involved. Always, the clinicians who do the study are involved and they have a say in interpretation. If they do not like the conclusions, that is because they have not spoken up. Q485 Mr Burns: When they have been ghost written, from your experience, does it say anywhere in the document it has been ghost written? Dr Boyce: We have to define what you mean by "ghost written". Many professors put their name on the end of a paper written within their own department and they may have very little input into that study. Q486 Dr Naysmith: In my experience they always say, "The original idea was mine." Dr Boyce: Yes. You could argue that the paper has been ghost written for the professor. The difficult bit is getting a blank sheet of paper into a first draft. Lots of people can do that but the honing and shaping requires input from everybody. Providing the clinicians, the sponsors and everybody has two pennyworth, I do not have any strong feelings about who writes the first draft but I do not call that ghost writing. Some people are better motivated than others at writing up papers. Q487 Mr Burns: I recognise that people are very busy but in the non-academic world if a politician, for example, writes his memoirs and they are ghost written it usually says, "Fred Bloggs with Joe Smith." People understand that it is not Fred Bloggs who has written from word one to the last word at the end of the book. If there is a professor who is an acknowledged expert in a particular field of research and his name is put on the document, it will be put on the document for one particular purpose, which is it will seek to give credence to the content of that document because that individual has a reputation for expertise in that field. If that individual has done no work on writing the document and it is the work of others, is that not somewhat misleading and very disingenuous? Dr Boyce: Yes, I agree entirely. There are rules about publication and authorship. In that instance you have just cited, it would be quite wrong of that opinion leader, which is the term people in the industry use for someone that is well known and influences prescribing habits, to allow his name to go onto the paper. Q488 Dr Taylor: Mr Kumar, I was pleased to hear you say that if Cancer Research UK are taking part in a combined study with industry you control the study and the design. You insist on publication? Mr Kumar: We do, of every trial we fund. Q489 Dr Taylor: And the MRC? Dr Solari: I believe it is the case for the MRC as well. Q490 Dr Taylor: I was very intrigued with Dr Boyce's suggestion that a condition of ethical approval should be that results are published. Is that a feasible condition to put on? Is it practicable? Dr Boyce: I believe it is, yes. It is also a requirement of the Declaration of Helsinki, the 2000 version, which has not been recognised under the EU Directive but I think it could be. It is in many protocols. It is also a requirement of good clinical practice that there be within the protocol a statement about publication. If I write the protocol, I always put "if the results merit." Sometimes, despite the fact that they are negative, if you are just doing a single dose rising study to assess tolerability, there is nothing of any scientific value in the study and nobody is really interested in publishing it. It is not hiding it; it just does not merit publication. Maybe when you start to get a randomised trial, which was mentioned by one of the speakers this morning, then obviously I agree it should be published. Q491 Dr Taylor: That sort of very early study probably would not have ethical approval. Dr Boyce: It would. Every clinical trial has to have ethical approval. Q492 Dr Taylor: I thought those were before you got on to the stage of clinical trials. Dr Boyce: Under the EU Directive, since 1 May this year, every clinical trial and investigation of a medicinal product, of a potential new medicine, must now have approval of the MHRA and the Research Ethics Committee. Q493 Dr Taylor: It would seem to me to be a very simple, straightforward recommendation for us. Dr Boyce: Yes. There should be a statement in every protocol. That is good clinical practice. Several years ago I wrote a publication policy for our own company along those lines. Sometimes the pharmaceutical companies are a bit naughty. We do the work but they go off and publish it. They do not tell us. Sometimes they give us recognition but they do not include us amongst the authors. Under the new rules of authorship, that is probably okay but it is very discourteous to publish something that somebody else has done and not tell them. Usually when we publish there is good collaboration. We discuss the paper. We have different interpretations. We come to an agreement about the wording. In the early stages, it is researched. It is in nobody's interests to distort the results in early studies. Everybody wants to know: is this a useful medicine? Does it need to go into late development? If not, it needs to be put in the bin and another one tried. Q494 Dr Naysmith: When I talk about negative results, it is when you do three or four trials and most of them are negative but one shows up as positive. You then suppress the four or five and use the one that shows that your drug is accurate. Dr Boyce: That is quite wrong. Q495 Mrs Calton: It seems to me that there is room here for a grey area around the decision not to publish trial results or parts of them. Who makes the decision? Dr Boyce: For the research that I do, we make it as a group. Often I say, "This is a very interesting result. It adds to the literature. We should publish it." Nowadays, somebody else writes the first draft. I never allow my name to go on a publication unless I have had a substantial input into it. Until recent years, I always seemed to be the fall guy who wrote the first draft and took it through because I enjoy doing that. There is nothing better than doing a study with a brand new molecule and getting a very interesting result that is going to set the development in process. The decision is usually made amongst the group, as in academia. Q496 Mrs Calton: Can you tell me who the members of that group would be? Dr Boyce: It would be the clinical pharmacologist doing the trial and representatives within the pharmaceutical company. Q497 Mrs Calton: Would they ever say, "We do not think this should go forward"? Dr Boyce: They may, yes. I have cited examples where it has happened to me, where I have said, "I would like to publish this. It is in the