House of COMMONS









Thursday 20 January 2005




Evidence heard in Public Questions 774 - 910





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Oral Evidence

Taken before the Health Committee

on Thursday 20 January 2005

Members present

Mr David Hinchliffe, in the Chair

John Austin

Mr Keith Bradley

Mr Simon Burns

Dr Doug Naysmith

Dr Richard Taylor




Memorandum submitted by MHRA

Examination of Witnesses


Witnesses: Professor Sir Michael Breckenridge CBE, Chairman, Professor Kent Woods, Chief Executive, and Dr June Raine, Director, Post-Licensing Division, Medicines and Healthcare Products Regulatory Agency (MHRA), examined.

Q774 Chairman: Colleagues, good morning. Can I welcome you all to this session of the Committee and welcome our witnesses. Can I thank you for your co-operation and for your evidence to us; we are most grateful. Can I ask you briefly each to introduce yourselves to the Committee.

Dr Raine: Good morning. I am Dr June Raine. I am the Director of the Post-Licensing Division at the Medicines and Healthcare Products Regulatory Agency and my responsibilities include all the issues that relate to medicines once they are authorised for use on the market.

Professor Sir Alasdair Breckenridge: I am Alasdair Breckenridge, I am the Chairman of the Board of the MHRA.

Professor Woods: Good morning. I am Kent Woods and I am the Chief Executive of the MHRA.

Q775 Chairman: Can I begin by asking you this, Sir Alasdair: you have been around for quite a long time in this whole area and obviously you have got some pretty detailed knowledge of many of the issues that we have been addressing during this inquiry. We are now towards the end of the inquiry and I have no doubt you will have been following some of the sessions and some of the evidence that we have had. What is our view, from your background, of the key issues that perhaps have been picked up in this inquiry in relation to the medicines regulatory system?

Professor Sir Alasdair Breckenridge: I think one of the impressions that I have gained is that a lot of the discussions which have taken place have referred to what happened many years ago in the old Medicines Control Agency and the one thing that I would like to stress is that since the MHRA came into being in April 2003, there have been many, many changes in the way in which the organisation works, partly because this is the aim of the organisation itself and partly because the climate in which medicines regulation takes place has changed totally.

Q776 Chairman: So what you are saying is that some of the evidence that we have had is outdated? Could you give examples in particular where you feel that the situation is being inappropriately represented?

Professor Sir Alasdair Breckenridge: Well, it is not misrepresented, but there was quite a lot of discussion about how the Agency did not release information, for example, on human albumen and on some of the other issues in the early 1990s. Well, we have changed that now and there are two big things which we are actually changing. One is the transparency under which we work and secondly is the communication skills which we have put into being, and there are some very important examples which I am sure we will be coming back to in terms of transparency. For example, you are aware of the report which the Agency published on the SSRIs at the end of last year and the other report which we put into the press in May 2003. Well, as part of that, we published all the evidence, published and hitherto unpublished, on which the Agency made its decision. Now, people may look at that evidence and disagree with it, but at least they have the evidence on which we made our decision, so that is the kind of thing which we are determined to do now and we are doing.

Q777 Chairman: I think that was a good example which will probably be picked up by one of my colleagues later on, but in terms of the future, do you see, from the evidence that we have picked up, any particular key areas where you perhaps would suggest there is a need for change?

Professor Sir Alasdair Breckenridge: I think that the other area that I would pick up is that of the education of the public in terms of risk and benefit. A lot of the discussions which have taken place in the Select Committee have been about the safety of medicines and relatively little about this concept of risk and benefit. When we change a licence, we do not do this purely based on a safety profile of a drug. If we did this, there would be no anti-cancer drugs available and there would be no anti-HIV drugs because the adverse reactions to them are huge. They have got to be balanced against the benefits which these drugs have and the one thing which I would like to see you concentrating on, with all respect, is this concept of risk and benefit. We are going to be communicating that very strongly with our new communications set-up, but I would like to see that as one important aspect coming through from this Committee.

Q778 Chairman: You had in 2003 a report from the NAO which was somewhat critical about your external profile. We have got a rough idea of the main findings. Now, in terms of the way you suggest that the information we have received perhaps is a little dated from some of the witnesses that we have had and some of the representations we have received, in relation to those findings what steps have been taken to address them and perhaps what further steps might you take in the light of some of the issues that we have picked up?

Professor Sir Alasdair Breckenridge: The main thing which the Agency did when it received this report is that we commissioned a report on our communications strategy and this reported to us in June 2004 and there were many recommendations from that report which we took up. The main two which we have acted on are the two I have mentioned already, firstly, setting up communications, and this is absolutely critical for an agency like ours. In the past, the old Medicines Control Agency and Medical Devices Agency, working in a different time, did not see this as one of their main purposes. Now it is quite clear, and we are determined, that this is one of ours. The second one is the issue of increased transparency and I have already mentioned the example of SSRIs. The other thing which we have done is that as of the middle of this year, when we give a licence, we will be issuing what we call a 'United Kingdom product public assessment report' which will give data of all the clinical trials on which we made our decision, so the public will be able to see again the evidence on which a drug has been licensed. The third part of the transparency move which we have made is that we have reviewed the yellow card system. This was done independently and we might be coming back to that later, but in fact as of this week we have published on our website all the adverse reactions to every licensed drug and this is accessible to everyone, suitably 'anonymised'. Therefore, we have taken concrete steps with respect to transparency, communication, and the other question which was raised by the National Audit Office was the question of interests and we have moved on that both with respect to the staff and with respect to the committee structure, and we can deal with that. The final one which I would mention is that we have increased greatly the patient voice in medicines regulation. We have been conscious for a long time that regulation was too inward-looking, not involving the public enough, and we can discuss again in some detail how we are actually increasing the patient voice in regulation.

Q779 Chairman: So taking account of the views we have had expressed about your external profile as an organisation, how would you describe it now?

Professor Sir Alasdair Breckenridge: We are moving very quickly from the time when we started business in April 2003 and if someone who worked in the Agency even in the early part of the 2000s came back and looked at the work that we are doing now, they would find huge changes.

Q780 John Austin: Can I raise the issue of Seroxat and your knowledge and involvement. In 1998, I believe you were on the advisory board of GlaxoSmithKline or SmithKline Beecham, as it was at the time.

Professor Sir Alasdair Breckenridge: No, let me just clarify that. From 1992 to 1997 I was a member of a scientific advisory committee of SmithKline. I resigned from that in 1997. This had been an extremely valuable exercise for my development in medicines regulation. We did not discuss specific products on that board; it was a matter of the larger picture of industry. I resigned from that in 1997 and this post had been taken up with the full cognisance of the then MCA. I discussed this with the MCA and I acted in a totally appropriate manner with respect to the decisions that I was party to there and in the drugs and medicines regulation.

Q781 John Austin: I was not suggesting otherwise. My question was whether you were aware or whether the company made you aware at the time of any testing that they were doing in relation to Seroxat and the use of Seroxat for children.

Professor Sir Alasdair Breckenridge: We never discussed any medicines at all. That was never part of the remit of the scientific advisory board.

Q782 John Austin: It is clear now that the company were aware of some negative results, particularly in terms of withdrawal. Were those ever communicated to you either in your role with SmithKline Beecham or subsequently in your role with the Committee on the Safety of Medicines or the MHRA?

Professor Sir Alasdair Breckenridge: With respect to me, as I have said already, certainly not and perhaps Dr Raine might like to answer the question about the communications of the Agency, if that is your wish.

Q783 John Austin: I also note that we do not have Dr Ian Hudson with us this morning, although he was listed as one of the witnesses. Is there a reason why not?

Professor Sir Alasdair Breckenridge: Yes, Dr Hudson is one of our delegates at the CHMP, the Committee on Human Medical Products at the EMEA and he is there today. He is fulfilling a different role for the Agency down there.

Q784 John Austin: Would he have been able to answer the questions and would he have been aware?

Professor Sir Alasdair Breckenridge: I cannot answer that on his behalf.

Q785 John Austin: What was his role at that time?

Professor Sir Alasdair Breckenridge: I cannot answer that question. I do not know that.

Q786 Chairman: He is a colleague in the Agency ----

Professor Sir Alasdair Breckenridge: He is the head of licensing in the Agency.

Q787 Chairman: Obviously he played a very key role in this respect and you have no knowledge of what that role was? You have not discussed it with him at all?

Professor Sir Alasdair Breckenridge: No, I have not discussed it with him. He was appointed to the Agency in 2000 because he was the best candidate for the job to head up the Licensing Division.

Q788 Chairman: And in advance of today's session, where no doubt you would have anticipated that this issue would have been raised, you have not discussed the possible involvement he may or may not have had?

Professor Sir Alasdair Breckenridge: I have not discussed that with Dr Hudson at all. I do not know whether any of my colleagues have, but I have not.

Q789 Dr Taylor: Would you be expected to be aware of everything that goes on in, for example, the expert working groups because we are told quite clearly that the expert working group on SSRIs was given evidence more than 18 months ago that withdrawal did cause suicidal hostility. Is it beyond the possibility of a job as large as yours to keep tabs on absolutely everything that goes on?

Professor Sir Alasdair Breckenridge: Well, it is, but I have an interest in the field, having served on the Committee on the Safety of Medicines, and I am aware of the recommendations as they went through, but I was not a member of the working group and it was not my role to be at them.

Dr Taylor: So we really have not got anybody here who can answer that specific question?

Q790 John Austin: I think it would have been useful if Dr Hudson had been here because, as far as I understand, he was at SmithKline Beecham and his department was responsible for the collection of adverse reaction information such as there was with Seroxat.

Professor Sir Alasdair Breckenridge: Yes, I know that, but I ----

Q791 John Austin: So he would have been a very key witness.

Professor Sir Alasdair Breckenridge: But I have not discussed that with Dr Hudson.

Q792 John Austin: So you must admit that it is very unfortunate he is not with us today?

Professor Sir Alasdair Breckenridge: Well, I apologise for that, but I think there was some confusion about who was going to attend and I think the Clerk was told that this was where Dr Hudson was going to be.

Q793 Chairman: It is a little bit strange then with an issue as sensitive as this that there appears to have been no discussion within the Agency. Does Professor Woods want to come in at this point?

Professor Woods: Yes, I would like to answer that because I do have some information which might be helpful to you. As Chief Executive, I have discussed with Dr Hudson his previous role within GSK in relation to the specific question of Seroxat and he assures me that he has had no direct personal involvement in those safety issues. However, because of his role within the company, we agreed, and have since scrupulously observed, that he should have no role within the Agency in any decision-making concerned with Seroxat.

Q794 Chairman: And this was not communicated to Sir Alasdair?

Professor Woods: I would regard it as an executive matter. I frequently do discuss issues with Sir Alasdair, but it is something I would consider, as Chief Executive, as my responsibility.

