Select Committee on Health Minutes of Evidence


Examination of Witnesses (Questions 680 - 699)

THURSDAY 13 JANUARY 2005

MR EDDIE GRAY, DR STUART DOLLOW, MR CHRIS BRINSMEAD AND DR JOHN PATTERSON

  Q680  John Austin: Can I go back to something you said earlier about when there was a discussion about the media and the way in which the pharmaceutical industry may be now viewed because of high-profile and perhaps exaggerated claims in the media, for example, "New blockbuster drug—miracle cure", et cetera. You seem to be suggesting that the media were at fault here. Is not the industry sometimes at fault by having sort of over-inflated claims for some of its new products? Perhaps I could put the question back to AstraZeneca and let's take Iressa, an innovative cancer drug, which you say in your evidence to us has been described as "the biggest advance ever in the treatment of lung cancer", yet I understand that last month the Food and Drug Administration indicated it was considering withdrawing Iressa from the market after the drug had failed to prolong the lives of people with advanced lung cancer. Are there any lessons which we should draw from this?

  Dr Patterson: Well, there are lots of lessons and I could spend a long time talking to you about them. Let me come back to your first point though, that somehow I had implied it was all the media's fault which I think the Chairman said in response to my first answer. I am not saying it is the media's fault. I am saying it is an outside world that has changed and that that activity is going on and, therefore, that is why there is so much visibility of what is happening with our products. Let me now switch to Iressa. It is a classic example of where sometimes we are damned if we do and we are damned if we do not. Perhaps later on you will be talking to us about only doing me-too products. Well, here is a very good example of something that is an absolute breakthrough product, brand new type of agent, an EGF (Epidermal Growth Factor Receptor) tyrosine kinase inhibitor, based on very good pre-clinical science and brought to the marketplace in Japan and the USA and a European licence applied for. The early data showed some dramatic responses in patients with lung cancer, many of whom had failed all previous therapies, actually having a complete regression of their disease and some of them going on to live for several years on this product and with very few side-effects, which is something that just does not happen spontaneously. In the open studies in third-line usage in previously failed patients we saw and we treated something like 70,000 patients, stabilising disease in about 40% and about 10% of them giving a very significant response. Now, interestingly enough, there were certain sub-groups who showed a very good response, in particular females and oriental people, Asian people particularly from Japan. We then achieved a licence in the United States under a system that does not exist here, called "Sub-part H" in their procedure which allows you to enter the marketplace while undertaking what are called "the definitive trials", and in this case the definitive trial was a placebo-controlled mortality or survival study in a very significant number of patients followed all the way through to death. That study was undertaken and unfortunately, (in spite of some of the evidence you have had, to the contrary) our studies are designed to give both positive and negative outcomes, they are balanced, this one showed that although there was the same response rate as we had seen previously, the same time to treatment failure, the survival benefit did not reach statistical significance. As a result of that, our European licence, which was under review, was withdrawn and we had further discussions with the Food and Drug Administration and we will go through some advisory committee processes as to whether it is appropriate to continue to sell that product. We have withdrawn all of our marketing support of the product while those discussions are ongoing. Interestingly enough, within that there is a sub-group of patients from South-East Asia who had a very good survival benefit, some 22%, so we are learning a lot about it. During the course of last year some doctors in the States described some mutation changes that seemed to associate with those people who were getting these very good proven responses, so it may well be we will be back later in the year to say that there is now a sub-group of patients whom we can identify who actually will be the correct sub-group of the population to give this agent to and who will much more likely get survival benefits. It is a rather long answer, but it is a classic example of how we, as an industry, develop modern, very potentially effective, but completely unknown medicines, the kind of issues we can get into and the kind of science we have to keep putting into these products over many years to get all the right answers.

  Q681  Dr Naysmith: Maybe the question I am about to ask is perhaps related to what you have just been saying in terms of the information you get from clinical trials, how they are designed and so on and how you get the right answer because we have heard quite a lot of evidence here to suggest that the design of clinical trials and the manipulation of the results is sometimes done in a way which favours the product which is about to be launched, things like what you actually test the product against, how much you put into negative results, how many negative results are published and that sort of thing. Perhaps Dr Dollow, who must have had a lot to do with a number of clinical trials, would like to suggest, if there is this criticism of the way clinical trials have been carried out in the past and you agree with it, why people, patients and clinicians, should trust the information they get from you in other ways?

