 Baron Cornelius Fahedin de Lancy was a multi-talented man, apart from speaking a large number of languages, he managed to be successfully a doctor, a surgeon, a dentist, qualify at the bar of the Middle Temple and an art historian. How in Curiety. And he made a lot of money in the course of his life and he was very public spirited and he set up a foundation to fund studies and thoughts and lectures on medical legal themes. And his foundation gave money to Cambridge, which we use to fund occasional lectures on medical legal themes and that is the lecture tonight. It's my great pleasure to welcome Sir Peter Lachman, a most distinguished scientist to give the lecture tonight, which is going to bear upon the interrelationship between certain rules of the law taught and the availability of medicines. Sir Peter trained in biochemistry and medicine at Cambridge originally and after being foundation professor of immunology at the Royal Postgraduate Medical School he came back to Cambridge as director of the MRC Molecular Immunopathology Unit and professor of immunology. Though he retired in 1999 he's still active in research and ran a laboratory till 2005 and will open a small lab in 2011. He was found a president of the UK Academy of Medical Sciences, biological secretary of the Royal Society, the president of the Royal College of Pathologists and served on UNESCO's International Bioethics Committee. And in these capacities he became involved in the ethical and social aspects of medicine. He served on the SAB of Smith Cline Beecham and was co-founder and chairman of SAB and ADRUPT, ad protect, a company spun out of SB to develop therapies aimed at modifying complement function. He tells me that he and his wife descend into caves in the course of archaeology and he's kept bees for many years so he's used to a hostile environment and being attacked from all directions by people who wish he wasn't there. So he is well able to descend as a Daniel into the lion's den or a Daniel into a den of lion, a lion into a den of Daniels as the case may be and say things which will infuriate the lawyers. Sir Peter, thank you so much for coming over to you. Thank you very much John for an over kind introduction and for inviting me to give this lecture. Unlike the founder who was a polymath and understood the law as well as medicine and unlike many of your previous speakers I feel very inadequately qualified to talk to an audience of lions or Daniels as the case may be. But I'm very grateful to John and also to David Howarth for giving me two supervisions to at least get me started. This is the 50th anniversary of the withdrawal of the drug thalidomide and what I'm going to talk about is the consequences that this had subsequently. And here's thalidomide for you. It looks entirely harmless as much as chemical formulae always do but actually it wasn't quite harmless. It was a drug that was probably developed towards the end of the wars and antidote to nerve drug poisoning but it was patented in Germany in 1954 by a chemical company called Grünenthal and who launched it in 57 as an anti-emitic, executable for women who were pregnant and treating morning sickness and it was licensed all over the world actually except in the United States where a very young inspector called Francis Kelsey who is still alive declined to license it. Not because she was worried about any side effects but because the rats and some of the experiments didn't fall asleep and she was therefore not convinced that it actually was an effective sedative. For that reason the use in the United States was very small. No studies at that time were done on pregnant animals because it was believed at that time that drugs either didn't cross the placenta or if they did wouldn't harm the fetus. That of course was a mistake. Between 57 and 61 more than 10,000 children worldwide were born with limb deformities in the United Kingdom as I show you here there were 2,000 of them of home 466 survived. Even in America it wasn't licensed there were cases because it was used in clinical trials. The most common abnormality and I decided I wouldn't show you a picture is fochamelia which is absence of the growth of the limbs. This was probably the greatest disaster concerning drugs that there's ever been with thousands of people. I do point out to you on the side that compared with the effect of withdrawal in 1972 of DDT as a pesticide it fades into insignificance because that actually caused millions of deaths from malaria since there was no substitute for it. There are many people who believe that Rachel Carson, the environmental campaigner and William Rickleshouse who was the head of the EPA in America who agreed to ban it may have between them with the best interest in the world have actually killed more people than Pol Pot did. But this is a bit outside our story today. Thalidomide has actually not disappeared. It's actually a very good drug. It's now used for quite different purposes. It's used for treating a form of leprosy and it's used for treating a form of blood cancer called multiple myeloma and it and its analogs are still in use. It's a rather sad story that in Brazil where there is quite a lot of erythema in a dose of leprosy in spite of the fact that it is known that it causes fetal abnormalities there have still been cases of fochamelia because it