Q795 John Austin: Presumably, Sir Alasdair, you were aware that the CSM had an expert working group which we now know reported in December looking at some of these issues?

Professor Sir Alasdair Breckenridge: Yes.

Q796 John Austin: In October you appeared on a Panorama programme in which you said that SSRI antidepressants did not cause suicidal behaviour in adults.

Professor Sir Alasdair Breckenridge: Yes.

Q797 John Austin: That statement at that time was completely at variance with the findings of the expert working group which reported two months later.

Professor Sir Alasdair Breckenridge: No, with all respect, what the expert working group reported were two things. Firstly, in May 2003, we said that with respect to children there was an increase in suicidal ideation in children and no benefits, and that was May 2003. In 2004, the results of the expert working group said that whilst the SSRIs were clearly beneficial in adults, there was no evidence of increased suicide or suicidal thoughts compared to the times before the patients took the medicines. This was highlighted by the large studies which had been undertaken, three large studies, using the GPRD database, comparing SSRIs with the tricyclic antidepressants and there was no increase in suicidal behaviour due to the SSRIs. My own belief is that clearly in depression suicide is a huge problem. When the patient starts to take SSRIs, there is a period of time before benefit takes place and in that time before benefit takes place the patient is at great risk of suicide and this is a time when there must be intense monitoring and great care taken of the patient.

Q798 John Austin: Could I also ask you in relation to this that after the report was published the MHRA informed doctors, following the report, that SSRIs were effective medicines in the treatment of depression and anxiety conditions. Now, nobody is disputing that, but do you not think that that required some qualification both in relation to the expert working group's report and also into the lack of evidence of the efficacy of the products in treating mild depression?

Professor Sir Alasdair Breckenridge: Sorry, maybe I am not picking this up, but you have quoted the results of the expert working group quite rightly and this is the line which we have consistently followed. Perhaps there is something else in your question which I do not understand.

Q799 John Austin: Well, after the report, my understanding is that your information to doctors merely stated that these are effective medicines in the treatment of depression and anxiety and did not have any qualification to that.

Professor Sir Alasdair Breckenridge: Yes, it did, it had qualifications. What the expert working group did was to look at three issues about antidepressants: firstly, the question of withdrawal; secondly, the question of suicidal ideation; and, thirdly, the question of dose. The problem of withdrawal has been well known with antidepressants, especially Seroxat, and I happen to have before me the information sheet, the data sheet which we published, which the MCA published in 1990 when Seroxat was first licensed. If I can just read it to you, it says, "As with many psychoactive medicines, it may be advisable to discontinue therapy gradually as abrupt discontinuation may lead to symptoms, such as dizziness, sensory disturbances, sleep disturbances, agitation or anxiety, nausea, sweating and confusion". That was in 1990. We returned to that in 1993 in our journal Current Problems and we published an article on this again in 1996, so this is an issue which we have worried about and kept under review for a long time. The second issue which came up at the expert working group was suicidal thoughts to which you have referred already and the third issue was that of dose. If I return to the data sheet in 1990, the data said that the recommended dose was 20 milligrams and in some patients if it was necessary to increase the dose, this should be done gradually and that is still what the data sheet says today.

Q800 Chairman: So you are saying that there was a clear qualification?

Professor Sir Alasdair Breckenridge: There was additional, clear information for the patients and this was ----

Q801 Chairman: And you say that was clear qualification?

Professor Sir Alasdair Breckenridge: Well, it is a matter of semantics whether that is clear qualification. I would say with what we are talking about, withdrawal, it is adding to information which was there already and with respect to dose, whether that is qualification or adding to the information which was there already is a matter of debate.

Q802 John Austin: But up until 2003, both the MHRA and the manufacturers were saying that the incidence of withdrawal reactions was rare and that has now been revised, so ten years after, when all this surveillance has been going on, that estimate has been raised to 25 to 30 per cent.

Professor Sir Alasdair Breckenridge: When a drug is licensed and for the first few years until there is good clinical trial evidence, one cannot say what the incidence of an adverse reaction is. You cannot tell that from yellow card reports. Yellow card reports give signals. You have got to rely either on clinical trials or patient databases. As that evidence became available, we were able to put a figure on the incidence of withdrawal which we had never been able to do before. Dr Raine was involved with this and perhaps she might like to take over on that, but that is the precise situation about the safety of medicines.

Q803 John Austin: With something like a hundredfold increase in the estimate?

Professor Sir Alasdair Breckenridge: Well, I do not whether ever anyone said what the first instance was. I was not aware that there was.

Q804 John Austin: You said it was rare.

Professor Sir Alasdair Breckenridge: Well, you said it was rare.

Q805 John Austin: No, the MHRA said it was rare and so did GSK when they were before us.

Dr Raine: Clearly quantification of the incidence was very difficult based on spontaneous reporting and it was only with gradual better understanding, and I would say that the patient reports that we had when we set up the expert group were very valuable in this regard, plus additional data that we sought that we were able to put a much more real-life quantification on it. If I may turn to one other point which you mentioned, Chairman, which was advising on the efficacy of these medicines, the important step that we took was to ensure that the advice on risk was accompanied by clear guidance from NICE at the exact time on the place of these medicines in clinical use. That in a sense was going beyond the responsibility of the regulator, but clearly the vital part of the jigsaw for those who are seeking to treat patients with this serious condition.

Q806 John Austin: Could I just go back to the question of when there was an awareness of the implications of withdrawal symptoms. I understand that in its original submission for marketing authorisation, which was submitted in 1990, SmithKline Beecham did provide an analysis of their clinical trial data which showed that the experience of adverse effects of withdrawal were much higher with the drug than the placebo, so in 1990 the company, when it applied for market authorisation, was aware of the severe problems of withdrawal and yet the MHRA was then still saying that it was rare.

Professor Sir Alasdair Breckenridge: Well, I repeat again what we said then, and this was what was put into the data sheet from the information, and I have read it out to you already, and the word "rare" does not occur in that. It said that it can happen. It said, "As with many psychoactive drugs, it may be advisable to discontinue therapy gradually as abrupt discontinuation may lead to symptoms", and it spells out the symptoms very, very clearly. There is no evidence and the word "rare" does not come into that.

Q807 John Austin: Well, we will leave that on one side. The company very clearly was continuing to argue that the incidence was rare when their clinical trial data suggested that it was not and that information was also in the hands of the MHRA. Now, given your acceptance that there is an issue around withdrawal and symptoms ----

Professor Sir Alasdair Breckenridge: There always has been.

Q808 John Austin: ---- why then, as the regulator, were you not requiring the expert working group actually to look for withdrawal problems in their examination? Although the expert working group has identified severe problems with withdrawal, their studies were not designed, nor required, to look actually at that. They discovered it, but it was not part of the design of the study. Was that a failing?

Professor Sir Alasdair Breckenridge: Well, we are looking back 15 years now and when the SSRIs were licensed from 1987 onwards, it was clear that this was an important group of drugs with many benefits over the previous agents, but with a different adverse reaction profile. That adverse reaction profile, as we have discussed already, was known, but the quantification and the importance of it was not clear.

Q809 John Austin: Would it not have been sensible to design the study to look at that and not find it by chance?

Professor Sir Alasdair Breckenridge: Well, the MCA, as it then was, was not in the business at that time of designing studies. It was a regulatory body at that time which did not design studies itself and set up investigations like that.

Q810 John Austin: Could I ask then whether any lessons have been learnt from the experience, in particular, how to improve scrutiny of drug licence applications?

Professor Sir Alasdair Breckenridge: Yes, there have been many lessons and the main lesson which has been learnt, as we have touched on already, the first lesson, is that the safety profile of a medicine, when it is licensed, is not very well known, the whole profile. Secondly, when yellow cards become available, they will put up signals, but these are signals and these signals must be tested in different ways. That is one of the main lessons that we have learnt.

John Austin: I think we will come on to yellow cards later.

Q811 Dr Taylor: Can I ask about another lesson, if perhaps you have learnt and changed it, because we gather in the past that you worked on company summaries of trial data rather than the raw data and we have been told that, particularly with Prosac, you or your preceding bodies chose just to take the trials or were given just the trials from America and not the trials from Europe and, therefore, you were relying on the choice of evidence given to you by the drug firm. Have you changed that? Are you now looking at raw data or are you making sure you trawl right across all the availability?

Professor Sir Alasdair Breckenridge: I think, Dr Taylor, there is a misconception about raw data and company summaries. Yes, we rely on company summaries. European medicine regulation says that we should and we do, but a company summary is for each trial that is done, and there may be 10 or 15 trials for each licence application, and what each company summary will contain is 80 to 100 pages of dialogue, several hundred pages of tables, and statistical analysis as well, so the submission for one agent will be many, many hundreds of volumes. This is what are commonly called 'company summaries'. Raw data are the individual case reports on each individual patient and we routinely do not look at raw data. We have done on occasion, but this is not a routine practice. I have noticed on one or two occasions before in the transcripts that this topic has come up and I think there is a misconception as to what is meant by a 'company summary'. When we get an application coming in to the MHRA, it is delivered in a pantechnicon there are so many volumes, and these are the company summaries which, as I have described, are very full and, if necessary, we go back to the company or the Agency can go back to the company and ask for the raw data and it does this on occasion.

Q812 Dr Taylor: And you have a method of making sure that you are getting all the data, the good data and the bad data?

Professor Sir Alasdair Breckenridge: The company signs an affidavit that they are delivering all the data. There has got to be trust in this. They sign that they are delivering all the data. When they come to a hearing, they are asked that and they are asked to give an undertaking. We also have the ability to send in inspectors to inspect the company for good clinical practice and pharmaco-vigilance should there be any suspicion that they are not producing all the data. I do not know whether Kent wants to add anything to that.

Professor Woods: No, I think that is a very clear account of the situation. The ability to inspect sites for good clinical practice has been recently strengthened by the provisions of the European Clinical Trials Directive which has been implemented in the UK with effect from 1st May last year, so there is at the level of the trial subject the opportunity, which we take, to carry out random audits to inspect that what we see in the records is actually representative of the data which has been gathered, so this adds another layer of security to the quality of data.

Q813 John Austin: Can I raise a question which I raised at the last session with AstraZeneca which related to the promotion, advertising and marketing of one of their products. I am wondering what the relationship with the MHRA is or what powers the regulator has. I raised the specific issue of Crestor and you were saying, Sir Alasdair, earlier that obviously many drugs with very real benefits do have adverse effects and carry real risks as well and there does have to be a positive assessment of those. With Crestor, AstraZeneca launched a very impressive marketing and PR campaign immediately after the MHRA had identified certain risks and reformed the advice that goes on the insert in the packet. Is there any way in which the behaviour of pharmaceutical companies can be regulated in those circumstances? Would you comment on that?