  Dr Dollow: Well, I think it might be helpful if I explained to the Committee how we design our overall clinical development programmes. When we are looking at a potential medicine before it actually gets to even getting to a pill that a patient might take, the programme is designed, first, to see if it has acceptable efficacy and safety in the target that we want and then we design the programme, saying that assuming that these are going to be correct, we will look at our phase two, for example, dose-range finding studies and then our phase three studies. All of these will be pulled together and seen as a global programme. We discuss this programme with regulatory authorities across the world and we discuss it with experts in the field to say that in some cases with some of the studies there is a need to prove that the product has some efficacy, and those will be, for example, placebo-controlled studies. In other cases, it is important to see the incremental benefit that a medicine may bring and those will be comparator studies, and the way we choose our comparators would be looking at which are important medicines which are being used across the world, so because all of our studies or the bulk of our studies are multi-national studies, something that is important in one market may not be important in another market, so we will look at that in the round. The other thing you talked about was around disclosure and, just to reinforce the point that Eddie made earlier regarding the clinical trials register, every single one of our studies for our medicines from the earliest clinical pharmacology studies in healthy volunteers through to every single clinical study that is done subsequently will be made available on the GSK clinical trial register at the time that medicine is first launched, and then subsequent studies will be publicised within 10 months of each study finishing.

  Q682  Dr Naysmith: Are you saying then that it is impossible to carry out trials at any stage in the procedure you have just outlined which produces negative results and for that not to be known?

  Dr Dollow: I think it is certainly possible that studies produce negative results, and John Patterson just gave you a very good example of when a study produces a negative result. We always try to publicise one way or another the results of our studies and we know and, as evidence you have heard previously has shown, the journals are actually sometimes reticent to publish negative studies. If I look at The Lancet or the BMJ websites, they say that they actually only publish around 10% of all the studies they receive, so as a result some of our studies are put into journals, some of our studies are published as abstracts and some of them are presented at conferences.

  Q683  Dr Naysmith: I am not saying it is necessarily your fault, but that in this whole process what sometimes obviously happens, and some of our witnesses have told us this, is that results are cherry-picked out of a pool of possible results to establish the effectiveness and sometimes the safety of products and others which might be used for other purposes are kind of ignored and sidelined.

  Dr Dollow: All I can tell you is our position, that, firstly, we endeavour to publicise the results of all of our studies, be they negative or positive, and, secondly, the clinical trial register will put an equal footing on that for all of GSK's studies from the year of the start of GSK in 2001.

  Dr Patterson: Perhaps I could just add a couple of things to that. First of all, when we apply for a licence to sell a product, we submit data on every single patient who has been treated with that product in positive or negative studies, the whole lot, so there is absolutely no selection, whether it is on efficacy or safety, and all licences, therefore, are granted on the totality of the evidence.

  Q684  Dr Naysmith: So where do you think this comes from, that witnesses have been telling us that sometimes there are negative results which are not published?

  Dr Patterson: Once the product is in the marketplace, then we continue, as I said earlier, to undertake clinical trials and we have had a policy within AstraZeneca now for a number of years where we would seek actually to publish all of our clinical trial data and we have lots of examples where we have done that. There is a product called Viozan that failed in phase three trials and we published all of that data in a supplement to one of the journals, but, as Dr Dollow says, it is not always easy to get negative results published and that is why I think, in response to the questioning that is going on, we are saying that perhaps the best way is we are going to put them up on a website ourselves and then everybody can see. The other criticism that some of your witnesses have given in the past is this one that we pick the easy comparator, we just go against the old medicine. I think the example they used was the COX-2 inhibitors and why did not Vioxx compare with Celebrex. Of course that is an interesting one because at the time when they were both doing their phase three trials and they were within one to two years of each other, remembering you do your phase three trials and they take about two years to run, you then go through a registration process which takes maybe another two years, so there is a four-year window, therefore, by the time they got to the market, neither product could possibly have done a comparison with the other one because it was not a registered, marketed product, so they did comparisons with Naproxen which was at that time the gold standard in non-steroidal anti-inflammatory drugs and they could not have done anything else. Post-marketing, then you can do head-to-head comparisons and most of our products that are coming to the marketplace now, unless we have done a head-to-head comparison with the market leader, and that can be, by the way, by volume use as well as by value and I suspect Naproxen is still probably, by volume, the market leader, then we are not going to get on to formularies and get acceptance.