is so difficult actually to control whether women who are being treated become pregnant or not. So what happened? Well, first thing that happened was that all drugs are now tested for effects on the fetus, teratogenicity and that certainly is a good thing. In this instance it was also perfectly appropriate that people should be paid compensation because fochamelia doesn't otherwise occur at least only with huge rarity and therefore a direct cause between taking the drug and having the abnormality is probably true. I understand that parts of the world, including here, there are still campaigns about the nature of this compensation going on. Subsequently there was another major consequence which I'm really going to talk about which is that the procedures for licensing drugs became very much more rigorous, took much longer and became increasingly expensive and I'll show you data about this. I'll give you a little quotation here from your active pointing out that it was a response to this thalidomide disaster that caused the first European directive about this. And the second and possibly even more difficult to deal with consequence is that the public tolerance of risk with regard to prescribed medicines became almost zero and became totally unrealistic because it must be pointed out. Without any doubt that any drug that has any pharmacological action can also have side effects. There is no drug and never has been that is absolutely safe and of course we use drugs all of us like aspirin which if they were to be licensed nowadays would certainly be refused a license because they are much too dangerous giving rise to gastrointestinal bleeding and quite appreciable numbers of people and they would never have got onto the market. I'll come back to the question of herbal medicines a bit later. So putting a little few figures on that I'm going to show you a few slides about actual figures. It now takes more than 10 years probably and on average costs more than a billion dollars taking into account failures of drugs that are withdrawn to take a new drug from discovery to market. That is quite a lot of money. One of the consequences of this is it's quite impossible for academic departments or small biotech companies to take a drug from discovery to market. This can only be done by large farmer who has the resources to deal with this and that isn't a tremendously good idea because large farmer which has major responsibilities to develop things may not be that interested in doing things that are fairly high risk. And which if it could be done more cheaply and more innovatively could be done much better by small companies. If you compare drug development with new developments for the internet which are largely produced initially by very small companies and where it's gone terribly fast you'll see the difference. And it's also led to the fact that companies tend to concentrate either on diseases that are very common where they can make blockbuster drugs and this causes a lot of metuism in drug development and not to deal with diseases of intermediate frequency. Very rare diseases are subject to separate legislation, the so-called orphan drug legislation, which makes them a lot easier to deal with. But the ones in between tend to get neglected, which includes actually. There's quite an interesting story. My own field is the complement field and we've been trying, as Don mentioned, to develop complement therapeutics for donkey's ears. And nobody was ever very interested because all the diseases we were interested in were pretty uncommon. A few years ago it became apparent that age-related macular degeneration is in fact largely due to abnormalities of complement which had not been suspected. And that of course is very common. That has a potential audience or client-ship of millions and millions of people. And now companies are getting seriously interested in this again so that it makes a big difference. And then the other thing we're going to talk about is litigation. It's become a habit to sue drug companies for harm from side effects. And that also has a very bad effect on drug costs and also, as I will tell you, has other highly undesirable side effects which will come to them. And these of course were not intended consequences. These were unintended consequences. And I thought I might just bring to your attention the origin of the law of unintended consequences. This is Robert Merton. He lived till about 2000 but after having written this paper in 1936 he always intended to write a book about it but never did. So it's more or less still there. His son actually won the Nobel Prize for Economics afterwards. And he says it's often cited rarely defined as actions of people especially government always have effects that are unintesperate or unintended. And he gives five sources, ignorance and error, which nearly always occur. The imperious immediacy of interest that counts for the problems we're having with the current reforms of the National Health Service. Basic values. Well an interesting example of that is the European physical agents directive which restricted the amount of irradiation that people could be exposed to. And therefore if implemented would have brought an end to all medical magnetic resonance imaging which exposes people to more than this amount of irradiation. And when this was pointed