Professor Sir Alasdair Breckenridge: Perhaps Dr Raine could answer that. She is in charge of that part of the Agency.

Dr Raine: The legal position is that as long as the company is advertising in line with their licence the summary of product characteristics, we do not have powers, say, to make them stay their hands while the new advice is adopted into clinical care and that is a fact.

Q814 Chairman: Do you think you should have those powers?

Dr Raine: I think it is something that we should consider. We are currently, having overhauled our advertising processes since 2003, consulting on how we interpret some of this guidance. Our guideline is out to consultation and clearly it puts into the current climate the capability to look to see how we would wish best to interpret these things nowadays and it is not just how actively and aggressively products are promoted, but matters such as inducements and hospitality.

Q815 Dr Taylor: I must just ask something about the Panorama programme because I think many of us who are doctors were desperately embarrassed and sorry for you with the way you were forced to come out. Now, you have made a much more robust defence of the situation to us today. Is that because some of your comments were edited out?

Professor Sir Alasdair Breckenridge: I was interviewed for 21/2 hours without a break for Panorama and I was shown on the programme with 71/2 minutes of what I said. The bits of my robust defence of the position of the Agency were not shown and I cringed from behind the sofa when I saw the bits which they did show of what I had said. It was very embarrassing.

Q816 Chairman: We have been through that process, don't worry!

Professor Sir Alasdair Breckenridge: Well, I am reassured by that.

Q817 Dr Taylor: We certainly have. We have been told that there are recent changes in the safety standards in the International Conference on Harmonisation which perhaps could put patients at greater risks from new drugs. Any comments on that?

Dr Raine: I would be interested to know how Dr Taylor has, if you like, been alerted to this. Our take on the International Conference on Harmonisation is that it is a vehicle actually to raise standards, and our own strategy to improve standards of pharmaco-vigilance and to turn drug safety monitoring from a reactive to a proactive process has used ICH. We have recently adopted the guideline on pharmaco-vigilance planning and worked with the European Legislature to achieve an amendment to the law this October 2005 to ensure that when a new medicine comes on to the market, we have a proactive plan to gather the safety data and to look for new risks rather than to wait until they come and hit us, so my take on ICH is that it is a tool for improvement rather than a danger to us.

Q818 Dr Taylor: If I may just quote from our brief because I am not an expert on this, our brief tells us that there appears to have been a certain amount of downgrading in standards relative to the higher standards practised at the time within ICH, that, most importantly for drugs for non-life-threatening illnesses, the requirement for expedited reporting of known serious adverse drug reactions has been dropped, and that periodic safety update reports from companies to regulators during the first three years post-launch have been reduced in frequency, those sort of concerns.

Dr Raine: These are actually not the true position at all. We have ratcheted up the frequency of periodic safety update reports. It is obviously six-monthly in the early stages, but they will now be coming in three-yearly rather than five-yearly and we are working with our colleagues in Europe to ensure that whilst every Member States has many thousands of these to look at, we can focus with different Member States taking the lead in different established products, so I would like to reassure you that this is not the case and we are pushing ahead with ICH.

Q819 Mr Bradley: Can we explore a bit further information and promotion. One of your stated objectives is to, "provide authoritative and accessible information". How successful do you think you are in achieving that and how would you say you compare with the information that is supplied by the industry itself?

Professor Sir Alasdair Breckenridge: Well, thank you for that question. There are several ways in which we do inform patients. The obvious ones are, firstly, the summary of product characteristics and the patient information leaflets which we have approved, and that is a very important bit of getting information about the medicine through to patients with perhaps taking a specific drug. The second broad areas that we are involved in are in disease awareness campaigns, the Ask About Medicines Week, the Medicines Information Project, and these are broader ways in which we inform patients as well. The other way in which we inform patients is when there is a safety issue. When a safety issue does come back and we are acting reactively, we have quite a good mechanism now for informing healthcare professionals and the media about the safety issue and this is picked up and usually well reported by the press, so the public do get to hear about safety issues as well. It comes back to something, Mr Bradley, that I was saying earlier on, that we believe it is important that we do more than that, that we have got to be far more on the front foot rather than on the back foot and the change which you will see in the Agency in the future is better communication about the issue of risk:benefit which I believe is terribly important and working with the press, with the media, putting our heads above the parapet and letting people know that there is no such thing as a drug which is a silver bullet, that there are risks and benefits everywhere that you look, and that is a change which you will see coming from the Agency in the future.

Q820 Mr Bradley: Can I take from that that to date you do not think that your information has been as good as that put out by the industry and the public are more likely to take that information and promotion rather than yours, accepting the point you are making that you will try and do better in the future?

Professor Sir Alasdair Breckenridge: Well, we have suffered as an agency for not being professional enough in our communications. That is the bottom line and we are determined, as I have said once or twice already, to change that. It seems strange that a regulatory organisation did not think that communication was important, but since 2003 it is quite clear, the importance that it has, and we are acting very greatly on it. I do not know, Kent, whether you want to add something to that.

Professor Woods: I would just add a word because it is a very important area of our business. We had an independent external review of our communications activities which reported some months ago earlier last year and, as a consequence of that, we are forming within the Agency the Communications Division. That will bring together some 26/27 people, many of whom are already in the organisation, but we are drawing this together as a focus of activity. We have appointed a Director of Communications, who will take up post in about ten days' time and we are also investing about 1 million in our website over the next six months, so this is a very substantial investment, as an organisation, in our ability to communicate information not only to the general public, but also to health professionals. We have quite a complex external environment who require communications from us and I think that one of the difficulties we have had in the past has been that because we did not make an explicit task of communicating in that way, others have done it perhaps with less disinterest and, therefore, I feel that we do, as regulators, have an important function in ensuring that we are a source of authoritative, independent and trusted advice on matters of drug safety, efficacy and quality.

Q821 Mr Bradley: In that review, did they comment on the fact that your independent review panel on advertising and on breaches of advertising did not meet at all in 2002 and has it met since?

Professor Woods: I cannot answer that specific question. Dr Raine may be able to shed some light on that.

Dr Raine: You are absolutely right, it has not met and, for that reason, and it is an appeal mechanism which industry may choose to follow, we are adopting different strategies and the main one has been to publish the complaints that we have. I think you will find on our website that there are 17 corrected statements out there now. It is adopting one of the successful strategies which the FDA has used which is the naming and shaming. If we cannot get the appeal forum used as a way to get a rigorous result, then we will adopt other measures and, as I have said, we are consulting on how we interpret the law at the moment.

Q822 Chairman: When I opened up, talking about the changes you are bringing about, one of the issues which was mentioned was openness and, in particular, your view that the public should be much more engaged and more aware of some of the difficulties and some of the implications of the work you do. I think a theme which has come through our discussions in this inquiry and, in particular, with the companies themselves has been their understanding of the need to be much more open and transparent, but of course at the end of the day in an area of quite vigorous competition you have got commercial confidentiality and I wonder whether you feel you can go further on openness and engagement where you have inevitably at the end of the day got the problem of this commercial confidentiality. Would you, for example, like to publish some of the data that you have referred to which you receive and which currently you cannot? Could we reach a situation where we could at some point achieve that possibility which will even more engage with the public and inform the public possibly?

Professor Sir Alasdair Breckenridge: Yes, I think, Mr Chairman, there are two changes which are taking place. Firstly, although we are bound, as you say, by the laws of commercial confidentiality, if an issue does come up of public health importance, we will publish that data irrespective of the commercial confidentiality and we have done this on several occasions. The second thing which is happening, and I know that you have discussed this as well, is that there are these proposals which are going ahead incredibly quickly now about the registration and the making public of clinical trials, so however these are worked out, and we are a party to these discussions obviously, once the public know that a trial has been registered and they will be able to access the results at some time, it will be impossible for companies who are starting bits of work to hide that away. We welcomed this move both to register and to publish clinical trials and that will make our job much easier, although we still recognise that there are issues of commercial confidentiality with which we will have to deal.

Q823 Dr Taylor: Can I go back to Dr Raine and the problem with the particular drug that I think Mr Austin raised. Is there a likelihood when patients are used in market research that this can indirectly sort of turn into a promotional campaign? Certainly with this particular drug, we have had evidence that their campaign was actually to target consumers and patients. Now, are you aware of that? Could you expand on what you said to Mr Austin before? What methods would you have of controlling that sort of activity?

Dr Raine: Would you like to name the medicine?

Q824 Dr Taylor: It is AstraZeneca and Crestor.

Dr Raine: Yes, of course. No, our controls on promotion do not extend to the activities and these would fall under the general controls on clinical trials and the nature of the consent that needs to be obtained and full explanation. It would not be within my domain in advertising to look to see the information that is provided to subjects in trials of this nature.

Q825 Dr Taylor: So would anybody be aware of promotional campaigns taken on, which could target the consumers directly?

Dr Raine: The issue of direct-to-consumer promotion of a prescription medicine is prohibited very clearly. The grey area which Professor Breckenridge referred to where we do have obviously a policeman role is what is called 'disease awareness'. Now, the law prevents us from getting involved so long as specific medicines, specific licensed products are not mentioned, but clearly, by implication, if there is a new medicine in a particular area, one can construe that a campaign might be referring, by implication, to Viagra, for example, if that is the only medicine in that area. Certainly we would take very careful advice, including legal advice, if we thought a disease awareness campaign was effectively promoting a medicine.

Q826 Dr Taylor: Promoting a particular drug?

Dr Raine: Yes.

Q827 Dr Taylor: So you would be able to do that?

Dr Raine: Yes.

Professor Sir Alasdair Breckenridge: Yes.

Q828 Dr Naysmith: Perhaps we can turn to an area really which you have mentioned already two or three times, which is this question of balance between safety and efficacy, and of course we have spent quite a lot of time talking about safety so far. Could I ask you if it concerns you that there are pretty reliable figures suggesting that under 50 per cent of new drugs which get on to the market offer any significant advance?

Professor Sir Alasdair Breckenridge: Thank you for asking that question. It is a very interesting question because when you see a drug being developed, it will be 10 or 12 years before it comes to the market. It is based on a pharmacological idea and many companies will light on this idea and start to develop the medicines. Now, the precise route which they go down differs and the drugs may well come to the market 10 or12 years later at about the same time and there are several very interesting examples of where the company, which was first in the field, in fact did not finish up the best and it was the second in the field which had a better efficacy profile or fewer dangers. The other thing which does happen of course is that as drugs are developed, they very often develop indications for efficacy in areas for which they were not intended, so whilst the drugs which are developed down the line from the leaders may not have obvious advantages in one area, they may well be incredibly important in other areas. There are many examples of that going back to the 1960s with beta-blockers and more recently with angiotensin-converting enzyme inhibitors where it was the second and third drugs in the line where people began to notice an effect in heart failure and not in hypertension and these are the mainstays of hypertension now, so it is a very interesting debate as to what a need-to drug really means.