  Q685  Dr Naysmith: Well, that brings us on to another topic which, I must say, has really surprised me since we started this inquiry, which is the question of ghost-writing and looking around for clinical scientists and medical scientists who have the reputation to put their names on papers which carry data which they themselves have not had very much to do with and may even know nothing about. Do you think that this practice is widespread?

  Dr Patterson: It is absolutely not practised in my company. We have a set of publication policies that we have had in place for a number of years and we work with doctors in the outside world in our clinical trials. Perhaps I can take a step back and just give you an example which I brought with me from a phase three clinical trial that we ran on an anti-coagulant. It was undertaken in 260 hospitals with some 3,400 patients. The amount of data that generates is staggering, with 16,000 events monitored, 30,000 blood samples, 50,000 patients visits, a total of 12.5 million data points. We then, as the company, analyse, collect that, quality-assure it by AstraZeneca personnel to make sure the data are correct at the hospital sites, and we then turn it into a report that is some 200 pages long. Those kinds of studies we start by having a group of doctors working with us or an individual who will help us design the study and they will stay with the study throughout. We will often have a separate data-monitoring or safety committee which will look at the data to make sure we are doing no harm during the course of it, and at the end of it we do employ professional writers within the company to turn that 200 pages into a draft publication, but it is done with the people who are going to become the authors and they have the opportunity to question and challenge every single conclusion and every single table that is put in there. At the end of the day they have a responsibility, just as we have the responsibility for getting the analysis right, in putting their names to it to say that they have taken adequate care and worked with us to deal with it, so that is, if you like, the one extreme.

  Q686  Dr Naysmith: I am not going to stop you saying any more, but if that is an example of what happens and you are talking about a really big trial, sometimes there will be, and it is hard to say how many, but dozens of names of people who have been involved in the trial.

  Dr Patterson: Yes.

  Q687  Dr Naysmith: So how would you decide which names go on the scientific paper?

  Dr Patterson: Well, there was actually in the case of this trial, and I have got a flow diagram which I can show you, the committee which we had set up to begin with which met and had a meeting to decide whose names would go on it. It is often quite a fight amongst them as to who goes on it, but then whoever does will get the responsibility on behalf of the others to make sure it is right. That is no different from, say, something that the Medical Research Council runs as one of its major trials or other co-operative groups outside of the industry itself, so yes, you will get a small number of names and if there is a significant AstraZeneca author as part of that, we would hope and expect that their name would be there as part of that report.

  Q688  Dr Naysmith: But you are saying that you would never seek someone who may be someone who is also a scientist at an institute where this trial has been carried out who is a big name and well known to put their name to the paper, not having been involved throughout?

  Dr Patterson: And not gone and worked through all the data and not had the responsibility? That is an absolutely unacceptable activity.

  Q689  Dr Naysmith: From what you have said, Dr Patterson, do you think that the stuff that we have had describing this, that it would not be an acceptable practice and do you think it would be open to abuse, what some of the witnesses have said to us?

  Dr Patterson: If what the witnesses are saying is correct and they have evidence to support it, then I think it is an unacceptable activity. The idea of hawking around a set of results and a cheque book and saying, "Put your name here and we will give you some money" is against every principle that we and the medical journals live by.