out to the director of worker protection in the EU she said that didn't matter. All workers are entitled to equal protection. A statement of quite unparalleled anonymity since the first consequence would be the abolition of the fire service followed shortly afterwards by the police and all of medicine. So that is the imperious immediacy of interest. Basic values. Yes. Basic value sorry we've done the self-defeating prediction. Yes there's another good example of that and that is waiting time targets in medicine because they believe that this will mean that people have seen more quickly. In fact of course if you impose waiting times on doctor surgeries you see fewer patients every time because in order that people don't have to wait longer you actually book fewer people in. So the effect actually is the exact opposite of what's intended. However this is all words this I recommend to all of you is the statement of the law of unintended consequences that actually says it all. This is a cartoon by Mike Walsh. The line at the bottom actually I add it when I gave a copy of this to Brian Mawini when he came to dinner instead of Virginia Bottomley who was then Secretary of State of the College of Pathologists. I thought perhaps he wouldn't understand it. He certainly wasn't amused and said he'd never been called a frog before. And I bit my lip very hard and refrained from saying what I say now which is minister you're not the frog that's the health service you are the princess's lady in waiting. If I make that in it's a small prince that's at the back and says it seems such a pity because it's not frog because they're really terrific. Yes I'm sorry if you can't read that that's right. And this is the princess and that's yes that's the prince who's just drowned because he can no longer swim. Yes thank you John I didn't realize this. But every every decision maker should have a copy of this hanging in his or her room. Now to come to the actual problems the problem of drug development as I say this applies to prescribed drugs alternative and herbal medicines are largely exempt from regulations. Although it has to be confessed the MHRA which is the Medicine Healthcare Regulatory Authority has recently tried to produce a regimen for homeopathic medicines which since they are only water is actually extremely difficult to do. But the tension of regulation is to ensure purity and consistency. That is very important and never applies to herbal medicines they never the same thing consistently studies of metabolism and clearance. Animal studies safety and efficacy safety and efficacy studies in man. And there is no dispute that these are necessary. If you don't have these there's a great danger of people being given things that are really of no value and this is vital importance to protect the public. And the process of this given briefly this is from NICE which is the National Institute of Clinical Excellence Excellence and I give you what MHRA and NICE mean here. This is very briefly the life cycle of a medicine. Somebody discovers it in some way we can't discuss there are many ways in which people decide things do things which may be useful in medicine. This is then explored further to see if it can be applied to human medicine. This is what's called translational research and then one starts having to do studies of efficacy and safety. And when these are being completed the drug is licensed gets authority to be sold to then manufactured and distributed and clinically used. But bear in mind that appraisal occurs here. I'll show you in the next slide experiments on how best to use the drugs go on forever after licensing. Licensing is not the end it's the beginning. And to put it in a slightly more formal phrase now this is by courtesy of Kent Woods who is the chief CEO of the MHRA. You begin with discovery research you go on to this preclinical development biological testing pharmacological screening half lives and then you have three phases of clinical testing. Phase one is done usually on normal subjects. There are exceptions to this. I mean highly toxic cancer drugs are never tested on normal subjects. But in general they're tested on normal subjects to see that they're safe. A slightly bigger phase two style is then done for efficacy which of course is done on people who have this illness you're interested in. So you can see that it does any good either against placebo or against best available treatment. And up to there it can be done by fairly small companies. These are fairly small trials and then you go on to what are now these huge phase three trials to look at efficacy and much more detail and to look at rarer side effects. And phase three trials comprise more than half of the total cost of developing a drug. They are then reviewed by the MHRA and then you get licensing or not as the case may be and then post marketing development where you continue to do controlled trials. To see how to use drugs better and where they may be used for new indications. Some drugs do worse when you release them than you expect others occasionally do startling and dramatically better. Aspirin was found a hundred years after it was introduced to be very effective in preventing colon cancer. Statins which many of us take to lower cholesterol actually have a far larger effect on cardiovascular mortality and cholesterol