Q829 Dr Naysmith: What I am really interested in is finding out what you can do to encourage less concentration on need-to drugs. For instance, the FDA in the States categorise new molecular entity drug applications according to significant therapeutic advance and what they do with them then is prioritise them for peer review and moving into the system. Now, do you operate anything similar to that?

Professor Sir Alasdair Breckenridge: No, we do not.

Q830 Dr Naysmith: Why not?

Professor Sir Alasdair Breckenridge: Well, the law says that we will consider a drug for safety, quality and efficacy. That is the law under which we operate. There are certain other countries which do, I am aware, operate policies which you describe, but the European law, as far as I am aware, under which we operate cannot categorise medicines in that way.

Q831 Dr Naysmith: Are you saying that it would prohibit you from doing it in that way?

Professor Sir Alasdair Breckenridge: I think it would. I think that if a submission came to us for a new chemical entity and its safety, efficacy and quality were sufficient, we would license it.

Q832 Dr Naysmith: But there is a backlog, is there not? There is a queue to get things through.

Professor Sir Alasdair Breckenridge: Well, the queue is much less than it was. You may care to ask Sir Michael Rawlins in the next session that question because that is very relevant to his role.

Q833 Dr Naysmith: I realise that, but it is also relevant to your role.

Professor Sir Alasdair Breckenridge: Well, with all respect, it is not because we are regulators. We do not say how people should use drugs and whether the National Health Service ----

Q834 Dr Naysmith: So you are criticising the FDA's policy?

Professor Sir Alasdair Breckenridge: I am not criticising it. Who am I to criticise the FDA? I am just saying that they operate under a different legal system than we do.

Q835 Dr Naysmith: But maybe if we thought it was a good idea here, we could start beginning to change the legal system here, if people thought it was a good idea. I am trying to find out what your views are on it and whether your Agency, in doing what you do, could be helpful in this.

Professor Sir Alasdair Breckenridge: For all the reasons I have just discussed with you about looking into the future as to what the role of an individual agency may be, I think it would be a very brave thing for an agency to say, "Look, this is just a need-to drug. We are not going to license it". I think that is not how I see the role of the Agency.

Q836 Dr Naysmith: I do not think people are saying that they are not going to license it, but they are saying that if there is competition for resources, they will maybe try to go for something which offers more advance potentially. Professor Woods looks as if he wants to have a go at this one.

Professor Woods: A couple of thoughts might be helpful. Firstly, the assessment times for new products have been very substantially shortened over the years and I do not think there is a queue such that one would need to prioritise in the way you suggest. The second thing is that although it would be nice if each innovative drug broke into a new therapeutic territory, in reality we do not actually fully understand what the utility of a drug will be at the point it reaches the market. We know about its safety, its efficacy and its quality to a degree sufficient to grant the product licence, but its actual utility and use will become clear. I think the distinction between safety and efficacy on the one hand and practical utility on the other is an important one. Speaking as a prescriber, and I spent 30 years prescribing drugs as a physician, it is certainly valuable to the prescriber to have a range of options available to suit the needs of the individual patient. Although you can say that drug A is not as good as drug B in large trials, when it comes to the individual patient if drug A does not work, you may want to try drug B and, therefore, there is that, if you like, redundancy in the system, but in reality it is the flexibility which allows patients to be better treated. The other point I would make is that if you were to consider legislating in a way which inhibited the development of what seemed like need-to drugs, there is a risk that we would lose things. For instance, if you take the antibiotic area, there is a multitude of antibiotics which might treat a particular infection, but we need all of them because patterns of resistance change and the likelihood that we might actually discard or obstruct the development of a drug which five years down the line is actually the antibiotic that we need because the first four antibiotics are no longer working, I think that is the kind of practical implication one would have to think through before considering new legislation.

Q837 Dr Naysmith: Some of the things you have said are really very interesting because we have had views expressed here, and I know from my own experience and background in various aspects of medicine and so on, that we need more, better, more efficacious new drugs and whilst I accept what you say about altering the odd molecule here and there can make quite a difference, there is a concentration, and I am sure many people agree with this, on diseases which are sort of easy to crack, easy to treat rather than looking at some of the very difficult ones. For instance, on a worldwide scale, it is ridiculous that malaria still kills so many people, but it has been suggested that because there is not a particularly good market for it in developing countries, maybe there is not nearly enough concentration. That is a very extreme example, but the same applies to lots of other drugs, I think.

Professor Woods: I think that is absolutely right.

Q838 Dr Naysmith: Witnesses have told us this.

Professor Woods: Indeed.

Q839 Dr Naysmith: All I am asking is if there is anything you can do as an agency to sort of encourage firms to do the right thing. Of course if you are saying you cannot do it because of legal constraints, then maybe we need to look at that.

Professor Woods: Well, I think there are limited things which regulators can do to ameliorate this situation. It is a problem, I do not dispute that and I think you are absolutely right, but the drivers which encourage or inhibit useful innovation in the pharmaceutical area are quite complex and regulation is only one of them. It can act negatively. If one creates a climate where innovation generally is made more risky, more expensive, if one over-regulates, if you like, it means that the available investment will go towards the safer products, safer in the commercial sense. To produce another beta-blocker is not going to be quite as much of a blockbuster as to produce a completely new treatment for something untreatable, but, on the other hand, it has a degree of commercial sense about it and, therefore, it is important to recognise that although regulators cannot do a great deal to stimulate innovation, and there are some things we can do which I will come back to, we can certainly do things to inhibit innovation and we must be careful that we do not inadvertently do that The ways in which we can simulate innovation are actually to engage with innovating companies at an early stage of product development to provide scientific and regulatory advice, that is to say to help the company understand the hurdles that will have to be cleared, perhaps a different mechanism of action, perhaps breaking new ground, to satisfy us as regulators that it is worthy of a product licence. I think that scientific advice is something which we have really only been doing over the last year or two and the number of scientific advice meetings we hold is going up really quite steeply. I think that is something very positive that we can do and the only constraining factors on us really is firstly industry's uptake of that option which they are very keen to do and the second thing is our resources, our scientific resources within the Agency, to provide that degree of assistance. The FDA, to whom you referred, I think have taken this even further and they have produced a very thought-provoking document recently called Innovation or Stagnation? which asks the question and delves more deeply into the matter of, what can regulators do to foster innovation? The areas they see as a difficulty are the growth of regulatory science, if you like. Are there better ways of predicting clinical hazards at an early stage of development in order that companies do not waste money on drugs which ultimately are going to fall down? Are there other surrogate markers which will detect potential hazards at an early stage and, if so, can the regulators introduce those into the assessment process? Are there therapeutic markers that we can pick up earlier in order that the process of development can by more accurately targeted on those things which are going to work and have an acceptable safety profile than those things which are doomed to fail at a late stage of development? Regulators around the world are thinking about this and both the FDA and ourselves have discussed it internally at length.

Professor Sir Alasdair Breckenridge: The other thing is that the picture for malaria, which is an area in which I am closely involved, may not be as gloomy as you are saying. There are some very interesting things happening in that area now, thank goodness.

Q840 Chairman: Professor Woods, can I just clarify your answer on 'me-toos' because you appear to be questioning the entire concept of 'me-toos' that has been raised with us on numerous occasions during this inquiry. Do you accept that there are 'me-toos' or are you saying that there are subtleties between different products that perhaps we ought to be aware of and that 'me-toos' do not exist and there are distinctions that are important?

Professor Woods: Yes. From practical experience as a clinical pharmacologist, there are no two drugs in a class which are identical in terms of their duration of action, in terms of their handling in the body and how they are eliminated. For instance, you might have a patient with impaired renal function. You would select a drug within the class that was not really excreted, you would choose one that was metabolised. Therefore, if you know the drugs and you know their individual characteristics, you can select in a way which maximises efficacy and minimises toxicity. So, I think the concept of a 'me-too' is a rather blanket description which does conceal some more fundamental facts.

Q841 Chairman: Are you saying that there are not any 'me-toos'?

Professor Woods: There are groups of drugs which contain an awful lot of agents which have rather similar actions.

Q842 Chairman: But 'me-too' is not a concept that you would use? I just want to be clear what your views are.

Professor Woods: One uses it as a kind of shorthand, but I think we probably have enough beta-blockers; last time I counted I think there were about 15 and I think that is enough. The point is that if one took the opposite approach and said that, in each therapeutic class, there will be one or two agents, we would actually lose.

Q843 John Austin: I accept your point that the 'me-too' might be efficacious with a particular patient, but in terms of the overall therapeutic benefit compared with the cost of the research and all that goes into it, it surely cannot be the best way to go, can it?

Professor Woods: It comes back to what I said earlier about the distinction between efficacy, safety and so forth and utility. The NHS now has - and you will be hearing later evidence this morning about the work of the National Institute for Clinical Excellence - a mechanism for providing guidance to practitioners as to which within a class are the most useful drugs and I think there is a difference there, a very important difference, between therapeutic utility, which can actually change over time, and the criteria of safety, efficacy and quality which allow a drug into the marketplace, and I think it comes to this question of the intelligent consumer and, by "the consumer", it might be the NHS as the purchaser, it might be the prescriber or it might be the patient who is actually taking the drug. I think that one needs to give those end users the information to allow them to make judgments about the actual place of a drug in the treatment of individual patients. It seems a little extravagant, it seems a waste of scarce R&D resources to develop a drug which is rather like a drug which is already there but, on the other hand, it is not something that one should legislate against because commercially it is not the most attractive option either.

Q844 John Austin: We have had a great deal of evidence or argument before us about the importance of accelerating patients' access to the drugs. I think one of the witnesses last week said that we were just behind Croatia in terms of new drugs, but we have also had discussion - and we have had some discussion this morning - about the slowness of the regulators in responding to safety problems with some drugs on the markets. One could draw from that a conclusion that, when it comes to early licensing of medicines, the regulators are willing to live with a very large amount of uncertainty but, when it comes to restricting or withdrawing drugs which are on the market, the regulators are demanding compelling evidence of injury and harm before taking any decisive action. Would it be fair to say that you give the benefit of the scientific doubt to the drug manufacturer, both at the pre-market review stage and the post-market decision making?

Professor Sir Alasdair Breckenridge: No, that is not true. The question of early marketing of medicines is an important one in that one does not want to withhold effective medicines from getting to patients. On the other hand, one is very aware that, as we have said already, the amount of safety evidence which is available for a new medicine once it is licensed, even under a normal route, is limited. It is going to be even less if there is going to be early licensing of a drug and what does happen under the situation is that the company who does ask for early licensing of the drug is given very strict tasks which it must fulfil by a certain time - and this is reviewed within fixed time limits - or the licence will be withdrawn. There are risks attached to it. It comes back to my theme again of risk and benefit. If there is overwhelming benefit of the drug, for example in the treatment of AIDS or a new drug for cancer which one may be prepared to take, but if it were yet, coming back to our previous discussion with 'me-too' drugs, another beta-blocker or something like that, it is not an area that one would want to follow.