protocol. It says, 'if the results merit'" which is usually my phrase. Then either the sponsor or us, the investigators, will write the first draft and send it to all the other individuals involved in carrying out the trial to comment in order to hone and polish the final paper. It is a group of people but occasionally when I have initiated that process the pharmaceutical industry says no. That has happened to me and I have always battled against it. I could give you examples. Once, when I worked in a pharmaceutical company - this is going back 20 years - when I wanted to publish something, I had agreement with academics. They said, "Will we be able to publish this?" I said, "Yes" and I put that in the protocol. It went through a protocol review process so the people in the company had seen it. I was not doing things on my own. When we wanted to publish it, we wrote the first draft and I submitted it to the company for comments. They said, "No, you cannot publish it." I said, "But you said earlier on I could" and I was threatened with a High Court injunction if I went ahead to do it. Unfortunately the academics backed off, not me. I was in the company. I was left very vulnerable for a period. It was published a year later. A lot of the time it is a storm in a teacup. There is not the need for secrecy in the early clinical development. Once a new molecule goes into subset humans, it does not go into humans until it is patented and protected. Then you have to produce an information leaflet for the subject. Aunt Mabel would know about it and the man in the street might be a volunteer. Why should it not be published? There seems little point in holding back. Q498 Mrs Calton: Effectively, from what you are saying, the sponsoring company that clearly has an interest might well block publication? Dr Boyce: Yes, often for the wrong reasons. Q499 Mrs Calton: Whatever the reasons, the point is the public and those who are buying the drug subsequently ---- Dr Boyce: This may be ten years away from becoming a product that is sold to the public. The attrition rate is very high. Mr Kumar: I think there is a relatively simple way of overcoming the greyness that you describe which is if that drug ever does make it to market, regardless of what the reasons were for not publishing when the early phase studies were done, whether it did not merit or commercially in confidence, as and when a drug hits the market all data should be published. That way you overcome any greyness that there might have been through the process. Q500 Mrs Calton: Earlier you said that Cancer Research UK would always publish the clinical results of the studies. Mr Kumar: We insist on publication. Sometimes, if we fund academics in universities, we do not employ those people. We can put pressure on them to do it but the terms and conditions are that they must publish. Q501 Mrs Calton: They must publish all parts of all studies? Mr Kumar: Everything, yes. Dr Taylor: By making publication a condition of approval, we remove the grey area and I hope that is a recommendation we will come to. Q502 Jim Dowd: Has anybody ever resisted that? Mr Kumar: If they do we do not fund them, but I am not aware of anyone. Q503 Chairman: Dr Boyce, on the issue of patient involvement, we were interested in Australia to see more patient involvement there in the research and approval process than we have here. I wondered how could the conduct of medical research be improved in terms of patient involvement and consent to the publication of the data obtained from all clinical trials? Have you any thoughts on this? Dr Boyce: Yes. The problem with the trials that we do is that the subjects are mostly healthy volunteers. By the time we get the results, we have lost contact with the subjects. Many of them do not want to know the results. That may seem strange but they do not. There are requirements within the European Clinical Trial Directive which encourage researchers to give their results to the research subjects. There is already the concept within the legislation - and as you well know the Directive is law - to encourage subjects to have access to research information. In the very early clinical trials, often the results do not mean very much to a healthy subject unless they are interested in the science or the medicine. Dr Solari: The MRC has an active policy called "Science in Society" which is to enhance the public's engagement in medical research, in clinical trials and health practice. We are very active and we commit a certain amount of our funds to trying to engage the public in a greater awareness of how medical research is performing. Q504 Chairman: Have you looked at examples from anywhere else in the world? We went to Australia specifically but I am sure there are other countries who are engaging with patients in a way that maybe we are not sufficiently. Dr Solari: I would have to check with the office. Mr Kumar: For all of our late phase trial work, that is carried out as part of a partnership through the MCRN, for all cancer trials. There is a very specific consumer liaison group that is involved in the design of all those studies and the initiation of several of them. Q505 Mr Bradley: Mr Kumar, you say there is a lack of industry funded research into studies that might identify the specific patient who might benefit from a treatment. Can you explain what the problem is, how it has arisen and how it can be solved? Mr Kumar: The problem is that the vast majority of drugs will typically benefit only a subset of the population who receive them. Historically, we have not had the technology to be able to distinguish between the patients who would best benefit from a particular treatment. I believe the technology is now there. It is still in its infancy but nevertheless it is there. Within CRUK, for instance, we are now initiating what we call translational studies on all of our clinical trials to try to determine as much as we can during the course of the trial about the specific subsets of populations that will specifically benefit or not benefit, or who may have adverse reactions or not have adverse reactions. You will see an acceleration of this over the coming years. The problem with respect to pharmaceutical companies is that the corollary of that is that it is a reduction of market size. There is not necessarily the incentive for pharmaceutical companies to do that, although it is not absolutely as black and white as that. Sometimes, if you can absolutely pinpoint the patients who will benefit, you have a greater