lowering effects can explain and the probably anti inflammatory. Otherwise quite often effects are less good. One of the reasons for that of course is that no trial population is ever representative of the population which finally takes the drug. Not least because their people are willing to take part in trials which is already a highly selective characteristic. And they also made sure that they actually take their medicines which of course a lot of people don't. Now the consequence of this and I'll show you quickly some figures to alarm you. This is from the Boston Consulting Group a lot of these things from the states. And this is the cost per molecule that comes to market taking into account the failures. And you can see that this is going up exponentially in an entirely alarming fashion. So that they at the present time they think it's about 2.3 billion dollars to bring a drug to market. That's even higher than the figure I quoted earlier. And these are all modeled figures so you must take them all with a slight grain of scepticism. And they predict this is going to go up to 3.8 billion by 2015. Who is going to pay for that is mysterious. This is putting it another way and it's from a different research group. And I'm very grateful to a gentleman from Roche whose name I've forgotten Dr. Richard Peck who very kindly sent me these. The NME is a new medical entities and this is per billion dollars spent. And this is the number of new drugs that come to market at this expenditure. And you can see they've drawn a line right through it. But actually it's fairly stable until thalidomide when it suddenly begins to decline in a rather alarming fashion. And it's continued to decline ever since. And this is structure of DNA. This is when molecular engineering starts. This is when human insulin is first made, genome product, dolly. Tremendous improvements in the basic science and a huge reduction in R&D productivity. And here when the FDA has a new law which allows them to charge drug companies for doing their investigation. So they had some more people to do it and they got a bit faster. But it's temporary and it's still going down. And that is actually also extremely alarming. And this particular group have identified three causes for this. The first one is the one that's of interest to us. The cautious regulator problem, which I'll come back to. The better than the Beatles problem sounds rather nice. That's a way of saying that all the easy drugs have already been made and what's left is much more difficult. I'm not sure that's true. The rational design fallacy, I don't think it's a fallacy at all. It is again quite common that when things appear such as the idea that you can design drugs rationally from the underlying biochemistry everybody thinks wow. Five years time, no drugs are going to be made by any other method. And that's never the case. These things are very slow. And in the first 20 years of rational design, the only rational design drugs ever made were the neuraminidase inhibitors used to treat flu, which are useful but were nevertheless unique at that time. But it's coming. But the cautious regulator problem is what concerns us here. And this is their definition of it, the cumulative ratchet-like effect of the regulator's low risk tolerance. Each sin by the industry, lovely term, or genuine drug misfortune tightens the ratchets and few events ever loosen it. In fact, what drives the caution of the FDA is fear of being phoned by congressmen, which apparently happens all the time. And they are driven to ever greater caution by fear of Congress. The amount of air I think personally is driven less by fear of MPs than by fear of the tabloid press. I haven't given you any examples, but you will all have seen plenty. Drug scares make the front page of tabloid press as much as you like. Now, this is some data about, again from America, on cancer drugs at launch, how much they cost per month. And you can see that's going up exponentially as well. So they did now cost something like 7,000 US dollars at 2,007 prices for a month's treatment compared with about 500 recently as the 1980s. And this is some British data. This is from NICE. And so Michael Rowland sent me this, who is the chair of NICE, shows the huge difference in development costs between different drugs. And this is expressed in actually a much better way. This is the eventual incremental cost per quality. Qualies are quality-adjusted life years, which is actually what people should be looking at. In other words, how much good do you actually do with the drugs? What is how many quality-adjusted life years do you get per dollar? And you can see with some drugs the amount of dollars you need, over 100,000 dollars, that is largely unaffordable. I can tell you the figure for developing vaccines in the United Kingdom and the Department of Health uses is 30,000 pounds per quality. So, you know, this is getting totally out of the region. On the other hand, some drugs are very good value. And I just want to say a word or two about this drug, Rituximab. Because that was developed in a rather unusual way and is of some interest. Rituximab is a monoclonal antibody against anantogen found on lymphocytes. And this was developed by a physician in Seattle, the original monoclonal antibody, to treat his father's B-cell lymphoma, which he