Q845 John Austin: What would the policy of the MHRA be if there was scientific doubt about the safety of a drug which appeared to offer no significant therapeutic advantages over other therapies? Would it be left on the market?

Professor Sir Alasdair Breckenridge: It would depend on what the indication was. As I say, if this were a drug which had the promise of curing cancer or curing HIV disease, then the risk of benefit decision would be different from if it were a drug which was going to treat nasal blockage. That is the answer.

Q846 John Austin: Dr Taylor may want to come on to the recording of adverse incidents and whether it is an effective system at the moment but, in evidence to us earlier, the Medicines Commission made the point about the amount of research being carried out into adverse effects of medicines and I think they said in their evidence that funding for research into adverse drug reactions was an extremely important aspect of drug therapy but that it has been impossible to find in the current research climate the resources and the funding to do that and they went on to say that the pharmaceutical companies themselves provide little funding for such research because they do not perceive it as being in their interests to do so.

Professor Sir Alasdair Breckenridge: Can I address that by telling you a little about how the Agency is funded now. The Agency is funded essentially, since 1988, by the industry, by licensing fees and that was recommended, and that had the result of accelerating the new drugs which were coming through, the backlog fell quite dramatically. The second thing relevant to your question, Mr Austin, is that, in 1991, the decision was reached that a fee would be charged for every medicine which had a product licence which was on the market and that annual fee brings in now 40 per cent of the income of the medicine sector. That is used for pharmacovigilance studies, for safety studies and for enforcement studies. So, we are in the position within the Agency of having a sizeable budget, 40 per cent of our income, which is used for pharmacovigilance studies and for enforcement. Many other agencies do not have this.

Q847 John Austin: Is it usual for you, as regulator, to request companies to carry out further studies of adverse effects?

Professor Sir Alasdair Breckenridge: Yes and that does happen and the other thing is that we do commission studies as well. For example, the Agency commissioned a study in fact from Liverpool, from where I originate, on the whole effect of adverse reactions on the morbidity and mortality of patients and this was published in the British Medical Journal last year, that six per cent of patients admitted to hospital suffered from adverse effects/was due to adverse effects. This had a financial effect of about 400 million a year. This was the first study which had been done in the United Kingdom for 15 years to look at the financial significance of adverse effects and the Agency does fund studies like that as well.

Q848 Dr Taylor: Can we move on to drug safety monitoring in more detail and the yellow card system. You have already mentioned the yellow card system saying that you are going to put things on to the web. We have also heard that the yellow card system is going to be widened to allow patients to fill in yellow cards.

Professor Sir Alasdair Breckenridge: Yes.

Q849 Dr Taylor: Are you going to have a method of selection before things go on the web? How are you going to play this? Do you have any idea of how to make it more effective, more all embracing than it is at the moment?

Professor Sir Alasdair Breckenridge: Dr Raine is in charge of this and she could answer but I would be very happy to start off. In fact, as of yesterday or two days ago, the adverse reactions/yellow card reports for every licensed medicine are available on the web. If you go to the website, mhra.gsi.golf.uk, you can call up the adverse reaction profile, all the anonymised yellow cards for every adverse reaction to every drug which is licensed in the United Kingdom.

Q850 Dr Taylor: So, you are putting on any card you get from Mrs Bloggs down the road without vetting it sort of thing?

Dr Raine: It will be an anonymised form clearly and the data is aggregated. It is to help patients who may be about to start a medicine or doctors who are making prescribing decisions to understand what we have in the way of data and it is very easy to access. It is there now.

Q851 Dr Taylor: So, whatever it is, however unlikely it might be, it would go on?

Dr Raine: Yes, but there is very clear guidance about how the data can be interpreted and how far it can be interpreted. Clearly, it cannot give any idea of the incidence of an adverse reaction and, as with many websites, you have to read all this and say that you have and you understand, if you like, the health warnings before you go further and look at the data. We are learning as we go and we have a patient reporting expert group which is chaired and largely constituted from patients and those with an expertise in consumer interests and they are helping us move forward with what are essentially some very important first steps to truly engage and inform in the way that patients want.

Q852 Dr Taylor: How can you get the medical profession to fill in more yellow cards?

Professor Sir Alasdair Breckenridge: Thank you for asking that question! I hoped you would ask that question because this has come up several times. Dr Taylor, we are very clear in the instructions which we give that we want reports of drugs which have a black triangle and serious adverse reactions. That is what we want. We are very keen to encourage yellow card reporting but what we do not want is a lot more reports of rashes on penicillin and bleeding on warfarin. The yellow card system is not there to give an incidence of adverse reactions. It cannot do that. It is there to give - and this is a terribly important question that you have asked - a signal where we can take that signal and explore it in other ways. So, while we do want more adverse reaction reports and yellow cards, the main thing is that we want better ones and the interesting thing, coming back to what June was saying, is that, when we have patient reporting, what kind of profile of adverse reactions will this give us? How will this add to our information on the safety of medicines? That is a very interesting thing which we are going to explore with the new way in which we are doing things.

Q853 Dr Taylor: Can you just explain the black triangle in case people do not know.

Professor Sir Alasdair Breckenridge: Every new drug and every drug which has, for example, a change in formulation has a black triangle put opposite its name in the British National Formulary, in advertising and in our publication Current Problems; every month or two we indicate to people who read that what a black triangle means. Perhaps we have not been as successful as we might in informing the public about this when they buy it because, when they buy it, the SPCs and the PILs will have a black triangle. This is what a black triangle means, it means report any adverse reaction which does occur with this drug.

Dr Taylor: Are there any incentives for doctors who fill in more of these?

Chairman: What do you have in mind?

Q854 Dr Taylor: I have to remember that I probably did not fill in more than a fraction of the number of yellow cards that I should have done and it is so important that I am just trying to explore ...

Professor Sir Alasdair Breckenridge: There is an apocryphal story that one of our fellow countries which is slightly to the west of us decided several years ago that they would give incentives to doctors to fill in yellow cards and the apocryphal story is that the number of yellow card reports went up a hundred fold by doing that but the therapeutic value of it did not rise commensurately.

Q855 Dr Taylor: What other major sources of information on adverse reactions are there?

Dr Raine: A broad range. We look at the published literature and we have studies that are commissioned post-authorisation and a very, very broad range. Internally, we have the general practice research database which has information on 35 million years of patient data in primary care and we are trying to develop tools to use the data there to help detect signals. So, it is a very broad range. Probably about 40 per cent of our new signals come from the yellow card scheme and others come from the published literature and so forth.

Q856 Dr Taylor: We get very worried when prescription drugs that have been licensed and released are withdrawn relatively soon after they have been marketed. How could we better prevent that? When we put that to the drug firms, they feel that the only way you are going to pick up side effects relatively quickly is if drugs are marketed on a big bang sort of approach. I would like to have thought that drugs that offer a very real advantage - and I do not just mean one of the minor developments that have been called 'me-toos' - should be released more on a limited basis, perhaps consultant-only prescribing which inevitably goes for the things with high risk like the anti-TNFs and the anti-cancer drugs. If the COX-2s had been liberated on a more limited fashion because they did potentially have a real advantage, would that have just delayed the declaration of all these side effects or would it have been beneficial in the long run?

Professor Sir Alasdair Breckenridge: That is a debate which is very active at the present time. As you are aware, when the COX-2 inhibitors were launched in the late 1990s, because of a knowledge of the pharmacology, it was predicted that these drugs would firstly have a beneficial effect on gastrointestinal bleeding, but secondly they would not prevent cardiovascular disease as the old non-steroidals did. My understanding is - and I have probably read the same literature as you have - that the company that marketed the first of these did in fact set up studies at that time, at that very time, to explore the possibility that there might be adverse cardiovascular effects and it is these studies now which are coming through, the so-called approved studies, which have shown that there was this increased incidence of cardiovascular disease. So, I think there are some adverse effects which are immediately apparent, there are some other adverse effects which take a long time to become apparent and of course, coming back to our discussions about yellow cards with respect to problems like cardiovascular disease, the yellow card is a very poor system of picking up adverse reactions which mimic a disease which is common in the population. So, as June was saying, you have to rely on either patient databases or clinical trials like I am describing to you with respect to the COX-2s.

Dr Raine: I do think that our new legislation which is coming through in October which gives us the powers to demand risk management plans at the time of authorisation, so studies will begin in a very proactive way to test these questions, will actually prevent the shock of a medicine being withdrawn in quite the way that happened with so many people exposed to risk. It will never prevent a medicine ever being withdrawn again, but it gives us a much better tool to be on top of the safety as it unfolds.

Dr Taylor: That is encouraging.

Q857 Chairman: Before we move on from adverse reactions, obviously you have talked about our system and you will be aware of different approaches in different parts of the world and we have looked at one or two. Do you have any thoughts of other systems that might have any merits to recommend them to this country or do you feel that, with the qualification you have just mentioned and the changes you have described, we are broadly in the right direction?

Dr Raine: I think we are moving in the right direction and I think that the world is moving in that direction too. We have to use better sources, more robust sources of evidence that are at our disposal. I think we actually do have to make a very active attempt to include the patient perspective. There are areas of our so-called excellence strategy such as decision analysis that need careful testing as to whether they are applicable. They are applicable in other fields but are they applicable? I am not aware of another regulatory system that is really delivering a better and more prompt identification and action on risk than we are at the moment but we must keep returning to transparency. Once the evidence for risk decisions is made public as a matter of course, then I think the whole discipline will move forward worldwide.

Q858 Mr Bradley: You mentioned the clinical trials register earlier and you said that you were in discussions about it. What form do you think such a register should take?

Professor Sir Alasdair Breckenridge: There are several proposals around just now. Let me start from where we are just now. With respect to the European Clinical Trials Directive, every trial which is started within Europe must be registered with the Agency in the country where the trial is being done and this will be collected on a European-wide basis and that information will be available to regulators. Broadening it from there, if the studies are being done in different environments to that, I think it very much depends on the willingness of the companies, because they are the people who do most of the studies, to conform to a single system and the companies are having these debates just now. Whether or not that will be sufficient or against some other discussions which are taking place just now that this should be made compulsory is, I think, an interesting decision.

Q859 Mr Bradley: Do you have a view on that yourself?

Professor Sir Alasdair Breckenridge: I would hope that, in the current climate, a voluntary system will be able to work combined with the European ---

Q860 Mr Bradley: Do you think the public will have confidence in a voluntary system?

