Select Committee on Health Minutes of Evidence


Examination of Witnesses (Questions 840 - 859)

THURSDAY 20 JANUARY 2005

PROFESSOR SIR ALASDAIR BRECKENRIDGE CBE, PROFESSOR KENT WOODS AND DR JUNE RAINE

  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 to 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% 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% 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 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 6% 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, yellowcard.gov.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 indication 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 health professions about this. 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 (GPRD) 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% 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, 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 here? 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. 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—


 
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