did, as I'll show you in a minute, without any regulatory approval because you don't need any. And when this was found to work, it was then sold to a drug company who made, humanized it, and IDEC then made it and released it for treating B-cell lymphomas. And then, lo and behold, I'm treating, I hate David Jane. There's so much more about this than I do that it embarrasses me to say so. It turned out to be immensely useful in rheumatoid arthritis and in lupus and in vasculitis. I'm quite unexpected. It's actually hugely successful and important drug. And it probably would never have got there as quickly as it did except for this invaluable exception to all the rules, which is the name, patient exemption. The legal statement is in paragraph one, interpretation for medical profession, is in the other paragraph which allows a doctor in good standing acting in good faith with therapeutic intent to treat his own patients who have given their informed consent with anything, including things he's made himself without asking anybody. And to give you a little example in Anbrox, we have for the last quarter century or more been making, harvesting our own wasp venom. And when we started this, there was no commercial wasp venom for desensitising people available there now is. Product is much worse than ours, much dirtier, but much more expensive. And we collect this from wasps nests, the pharmacy still doesn't sterilise it, and we inject it into patients, our own patients. And we have been assured we can do this forever. And it has never been tested for toxicity. I mean, we know wasp venom is toxic. We know its effects on humans when they get stung by wasps. I mean, it's all quite pointless. And this you're allowed to do. If we wanted to sell it, we would have to go through all this room alone. And then it would take years and years and years and cost a fortune. But this is terribly important in patient exemption and vitally needs protecting from interference from Europe where it's always in some danger. This is just to point out to you that even the richest countries are not going to be able to afford this. This is comparing gross national product with health expenditure in dollars. And you can see that even in countries with the highest GDP, United States presumably at the top there and others, the expenditure on health care expenditure is reaching figures that are really almost important. They don't sound huge, but of course this is per person, including all the healthy people. That actually is becoming extremely expensive. If you multiply this by the millions of the population, you'll realise that this becomes to a huge figure of the part of the GDP. Now, the remedies. Now, it is the 10th anniversary of my starting to campaign on this. And the first, I actually like this, I thought I would show the lawyers a slide at the beginning of how the law keeps the city. This is an article by my friend Mike Hanlon who is a journalist which he wrote largely at my instigation. And he writes terribly well, but we can't go all through this. But the points he's making, all the ones we actually want to make, he says that while there have been tremendous scientific advances, its development has been very slow and this is due to the new pound obsession with 100% safety and the growing law's role of lawyers and litigation. So it's all your fault. I said that the regimen for drug approvals imposes very high costs for the few life saved, which I would still say now. And mindful of thalidomide, it now exists and tests so rigorous that the introduction of new product can take a long time and be very expensive. And the example he gave here, which is also worth exploring a little bit is a drug called opron, which was a drug at that time for treating rheumatoid arthritis, very effective painkiller. It did give rise to side effects and it could cause mortality and elderly people particularly if they exposed themselves to light. And because it'd been rather unfortunately advertised, it was simply withdrawn. And the interesting story is that the pharmacist at Edinburgh, who had rheumatoid arthritis when it was withdrawn, took the whole supply home. So she at least could continue to take it, she knew the risks and actually it was an extremely effective drug. It isn't any longer than a much better drug. And finally, this business fueling all this precaution as the fear of litigation, which I'm going to talk about in a moment, and he says already patients who willingly took part of trials and drugs to combat AIDS are starting to see side effects. This lovely phrase of his when the lawyers start to circle, disclaimer signatures are worth far less than the paper they are scrolled on. And the final point, which I hadn't highlighted but verse their word about, we took this up with the Department of Health. And one of the people said yes of course in theory they approved fewer people dying rather than more people. But actually if one of the fewer people happened to be your mother they wouldn't see it like that. And I thought that was a deeply shocking remark for somebody who makes public policy to make actually. Well five years ago David Cooksian, a report he wrote for the government actually made much the same points. Again he, this is, he just said the regulations are too complicated and health technology assessment happens too