Professor Sir Alasdair Breckenridge: I would hope so, combined with the European Clinical Trial directive. Kent, you have had experience with the Clinical Trial directive and I wonder if you would come in on that.

Professor Woods: There are of course these two separate issues which have been referred to before. One is the registration of the fact that a trial has been started and the second is the availability of the results of that trial when the study has been completed. From the point of view of the regulator, the first part is important in terms of enabling us to ensure, as we are still here, that we have everything. In terms of the general public, it is the availability of clinical trial results in an accessible place which is perhaps more fundamentally important. The voluntary system which the global pharmaceutical industry has come up with in the last week or two offers a promise of how that might work but it is early days and, as we say, there must be public confidence that it will be actually implemented. Secondly, there are some technical questions to be sorted. Where do you put the trials data in a site which can actually be accessed by people? Thirdly, what should those records contain? Are they intended to be totally comprehensive, in which case they will be almost inaccessible to the general public, or are they in some way summarised data? I think there are some very important practical issues and issues of trust too which do need to be clarified. I think the default position would have to be some form of legislative requirement if that voluntary system does not work. We will know, I think, quite soon.

Professor Sir Alasdair Breckenridge: As I have said already, we hold out great hope for the European Clinical Trial directive registering trials on that system and this will teach us a lot which may well help to inform the other systems which Kent was describing.

Q861 Mr Bradley: Do you think there are any anomalies in the situation where clinical trials information is voluntary given by the companies but you may feel that you have to protect that same information because of commercial confidentiality? Do you think there are potential conflicts within that?

Professor Woods: Of course, the Freedom of Information Act which came into effect at the beginning of this month does substantially shift the rules of the game in effect in that the default position is disclosure whereas the tradition, the legal position in UK medicines regulation going back to the 1968 Medicines Act, was very much that the presumption was that data submitted for licensing purposes were confidential data and indeed, under section 118 of the 1968 Medicines Act, it was an offence to release information unless, in the course of one's duty, it was necessary to do so. The Freedom of Information Act is shifting that towards the presumption of disclosure and therefore it is no longer the case that information submitted to us as a public body is protected from the Freedom of Information Act and any exemptions from disclosure, that is relevant exemptions, are conditional on a test of the public interest of disclosure versus the public interest of non-disclosure. So, I think that does quite fundamentally shift the accessibility of trials data and we welcome this. We, as an agency, would sooner have information out in the pubic domain provided, from the company's point of view, there will be occasions when the exclusions built into the act will be necessary, but the default has changed.

Q862 Mr Burns: Sir Alasdair, you slightly dealt with my first question in answer to my colleague Mr Austin, but, on your funding, as we know, it is from fees from industry and you have to compete with other European regulatory agencies for business. Do you think this creates a situation in which drug companies are your customers whom your organisation is competing to please and thereby perverting the priorities of your Agency away from the protection of public health and more to the advancement of new and effective drugs and, if your answer is "no" which I suspect it will be, why?

Professor Sir Alasdair Breckenridge: There are several parts to that question and let me start it off. We are part of Europe. There are three ways in which medicines in Europe can be licensed. Firstly, they can be licensed nationally and the companies will come to us for a licence and that is quite clear and I think you understand that. Secondly, there is the centralised programme - and this is increasing all the time - where a medicine is licensed within the whole of the EU and what happens there is that the company will approach the EU and their Scientific Advisory Committee will decide which of the countries are going to act as the assessors, as the rapporteurs and the co-rapporteurs, and that carries money with it, and that accounts for a sizeable amount of the funding of our Agency. We are one of the biggest gainers from that system because of the stature which our Agency does have. So, this contributes quite a lot to the funding that we do have. The third process by which a drug can be licensed is the so-called decentralised or mutual recognition process whereby a company will come to, let us say, the MHRA, to the United Kingdom, and, if we give it a licence, then it will go into Europe from there once it has been recognised in one country and mutually recognised and clearly that is financially beneficial again. So, you have to balance each of these three systems of funding which we do have against the incentives which you are talking about and it is clearly terribly important that we retain and advance our position in Europe not only from a UK plc point of view but also from the funding point of view of our Agency.

Q863 Mr Burns: Do you think you have adequate resources, both financial resorts and in terms of personnel, to be able to provide the high quality service to which you aspire?

Professor Sir Alasdair Breckenridge: The funding of the Agency comes from two sources. Firstly, there is the medicines part which we were talking about just now and we have discussed the ways in which we fund that and, in many respects, if we get more user fees, we will get that because of the excellence of the Agency and the excellence of the service which we provide. The second part of the Agency - and perhaps this is not the concern of this Committee - is for medical devices and medical devices are funded by Government. The very interesting areas which are now arising as we speak are that there is a huge interface between medicines and medical devices and how these are going to be licensed and how these are going to be regulated. We are in an advantageous position because of the actions that were taken two years ago to join the Medical Devices Agency and the Medicines Control Agency and this is an area in which we are very active just now and we want to make our imprint in Europe that we are an agency which is looking towards that possibility and thereby gaining more funding for the Agency in that way.

Q864 Mr Burns: You have dealt with funding, what about personnel?

Professor Sir Alasdair Breckenridge: Let me ask the Chief Executive about personnel.

Professor Woods: We are one of the larger regulatory agencies worldwide. I think that there are specific areas within the Agency where we will need to recruit additional expertise because science marches forward and we need to ensure that we have the most up-to-date skills and science base within the Agency. I see that as an incremental process. I do not think that there are any major shortfalls in our resources but we will need, over the years, to ensure that, as we recruit and develop our staff, we are able to handle new technologies, we are able to keep abreast of developments and we are able, also in the safety area, to use the latest techniques in epidemiology to study adverse effects of drugs and devices in the population.

Q865 Mr Burns: Do you think Mr Jim Thompson's comments from Depression Alliance where it says that the regulatory body is woefully under-resourced is wrong?

Professor Woods: I think it is certainly not the case that we are woefully under-resourced. Perhaps that is a rather rash statement to make but I think that statement is wrong. Clearly, there are issues that we would wish to pursue in greater depth, but I think those are within the scope of that current funding mechanism and, as much as anything, it is a shifting of resources rather than an absolute shortfall. I really do not think that we are woefully under-funded and I think that we have some world-class scientific resources within the Agency, not just in terms of people but in terms of databases. We have databases that are absolutely unique in the world and our task over the next year or two will be to ensure that we have those additional very rare skills which enable us to exploit them fully.

Q866 Mr Burns: If you look at your own website say on 1 December 2004, you will see that there are currently delays in processing certain applications. Why is that the case if your financial resources and your personnel resources are fine and would it not have been predicted that there was going to be a problem and should the necessary measures to seek to minimise those delays not have been taken? Also, what impact are those delays having on the overall work and performance of the Agency?

Professor Woods: That is the one area where we have of late been falling short of our own demanding performance targets and the history of it is this. There was a change in the paperwork/documentation required for particular types of licence application. Before the change came in - and this related to abridged applications - there was a rush of applicants wishing to get their applications in before the paperwork changed, before the common technical document came in. That meant that there was a short surge in demand which we could have predicted though in fact it is rather difficult to handle a short surge in demand because, if you recruit more staff and the demand goes away again, you have a slight problem. So, there was that initial surge of demand which knocked us off course. The other factor which we had not allowed for was that actually the number of applications coming in year on year is rising too. So, this is not simply a transient ---

Q867 Mr Burns: I am sorry, can I just pick you up on one point before you carry on. You said - and there is a logic to your argument - that it would not necessarily be wise to take on extra staff to deal with a short-term surge, but why are you taking on more staff?

Professor Woods: If it were a simple matter of a surge where applications we were expecting to be spread across a year all turned up in January, then if we recruited to handle January, we would be overprovided with staff in February onwards. There is this more complex question that actually the number of applications coming in has shown a sustained rise. I have discussed this with the industry associations, firstly why has it happened and, secondly, can they give us more precise information about their commercial plans. I think the answer to your question as to how we cope with this is that, if we can better understand the commercial drivers from the industry which influences the timing and the number of applications, we can start to deal with that but, if we have these rather unpredictable fluctuations, we have a problem.

Q868 Mr Burns: Finally, we are told that it takes longer to process applications for generic products rather than for new chemical entities. Is that factually correct and, if it is, can you explain that?

Professor Woods: It is predominantly in that area that this particular difficulty of surges in demand arises. There is another factor which is that generic products will suddenly appear on the market when a branded product goes out of patent. Therefore, there is a starting point when every company which is going to start producing a generic produces a generic. So, intrinsically, it is a rather lumpy line of activity to cater for but, as I say, there is discussion which has been, I think, productive with the industry association for them to do work among their own members to give us a forward view of what those peaks and troughs are likely to be and, if we can map on to that internally, we can make sure that the absolute number of scientific staff is right and, on a micro basis, we can actually move scientific staff from one form of licensing to another as the demand arises.

Chairman: As you know, we have a shorter session - hopefully it will be a shorter session though we are not sure yet - with NICE following on. We have a couple of brief questions before we conclude.

Q869 Dr Taylor: Do you have a set scale of fees for licensing pre-marketing trials?

Professor Woods: Yes, we do have a set scale of fees. All our statutory fees are subject to external consultation and scrutiny by the Treasury and final agreement by ministers. It is a set scale. We do provide quite a range of regulatory activities which have their own fee structures but they are all, as I say, approved by that process.

Q870 Dr Taylor: So, a huge firm like Pfizer would be charged the same as a very small firm working on a specific vaccine, for example?

Professor Woods: The details of that are a little more complicated. The service fee which we charge, as it were, for the post-marketing surveillance of products is influenced by the size of the company, the number of products and their volume of sales. So, the actual calculation of the fee does have that variable in it. It is quite a complex fee structure.

Q871 Dr Taylor: That is post-marketing but not pre-marketing?

Professor Woods: That is right, yes.

Professor Sir Alasdair Breckenridge: We could let you have details of the fee structure.

Chairman: That would be helpful.

Q872 Dr Naysmith: My question is a little similar to Richard's but it was triggered off by what you said, Sir Alasdair, about the three different routes that materials can be passed through your Agency depending on whether it is for UK or it is for Europe or it is for a company which will start here and then ...

Professor Sir Alasdair Breckenridge: Yes, mutual recognition.

Q873 Dr Naysmith: Are they all treated in exactly the same way?

Professor Sir Alasdair Breckenridge: Yes.

Q874 Dr Naysmith: The standards are exactly the same?

Professor Sir Alasdair Breckenridge: Yes, absolutely. The standards are exactly the same.

Q875 Dr Naysmith: So, it is not easier for a company to go one route rather than another?