  Dr Dollow: I was just going to add to John Patterson's point that the International Committee of Medical Journal Editors have set out some guidelines for authorship and they read that, "Authorship should be based upon substantial contributions to conception, design, acquisition of data, analysis and interpretation, drafting the article, revising it critically for important intellectual content and final approval of the version to be published". That is something that we strictly abide by. We may well have people who put the first draft together, but absolutely those people who put their name to the authorship must have been involved at every step of the way. It says, "Authors should meet conditions 1, 2 and 3". The other thing that Dr Horton mentioned in his evidence was that people who contributed can also be listed as contributors, if not formal authors, and again that is something we support as well and is something we have been doing for many years. The issue of ghost-writing, as alleged, is not something I recognise at all.

  Q690  Dr Naysmith: So you would say that it is an unacceptable practice if it does happen, trying to get a prominent scientist or a prominent medical person to put their name on it without having any kind of involvement in the process at all?

  Dr Dollow: We would not support that in any way, shape or form, absolutely not.

  Q691  Chairman: Are you saying in your experience that it does not happen within the industry? You have explained your own company's position on this, but it does not happen in the industry, as far as you are aware?

  Dr Dollow: I can only speak for GSK. My personal experience is that I was working for one other company before I worked with GSK and it certainly did not happen in that company and I have been in the industry for 14 years now.

  Q692  Chairman: But you are not making the point that it does not happen at all, but that in your experience of the company you worked for and your current company it does not happen?

  Dr Dollow: Absolutely.

  Q693  Dr Naysmith: Is that the same for Dr Patterson?

  Dr Patterson: It is completely unacceptable in my company, but I cannot say it has not happened in other parts of the industry.

  Q694  Mr Jones: I just want to clarify a slight ambiguity that I thought arose in those two answers. When Dr Dollow read from a code of practice, one of the requirements was that the author drafted—

  Dr Dollow: ". . . a substantial contribution to drafting", so they have to have been involved in reviewing and writing, so absolutely, yes.

  Q695  Dr Naysmith: But in Dr Patterson's answer, he referred to professional writers, so perhaps you forgot about the drafting.

  Dr Patterson: Not at all, no. We do employ professional writers and they are involved. Most of them are not experts in that particular field of medicine, but they are very good at writing good English and they also understand what it takes to write an article that can be published.

  Q696  Dr Naysmith: Perhaps we have difficulty in understanding what "drafting" means then. If the person whose name is at the bottom did not either write part of the article or how the article would come out, then they did not have any involvement in drafting, as I understand drafting, and, therefore, the code of practice is broken.

  Dr Patterson: The way that it works with professional writers is that they will possibly produce a first draft which will then be reviewed by the author or authors or a committee and who will have significant input into that drafting and how it should then subsequently go forward, so we start with a 200-page report, as I described, and the medical writer will then pick that up and try and turn it into something, if it is going into The Lancet, that is in the format that these people recognise, remembering that many of the senior doctors who have worked with this may not have English as their first language or are not going to have the time, the effort and the knowledge as to what it takes to have the right format for these journals. That is drafting, but that is not the whole of the drafting. It then goes through a series of iterations.

  Q697  Dr Naysmith: I would guess there would be a problem if you are talking about translators. I think I would not be asking these questions if you said you employed translators.

  Dr Patterson: No, this is not a translator who takes somebody's foreign language into English. This is somebody whose native language is English who is a professional writer who takes a report and turns it into a draft which would be acceptable to a medical journal.

  Q698  Mr Burns: Just to clear this up, maybe you could help us with this analogy. Between 1994 and 1997 in particular, but also thereafter, there were dozens and dozens of articles that appeared in papers like The Sun, The Daily Express and The Daily Mail, written by Alistair Campbell or Peter Mandelson, but having Tony Blair's name on them, although he had clearly never seen the articles! What you are saying is that that does not happen, but there are some people who may not be as fluent in the English language who need a professional draftsman to put their thoughts and their research into English to make a compatible article for reading. Would that be helpful?

  Dr Patterson: Yes, or who even collects together the information for a first draft from which you can then present your thoughts.

  Q699  Mr Burns: But it is more accurate that way than just having some skivvy writing an article for a newspaper that you have never seen until you read the newspaper?

  Dr Patterson: And then putting somebody else's name to it, correct.

  Chairman: Are you making a point there, Simon!


 
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