late. He made some firm suggestions that should be earlier conditional licensing of drugs and the use of the NHS information programs should be used to assess emergency side effects and efficacy over longer periods. In other words it should be done post marketing. It's quite interesting that although some of the Cooksian report was implemented, this part of it was totally ignored and no action was taken by the government of any kind about this. And at the time still it was unpopular. I remember being invited by Alastair Brackenridge to a meeting about these Cooksian proposals. And he said he was asking, he was the only person, I was the only person he'd met at that time, we actually agreed with Cooksian. Time has changed, it's an idea whose time has come. This is much more recently, this is from an American source, not a source I actually approve of. This is somewhat right politically unsatisfactory think tank. But what he says is quite right. What he says there should be more choices and better health and one should be free to choose experimental drugs. And he says it's another question of reforming the federal drugs agency. There should be a dual system where patients who wish to can take drugs much earlier. And what he actually proposes is very much what I'm proposing, which is, the slide is now familiar to you, that patients at the end of phase two should be allowed to take the drugs if they wish to. And curiously enough, only half an hour before I came out today, there appeared an item on the scientists website reporting from Bloomberg News 48 hours ago that an American senator is proposing to the American Congress, lady called Kay Hagan, to get a faster approval for drugs, especially for rare diseases rather than common ones, to get this through the American Congress in the near future. So it will come, one hopes. So what we're proposing is the abolition of phase three trials. It would cut both time to market and cost by about half. It would encourage companies, as I've said, to develop drugs for less common diseases and allow far more companies to do this. Post-marketing surveillance would be used for monitoring both efficacy and side effects. The UK is an extremely good place to do this because there are now growingly efficient information systems and again some of my medical colleagues may laugh at this because there's been a frightful problem with the NHS information technology, but it is getting better and there will be a database which will allow efficacy as well as side effects to be monitored. So one doesn't need to put anything very new in place for this and trials to improve the use of drugs will of course continue after licensing. Some drugs will fail after licensing, some already do and some unproceed side effects occur. That also happens. The frequency of side effects at phase three trials takes it from about one in a hundred to one in a thousand. Things that occur much less than one in a thousand you're very likely not to pick up anyway except post-marketing surveillance. The real question is whether phase three trials actually save any lives at all. In other words whether the number of people who come to harm by not having the drug for many years when it could work actually outweighs the side effects that you're preventing by phase three trials. And that is something which it would be interesting to get data on. I've put it here in slightly simpler terms but it's important for this audience because what one wants is that after phase two trials remedies should be made along to those who want them, who've be given all the information providing they can waive the right to sue in a form that will stand up to the law and will also agree to participate fully in surveillance. They'll also have to recognise that no remedy is ever drug free and the point I've just made to you is that one might then actually be able to decide whether phase three trials have a positive or negative effect on calliers and the guess is it has a negative effect. We're actually hoping to have some data for you from the Institute of Arthymology about how many people have gone blind because it took so long to license VAJ inhibitors for the late stages of macular degeneration but they're not yet available. So how would we do this? Would itself need to be trialled? You wouldn't, the way that politicians love, do it all over immediately, all over the country for every drug. It would need to be trialled to see how it worked. The potential patients would be given all the information and would be explained the risks of uncertainty. They would then sign an indemnity and here is the problem that I've learnt about from my colleague. This conflicts with the strict liability provisions of the Consumer Protection Act and of the European Directive on Product Liability and this is a problem for you lot to sort out. Here's the Consumer Protection Act. I apologise. I couldn't get rid of this blueness from Wikipedia. I was interested to find that this was the first time that a European Directive had been directly put into English law. That introduced strict liability which was new. The main criminal offence of giving misleading prices that doesn't interest us particularly here. It was the first time that a European Directive had been implemented. Not a good start. The Consumer Protection Act and I thank David Houth for