Professor Sir Alasdair Breckenridge: That is very often a commercial decision for the company. Is it going to go and get a licence very quickly over the whole of Europe? The centralised procedure does specify certain areas where they must go for a centralised procedure such as high-tech products: anti-cancer drugs, HIV drugs and drugs for diabetes must go centrally. However, it is still up to the company. If they decide that they want to try for a licence over the whole of Europe, they can apply on the centralised procedure.

Q876 Dr Naysmith: It is not that the European standard imposes higher standards or lower standards than ---

Professor Sir Alasdair Breckenridge: No because, for a centralised procedure, if we are the rapporteur or co-rapporteur or even an interested Member State, we will apply exactly the same standards to assessment and our opinion as we would to a national licence.

Q877 Dr Naysmith: What do you think it is that makes a company choose one route rather than the other?

Professor Sir Alasdair Breckenridge: I wish I knew. I have no idea. I think there are forces within industry which must make that decision. I guess it may well be if they are first in the field or if they are, using our vernacular again, a 'me-too' drug. I suspect that these are influences which may affect them, but I think you would have to ask industry that rather than us.

Chairman: If there are no further questions from colleagues, can I thank you for a very interesting session. We are most grateful to you. If you wish to remain for the subsequent session, you are very welcome to stay. Thank you very much.

Witnesses: Professor Sir Michael Rawlins, Chairman, and Mr Andrew Dillon CBE, Chief Executive, National Institute for Clinical Excellence, examined.

Q878 Chairman: Colleagues, can I welcome you to this second session this morning and particularly welcome our witnesses. We are very pleased to see you again and thank you for your attendance. Would you briefly introduce yourselves.

Professor Sir Michael Rawlins: I am Michael Rawlins and I am Chairman of NICE.

Mr Dillon: I am Andrew Dillon and I am Chief Executive of NICE.

Q879 Chairman: Before I begin, I think it is appropriate to say on behalf of the Committee that we do appreciate your response to the recommendations in our report some time ago. It is not always that we can say to agencies, "Thank you for listening to what we had to say and for doing something about it." I think generally we have been very pleased with the response and I wanted to place that on the record. Before we get into some of the detailed questions, could I ask a similar opening question to the one that I asked at the start of the last session at which I think you were present which is, what lessons do you feel may be learned from the evidence that we have received in this inquiry as it relates to your area of responsibility? What do you feel are the issues that perhaps we as a committee, in moving towards the conclusion of this inquiry, ought to be particularly concentrating on? You have a unique insight into many of the areas that we have talked about. As a starter, I would be very interested, Sir Michael, in what your thoughts are on that.

Professor Sir Michael Rawlins: Yes and Andrew may have some additional ones. As far as I am concerned, the part that particularly concerns me, partly as a physician - they still let me practise a little - and partly from NICE's point of view is the public availability of all clinical trials. It does not just apply to the industry, it applies to people in academia who do clinical trials too because sometimes they do not get published or do not get made publicly available and there is overwhelming evidence to show that it is the negative trials that tend to not get published and I think you heard from Dr Kendal a few weeks again of his paper in The Lancet comparing the published and unpublished trials of SSRIs. That paper incidentally, since he saw you, has been awarded the 'Paper of the Year' by The Lancet, which is pretty remarkable. So, it is the public accessibility of the results of all clinical trials. I know that sometimes people talk about intellectual property rights - and I am sure in legal terms that is right - but I am also very struck by the fact that it is patients who take part in these studies and we have an obligation to them to learn from what they have done because being a patient in a trial is inconvenient and sometimes can he hazardous and we owe it to them to make sure that their efforts and their discomfort has not been in vain.

Q880 Chairman: We have actually had that point made by patients.

Professor Sir Michael Rawlins: I think they are absolutely right.

Q881 Chairman: Do you have anything to add to that, Mr Dillon?

Mr Dillon: Just a thought that those who produce and those who use our technologies have some strong common interests, that ultimately the benefits of what is produced have to go through to patients, but they also have some different interests too. They help to produce health technologies and have a need to make a return on their investment and to keep the businesses that they are responsible for viable in order that they can produce good things in the future for example, and those who, like NICE to some extent, value those products have a different set of responsibilities. Because of that, I think it is really important that when those different interests engage, there is actually a structured and open and transparent process that recognises the reality of those different drivers and makes sure that they can be reconciled in a way that enables those who look at how decisions are taken to understand how they are taken and to be satisfied that they are taken objectively.

Q882 John Austin: In your submission, you acknowledge that there is a potential conflict of interest with the pharmaceutical industry's involvement in NICE's processes given their key responsibility to their shareholders to secure markets for their products and you have given a detailed description of the processes you follow to minimise this risk. The industry is also involved in selecting the topics that NICE addresses in its advisory programme.

Professor Sir Michael Rawlins: It is ministers who fall responsible. The industry can comment on it. No companies have refused to take part in an appraisal or a guideline but it is not them who decide whether their product will go forward, it is actually ultimately ministers.

Q883 John Austin: So, they do not have an independent involvement in determining ---?

Professor Sir Michael Rawlins: They are present in ACTS, the Advisory Committee on Technology Selection.

Mr Dillon: There is an advisory committee within the Department of Health and the industry has seats on that quite large committee, but ultimately decisions are taken by ministers.

Q884 John Austin: Do you see any benefits or disbenefits of the industry being involved at that stage?

Mr Dillon: For us, the really important thing is that we pick up emerging technologies as early as possible in order that we can start work on evaluating them so that we can provide advice to the NHS as quickly as possible after they introduce them to the UK market. The people who know earliest and most about those emerging technologies are those who manufacture them. So, an understanding of how products are developed and the ways in which information can be obtained about developing products properly through publicly available data is quite important and I think one of the benefits of industry participation in that selection process is to provide that sort of perspective.

Q885 John Austin: You will be aware from our previous inquiry that we know your position and how you share our view on the importance of involving patients with patient organisations. It has been suggested now that some patient organisations might be very closely in bed with the pharmaceutical companies and many of them are funded by them. Do you think there are risks there and what is your view towards patient involvement where there is a clear link with the pharmaceutical industry?

Professor Sir Michael Rawlins: We do not exclude patient organisations or professional organisations because they have some relationship with a pharmaceutical company but we do formally ask them when they come to give evidence at the present committee meetings if they know what those interests are and we record them and they are placed in our minutes and the minutes of the meetings are placed on the website and I have a copy here of the guide which indicates the approach that is taken. We do not exclude them because they have an interest, I think that would be wrong, but we make sure that we know about the interest and we make sure that the members of the committee know about the interest and take that into account as part of the judgment.

Q886 John Austin: Can I ask an unrelated question arising out of the exchange between myself and Sir Alasdair in the earlier session when we were talking about SSRIs. I put a question to Sir Alasdair following the report of the Expert Working Group when the MHRA put out a statement following the report saying that SSRIs are effective medicines in the treatment of depression and anxiety conditions and I asked Sir Alasdair if that should have had some qualification to it. Could I ascertain the position of NICE because I asked specifically about the use of antidepressants in the treatment of mild depression. Could you confirm that NICE does not recommend the use of drug treatment in mild depression.

Professor Sir Michael Rawlins: I think it depends on the circumstances. We have recently produced a guideline on the management of depressive illness and that guideline indicates that, in mild depression, it may not be appropriate to go for pharmacological treatments but other sorts of therapy too. It is a very difficult decision if you are a general practitioner or psychiatrist as to the circumstances when you think that drug therapy is appropriate and circumstances when it is not. It is not all that easy to tell in the real world. We did want to shift a little bit away from automatically prescribing and availability of other forms of treatment. We were also very conscious that clinical psychologists are in short supply in the Health Service and those sorts of techniques, what someone would pejoratively call talking therapies, are important and that is one of the reasons why we have actually done an appraisal of computer behavioural therapy and they are at an early stage but they are another alternative route to that sort of form of treatment. Andrew, do you want to come in there?

Mr Dillon: No, that is a good summary.

Q887 John Austin: Would you acknowledge that there appears to be a difference of view between NICE and what the MHRA were saying?

Professor Sir Michael Rawlins: I do not think so really. Having been Chairman of the Committee on Safety of Medicines for six years and Vice-Chairman for six years, I am well versed in the archaic rites of it all although it is six years since I was involved but it is slightly different. The regulatory authority is primarily there to regulate the industry, that is what the Medicines Act is set up to do, and previous chairmen used to shout at me when I was a raw young youth on the committee with Alasdair, they used to shout at both of us, that we were the Committee on Safety of Medicines and not Medicine and our role was regulating the industry and not regulating the profession. It is a difficult thing to balance and do; it was difficult when I was chairing the CSM and I am not sure it is not easier now. I think there has been a shift over the years to being more engaged with the professions, more helping them to prescribe appropriately and so on, which was not the original intention but I think that is the right direction to go in.

Q888 Dr Taylor: Could you remind the Committee about the selection of drugs for evaluation, how you do it or who does it.

Professor Sir Michael Rawlins: The topic selection is formally made by ministers. There is a somewhat complicated process which Andrew is much more well versed in because he goes to the committee meetings.

Q889 Dr Taylor: So, you do have some influence in guiding the minister on what to select?

Professor Sir Michael Rawlins: Yes.

Mr Dillon: Very briefly, there is a whole series of sources of information about the kind of pharmaceuticals that NICE might look at and bear in mind that we only ever look at a small proportion of the total of new drugs introduced into the UK market at any one period of time. All that is looked at by a group called the Advisory Committee on Topic Selection, which is a Department of Health Committee with a whole range of membership from inside and outside the NHS. That creates a shortlist which is reviewed by a joint planning group that has NICE and Department of Health membership on it and that group makes final recommendations through civil servants to the minister.

Q890 Dr Taylor: Would you tend to try and concentrate on drugs that offer a real advantage but fill a real gap?

Mr Dillon: Yes. There are actually published criteria for selecting pharmaceuticals, those where there is the potential for real therapeutic gain, and another criteria might be where there is potential for very substantial resource impact on the NHS, and another would be where there is already considerable uncertainty in the Health Service about the therapeutic value of the drug and therefore NICE can add value by perhaps reducing some of that uncertainty.

Q891 Dr Taylor: How are you getting on weeding out some of the things that do not provide particular advantages or particularly good value?

Mr Dillon: Not well enough because we have not done enough on that, we have not had enough topics fed through to us and it is something that we, the ministers and the NHS think should change. In fact, the Department of Health is about to launch a series of workshops or seminars with the NHS to identify those topics in order that they can be fed through to the Institute.

Q892 Dr Taylor: Can you not feed them in yourselves and say, "This needs looking at. We want to get rid of it"?

Professor Sir Michael Rawlins: We could do but actually the Formulary does not have many totally inactive things in, I would be ashamed if it did since I was on the CSM for so long, and some of the very old things that you and I used to have to learn about in our youth are in the Formulary but are hardly ever used and to go through the whole ...

