Select Committee on Health Minutes of Evidence

Examination of Witnesses (Questions 800 - 819)



  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 10 years after, when all this surveillance has been going on, that estimate has been raised to 25 to 30%.

  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 monitoring the safety of medicines.

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

  Professor Sir Alasdair Breckenridge: Well, I do not know 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 MCA 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 MCA. 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 Prozac, 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 pharmacovigilance 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 1 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 2½ hours without a break for Panorama and I was shown on the programme with 7½ 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 pharmacovigilance and to turn drug safety monitoring from a reactive to a proactive process has used ICH. We have recently adopted the guideline on pharmacovigilance 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 perhaps taking a specific drug. The second broad areas that we are involved in is 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.

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