these explanations is that the safety of the product is not such as persons generally entitled to expect. The court must take into account warnings with respect to doing or refraining from doing anything with or in relation to the product. I do love legal language. This means that although it's not possible to exclude liability by notice or contract, i.e. you agree that you can't see us if this goes wrong, which is what is needed, it is possible to affect the level of safety persons generally entitled to expect by giving suitably clear warnings about the risks. Now there is this case which apparently is still in force which said that people are not entitled to expect absolute safety in all circumstances, which is true and helpful. There can still be liability even when the level of safety they do expect is in fact physically impossible. That is actually a totally meaningless statement when you think about it. It doesn't mean anything. But the third statement is much worse. It says that risk-benefit calculations don't count and it doesn't matter that nothing could have been done to make the product safer. That is totally mad. It is totally mad because risk-benefit is at the centre of all medical decisions. Whenever a doctor is confronted with a patient and has to make up his mind, he takes risk-benefit ratios into consideration and sometimes costs benefit as well. This is absolutely essential and to say that it doesn't matter with regard to drug toxicity is simply crazy. It's also important because it allows consideration of public as well as individual benefit. There's a utilitarian aspect to it, very important with regard to vaccination. Again, David pointed out to me that risk-benefit now is a standard practice in the tort of negligence and judging reasonableness. That includes benefit to others. He says the case laws contain the idea for more than 60 years and were somewhat pointlessly repeated in the statute in 2006. One of the central problems of strict liability is that it fails to take account of positive externalities with all the things we're talking about. In other words, it really is not reasonable that strict liability is applied to this at all. It's not appropriate. Nevertheless, drug regulation aims or claims, whatever you wish, to achieve favourable risk-benefit and cost-benefit ratios. That's why we have NICE. We've set up a whole organisation to look at this. In practice, however, it's a past fiction. The real concern, particularly in the States, but increasingly here, is actually fear of litigation. The public, at any rate, those who write on blogs, because I've been actually looking at this on websites, enthusiastically support suing drug companies for anything under the sun. They do not realise that the person who pays the damages is not the drug companies, it's the consumers, because these damages are simply added to the cost of drugs. Drug companies have to make a profit. This is just written into the expenses, both the damages and the lawyer's fees are written into the drug prices. This, therefore, is not a public good. Litigation is also unfair because it compensates only where fault can be shown. I point out to you, in many of these statistical side effects, you don't actually know whether the drug is at fault. So somebody who has a heart attack because they think it's due to a drug may get a lot of compensation, or he also has a heart attack, it's nothing at all. I will come back to this other question of whether there are better ways of doing this. What I'm not saying is that where people are harmed by negligence in the conventional sense of the word, not taught or knitted, fraud, deceit or other bad things, they should certainly be expected to be held to account. People who advertise drugs improperly should be fine. There's no doubt about it. I've been very unfortunate after those of people being deceitful about drugs, and there's no doubt that the law has an important role there. But these are all relatively minor cases. What most litigation is based on are statistical side effects. You have a drug, and I'll give you a couple of examples in a moment, where your likelihood of having some event, getting diabetes, having a heart attack, various other things, is increased by some percentage, usually quite small. It can never be shown in any individual case that this is causal, because these are just statistical side effects. This has become the main feeding ground of class actions against drug companies, and it probably is unjust. It probably has no proper justification, and it certainly does great harm to health care. I'll give you a couple of examples. Both of British drug companies. AstraZeneca have an antipsychotic called Cerroquel, which is quite effective, and that is claimed to cause diabetes and obesity. Very difficult to establish in a population which has lots of obesity and diabetes anyway. When this was tested in court in the United States, it was actually ruled against. The jury did not consider that the claim was worthy, and various other cases had also been dismissed in the States. Nevertheless, a few months later AstraZeneca settled class actions from another 17,500 patients and paid about $198 million as damages in this class action suit. Money which will undoubtedly be recovered in the cost of drugs. The other example, perhaps even more