chance of getting that drug to market. We would advocate a partnership between the NHS, the pharmaceutical industry and organisations like ourselves to carry out these studies because, from the point of view of the Department of Health or the NHS, there will be savings on the drug budget if we target the treatment to the patient who will most benefit. Q506 Mr Bradley: Presumably you have had discussions on those lines. What sort of reaction have you had to that proposal? Mr Kumar: The pharmaceutical companies we talk to are increasingly waking up to this as a necessity. I think we are pushing against an open door. Dr Solari: From my experience, having worked in the pharmaceutical industry for about 12 years, the right drug to the right patient is a concept coming out of improved genomics and molecular biology. We are not there yet. I think it is still a wish and we are still many years away from that. I think the pharmaceutical industry is very aware of this and is investing a great deal of money. The jury is still out though on whether it will fracture markets and decrease their profit margins or whether it will create new opportunities for them. Until these technologies have really matured, I do not think it is clear which way it is going to go. Dr Boyce: A large proportion of the early clinical research on potential new medicines is molecules from outside the UK. Two thirds of our work comes from companies outside the UK. When I am talking about pharmaceutical companies, I am talking about the global industry. I am not just talking about the UK. The examples I have given are not necessarily in the UK. They may be in America or Japan. Q507 Dr Naysmith: This is a question again for the Medical Research Council. You have said in your evidence that you need to avoid duplication of research. Personally, I would not avoid duplication. I would certainly want to avoid triplication and quadruplication but sometimes it is good to have checks and at least one other group working. Why do you think this is so important and what can be done to ensure that duplication does not take place? Dr Solari: Are you referring to early, basic research or to more late stage, clinical type research? Q508 Dr Naysmith: I think both apply. You would have less control over the early, basic research, I suspect. Dr Solari: As an academic yourself, you know that we do not read publications that are more than ten years old generally. As scientists, we often repeat what has gone before without reading the literature. We want to avoid wasting the public's money repeating studies. Q509 Dr Naysmith: You do not want to rediscover the stuff that has already been discovered. Dr Solari: You do not want to rediscover it but it is an important part of the academic process that a piece of research should be able to be replicated in another lab. That adds to the validation that it is correct. That is all part of the publication process. I think that is very important. Sir Iain was making the point earlier that systemic reviews on all the literature are very important for the whole progression of medicines to man and I think the MRC would endorse that observation. Q510 Dr Taylor: Mr Kumar, trials of combination therapies are particularly important in cancer and other diseases and I think you tell us that sometimes the companies do not make their products available for these combination trials? Is that a problem? Can you give a bit of detail? Mr Kumar: I do not think I can say that we have lots of evidence that companies do not make their products available for combinations but I think this is again an emerging area in cancer drug development. There is a wide expectation that combination therapies are the way forward. It is for commercial reasons difficult for pharmaceutical companies to test their drugs in combinations with the drugs of their competitors. It is an opportunity; it is a responsibility that organisations like Cancer Research UK see for themselves, to undertake that kind of research and what we would then seek is the cooperation of the pharmaceutical companies in making those drugs available to us to test those combinations. Dr Solari: In the MRC I do not believe we have had any experience of difficulties. Drug companies are willing to provide their drugs for combinations. The breakthrough, for example, in childhood leukaemia has come about because of new combinations of drugs. Q511 Dr Taylor: We do not need a strong recommendation for that? Dr Solari: I do not think so, no. Q512 Mrs Calton: Dr Boyce, does your contract research organisation carry out any studies that you think are for marketing purposes as opposed to understanding how the drug works or how safe it is? Dr Boyce: No. Q513 Dr Naysmith: People have suggested to us that it would be a good idea when a drug gets to its pre-market stage that the regulatory checks that have to be carried out on it are carried out by an independent unit that would do clinical trials independently of the industry. Presumably the Medical Research Council could do that sort of thing and if you do not think it is a good idea tell us why not. Dr Solari: I think the MRC could do it. It has the infrastructure to do it along with the Department of Health. I am sure it does not have the budget. Q514 Dr Naysmith: Always assuming that the budget will come. I know these promises are not always acted on. Dr Solari: It is an interesting idea. I would need to think about it a little more rather than giving an off the cuff reply. Chairman: Write to us because obviously that would be very helpful. Q515 Siobhain McDonagh: Mr Kumar, you are concerned about the influence that the industry has on the topics chosen by NICE. Why are you concerned and what problems might arise if there was excessive influence? Mr Kumar: We were concerned that there was a lack of transparency on the topics chosen by us. I do not think we would say that there is an inherent problem but that we do not know if there is a problem. What has happened over the last several months is that my understanding is that NICE now, at least as far as cancer appraisals go, relies on the NCRI, which is a forum of all the major cancer research funders, to determine or at least to take advice on the areas that should be addressed. At least as far as cancer is concerned, I think we have moved forward. Chairman: Gentlemen, can I thank you for what has been a very valuable session? It has been rather short and somewhat constrained by time but we appreciate the help you have given us. Thank you very much. |