Select Committee on Health Minutes of Evidence

Examination of Witnesses (Questions 440 - 459)



  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, 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 public values 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 access the 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 15 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 15.

  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 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 Vioxx 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 Vioxx, 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 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 patients may not value, but which is seen as relevant . In those circumstances, if you want to find out whether it holds value for the patients, 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 to prevent arrhythmias because arrhythmias were a risk marker for subsequent premature death. These drugs were very good at suppressing arrhythmias , 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 all the 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 a drug or a device or a surgical operation—only in the context 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 Vioxx, 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 estamlishing 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% of the world market.

  Q455  Dr Taylor: By pure chance we started this inquiry at the stage when Vioxx 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 industry, if it is not 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 the scientific record, which at the moment is indefensible, and sly 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.

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