Q893 Dr Taylor: So, it is not much of a problem?

Professor Sir Michael Rawlins: I think it is but I think it is more subtle. I think it is much more in areas like diagnostics. The pathologists have made proposals about the sorts of things which should not be done any more. The radiologists displaying films of the skull say this should not be done any more. I think it is those sorts of areas that offer opportunities that we really need to explore to a greater extent, even complementary and alternative therapy.

Q894 Dr Naysmith: I want to explore this concept of substantial therapeutic advance just a little further and ask if there are any other implications for NICE in this. Some of the witnesses have suggested that it would be good if NICE could set criteria about what does and what does not constitute a therapeutic advance. Would that be something you would be interested in doing or is it so bound about by circumstances and depends on this, that and the other that it is not worth trying?

Professor Sir Michael Rawlins: There have been discussions across the world about, what is innovation? I think the first group is where there is a substantial health gain in areas that have been previously untreated and those, I think, are the ones that we, as a society, would like to encourage. There is a very interesting report from the WHO commissioned by the Dutch Government on priority medicines making some really fundamental points about areas of great need, not just the sort of diseases of the third world like malaria but many other conditions which are common both in developing countries and in developed countries for which there is virtually no really effective form of treatment and for which there is great, great medical need. Somehow, we need to encourage those areas of researches and I think there are a number of moves in that direction. Professor Woods was just talking a few minutes ago about the regulatory part of that. One of the very interesting things and I think a very important thing is that there is much more pluralism in drug discovery nowadays. University departments and so on are much more actively involved. The National Institute of Health is setting up its own chemical library for academics in the United States - I do not know if others will have access to it - to be exploring drugs. I do not think that is regarded as a failure of the pharmaceutical industry, I think it is a good thing that others are involved in an area which for 50 years pharmacologists have not been in universities.

Q895 Dr Naysmith: But it is not an area in which you see much role for NICE?

Mr Dillon: In a way, NICE has done because all the decisions that we make together act as a kind of case law. Those who want to understand in a sense what it takes to obtain support for innovative interventions or want to identify what it takes in a sense to get NICE's support and endorsement for real therapeutic value, just take a look at the decisions and indeed how the decisions have been taken. You can look at the standard methodology that we have published on evaluating the clinical and cost effectiveness of interventions and look at how that methodology has been translated into specific decisions and there is a story really over the last five years or so which is, as I say, a kind of case law which could be used by those who want to understand how innovation is interpreted, at least in the UK.

Professor Sir Michael Rawlins: Just to finally follow on from that, I have often used this example but Riluzole for Motor Neurone Disease which prolongs life by up to a year, we felt that was an important innovation for a disease that had previously never had anything at all specific. It was expensive at 38,000 per QALY. Relenza for influenza which you give to everybody also comes in at 38,000 per QALY and reduces your symptoms by a day and we said no to Relenza for everybody and yes to Riluzole. So, I think that demonstrates how we interpret it anyway.

Q896 Dr Naysmith: Can we move on to something different. What, in your view, are the factors that contribute to the time lag between the launch for a new drug and the publication of NICE guidance on new technologies?

Professor Sir Michael Rawlins: The processes - and Andrew will go into some of the detail - involve a very careful scrutiny of the relevant literature, full systematic review. That takes quite a considerable amount of time. Many hundreds, sometimes thousands, of references have to be looked at. We also have a very liberal, I believe liberal in the best sense of the word, approach to engaging our stakeholders and they have opportunity to comment and even to appeal against decisions. All that takes time. If we curtail it in any way we will do either a less robust job or we will end up disenfranchising some of our stakeholders. I believe the route we should be taking is to start with the appraisals around the same time as the licensing process and then complete the appraisal once we know the outcome of the licensing process. We have been doing this for the last couple of years. One of the difficulties, which happened, is that halfway through the licensing process and halfway through our appraisal the gentleman behind me finds there is a problem in the licensing, so it gets held up for a perfectly good reason I am sure, which means then we get held up in our appraisal process and have to stick that on hold.

Q897 Dr Naysmith: You are trying to get to the stage where the appraisal will be published about the same time as the drug's launch?

Mr Dillon: We have to wait about three months, I think, but we need to know the precise indications the MHRA are granting.

Q898 Dr Naysmith: Are there any lessons to be learned from the drug licensing process for you in this in speeding things up? It used to take far longer 20 years ago than it does now for licensing.

Professor Sir Michael Rawlins: I think we are fortunate, unlike the licensing process where they have to react to demand and the problems of surges and so on. I remember it from years back, it was always happening. For example, when they introduced a fee in 1988, there were huge surges the week before it came into force, which might have been predicted. We do not have that problem, we can control the rate at which things come in, which is an advantage to us.

Q899 Dr Taylor: Are you working more closely with the MHRA than we got the impression you were when we did the short inquiry in 2002, I think?

Professor Sir Michael Rawlins: I think we are and we have developed very good relationships. When we launched our depression guideline, we did it, as it were, as a joint enterprise with the MHRA because of the licensing issues which came up at the same time. I think that is a way we would wish to work, but nevertheless, we have separate functions.

Q900 Dr Taylor: I think one of our ideas and hopes was that this might give you better access to some of the commercially confidential details which you did not have. Has that happened?

Professor Sir Michael Rawlins: Not to that extent. That is not necessarily the duty of the MHRA, they are circumscribed by the European route. I have to say it was to the eternal credit of the MHRA that Tim Kendall and his colleagues discovered the basis of the SSRI problem in children because they published the data on the website. That is something which would never have happened when I was chairman, you were not allowed to think about such things. Those sorts of things have been very important in helping us. I am sure it is the intention of the MHRA to carry that forward.

Q901 Dr Taylor: After our inquiry you got the WHO to do a report. One thing it advised was to make public the basis of any of the advice you published. Have you been doing that more?

Professor Sir Michael Rawlins: We have been discussing with the pharmaceutical industry in relation to commercial and confidential data. Andrew will comment on that. The WHO did admit they wanted to use us as stalking horse for getting more clinical trials out into the open.

Mr Dillon: We never had a problem in being able to publish enough information to justify, we believe, the decisions of taking the recommendations we made. Sometimes we had to negotiate hard with individual companies to obtain agreement on the release of particular pieces of data to allow that to happen, but we have always felt confident that we have been able to say enough. Following our last appearance before the Committee, the ABPI and NICE sat down and reached agreement on formalising what up until then had been informal episodic arrangements with individual companies in the form of a recommendation to all the associations' members. That is now in a protocol which is operated both by NICE and the industry.

Q902 Dr Taylor: My memory is before the last inquiry we did get a lot of comments from people who felt you were working in a slightly obscure, less than open way. Do you think you have changed that?

Professor Sir Michael Rawlins: I think they were under a misapprehension and after the WHO report - which we were very grateful to you for suggesting in the first instance because it was not something we had contemplated - I think they recognised that it was more transparent than any other process in the world in that sense.

Q903 Dr Taylor: Can we turn to implementation. I am sure this is a fairly sore issue for most of us because certainly I get constituents writing to say: "This has been passed by NICE and I cannot have it, why not?". Have you any idea of the rate of implementation?

Professor Sir Michael Rawlins: The best information we have is probably from a survey we commissioned 15 months ago by Abacus who looked at 28 pieces of guidance which had been produced in the previous two or three years. They estimated there had been full uptake of 12 of those 28. There had been over-implementation of four - we will come back to that - and under-implementation of another 12. It was not a catastrophe but it was not nearly as good as it ought to be and in fact, we are setting up an implementation programme within NICE. The over-implementation was sort of curious. For example, we did an appraisal of metal on metal hips, instead of having the whole thing put in you can just put a bit of metal on the two surfaces. We estimated there were about 5,000 people a year who would warrant this type of thing, particularly young people. In fact, within a year 14,000 had been done. We may have got the wrong estimate, the epidemiological data might not have been that reliable. That is what I mean by over-implementation.

Dr Naysmith: There could be other explanations for it.

Q904 Dr Taylor: Were you able to tie down the implementation and the degree of it to any particular areas of the country, any strategic health authorities or specific PCTs?

Professor Sir Michael Rawlins: We have not done that but we have some data on it.

Mr Dillon: Yes, particularly with cancer drugs. We have data which shows the uptake of specific drugs, probably about eight or nine, by Cancer Network, which is probably the right geographical unit given the nature of those drugs. That shows the distribution before and the abuse of those drugs against an assumed appropriate target, given the nature and size of the population for each cancer network, both before NICE guidance was issued and after NICE guidance was issued.

Q905 Dr Taylor: Have you been able to relate that to whether the particular area is struggling with its finances or not?

Mr Dillon: Most of the NHS struggles with its finances most of the time.

Q906 Dr Taylor: The Government tries to deny this.

Mr Dillon: It is all relative.

Q907 Chairman: It is a good job Mr Burns has left.

Mr Dillon: Of course all organisations struggle with their finances in order to make the best use of available resources. What is interesting about the data is it shows that high performing cancer networks and strategic health authorities, where other data is analysed in that way, tend to improve their performance. Generally, all parts of the NHS improve after NICE guidance has been issued. The rate of improvement is greater in those that were already doing well, which is an interesting phenomenon.

Q908 Dr Taylor: Can you tell us where we can find the details of this data?

Mr Dillon: On the NICE website.

Q909 Dr Taylor: Again, when we were doing the previous inquiry we did have some worries that perhaps the selection of drugs for NICE guidelines did have an impact on other services and got preferential prescribing for these things against things which are time-honored and terribly useful, but did not have NICE guidelines. Have you had any further comments or thoughts on that?

Mr Dillon: When we go, as we do regularly, around the NHS and ask questions about the impact of NICE guidance, it is still an issue which comes up, but the reality is with or without the NICE guidance these interventions are going to be available to the NHS. Decisions are going to have to be taken relative to other desirable improvements in the service and funding interventions and practices which have been available for some time. The benefit of NICE guidance is that at least it informs those decisions in a way which quite often in the past simply did not happen. It reduces the variation in the way those difficulties are handled. In the end, the NHS and all the healthcare systems will always be presented in a way with more than they can consume, therefore, there is a need to make decisions, critical things to make sure they are evidence based.

Q910 Dr Taylor: Is 100 per cent implementation of your guidelines possible or desirable?

Mr Dillon: In the end, probably not because they are guidelines and not every single patient presenting with a particular condition will benefit necessarily in the way we have described, so no it is not likely that is the case.

Professor Sir Michael Rawlins: We estimated that about 80 per cent of patients would fit into a conventional guideline and, for all sorts of very good reasons, 20 per cent would not.

Dr Taylor: I am very glad you said that because one gets the feeling that some people feel it has got to be 100 per cent. I am grateful for that.

Chairman: Thank you very much, gentlemen. We are grateful for your help.