interesting, because it's a bit more difficult, is Rosiglitazone or Avandia, which is a well-known anti-diabetic drug. It belongs to a class of drugs known as PPygamera activators, which increase insulin sensitivity in type 2 diabetes, an important thing to do. That is claimed to increase art attacks and gynaen things, and compared particularly with another drug on the market, which is very similar, which is said to do this less. Actually there are some figures here for those who like the odds ratio for the composite harm of acute myocardial infarctional stroke, heart failure, or all cause mortality in patients 65 years or older was 1.18. That is not a great deal. It corresponds to somewhere between 1.5 and 2 extra events per 100 person years of treatment. Now at the age of 65, 100 person years of treatment is quite a lot. You're dealing with a population who are going to die rather sooner than that. Pyroglytazone is slightly safer with regard to the CVS events, but has also its own problem that there is some association with bladder cancer. They are both valuable drugs in controlling type 2 diabetes, and it's not immediately clear that the drugs one could use to replace them wouldn't have equally unfortunate effects. But in February this year GSK paid 250 million pounds to settle 5,500 suits at average of $46,000 per pletif. They've paid that before, so they've paid a total of $770 million for something which probably has no real merit in it at all. I regard this as the equivalent of paying hostage takers actually. It just encourages this unfortunate practice, and it is unfortunate. Just have a look at this for example. This is from an American website. This is sort of ambulance chasing lawyer. They're actually seeking these patients. They advertise in the public to find patients who would like to take part in these class actions so that they can make a lot of money out of it too. And just for good reason they're doing the other one for bladder cancer as well. All cases investigated with no fees unless recovery is obtained. Well, that's America, but I think this is even worse. I was sent an email with this just the other day. This is somebody who wishes me to invest in a fund which is going to pay me a high lot of interest by running class actions. I think this is totally immoral. They're hoping to raise 5 million pounds. They guarantee a fixed rate of 8% or 9% if you have annual income. And they're 25% of each winning case is net profits. I'm actually quite surprised that this is still legal. It's certainly immoral, and that's in this country. The Legal Services Commission comes out of it slightly better. This is a class action against Senefi Pasta, a French company about sodium valprate, which is a very valuable anti-epileptic drug that's also claimed to cause birth defects. The Legal Services Commission spent 3 million pounds on a class action which never came to conclusion and then withdrew it because they were advised by council that there was no prospect of success. The second thing that plenty of lawyers were not at all pleased with that not because the battle in court was lost, was continuing with too great a financial risk for the claimants. Also concerned about legal aid funding for group actions to ensure proper access to justice for individuals who suffer serious drug-induced injuries. They would say that, wouldn't they? But it isn't just money. The litigation ourselves can also kill. And this is perhaps the most tragic case of all, and this is the Wyeth Rhetivirus vaccine. Wyeth made a Rhetivirus vaccine in 1998. It's a good vaccine, quite effective. Against this virus which causes 40% of all severe diarrheal diseases all over the world. In the west, of course, it doesn't usually kill people, though it can send them into hospital at a time. In Africa, this is a major cause of death, as I'll show you in a moment. It has a side effect. It causes inter-susception where a bit of gut folds itself into the next bit of gut because the lymphoid tissue in the gut has swollen. It happens in children at times. Anyway, it's not usually lethal, but it was found to be a social increased incidence. I've given the higher estimate here, one in 10,000, others say one in 16,000 extra cases. Wyeth then withdrew the vaccine in the United States because it felt that it might not be acceptable because the disease isn't that safe. On legal advice, I am told, they withdrew it worldwide because they've told they would certainly get sued if they've withdrawn it in the United States and continue to use it in the third world. Although the risk-benefit ratio is totally different. New vaccines took eight or more years to evolve. Merck had a new one in 2006 and GSK in 2008, which give a little bit less. Well, they do give less, probably about 150,000 extra cases, but they also give them a slightly different time. Between 1999 and 2006, approximately 3 million children died the rotavirus infection in Africa. That's really quite scandals. Just to give you some idea about childhood deaths less than five. This is Africa. This is all of Europe. This is South Asia. There's almost none you see here. This is the diarrhea bit. You see the big yellow one near natal causes, which are quite different. Birth increases and things. Padawnia is slightly more common, but it's a huge cause of death. About 3 million children may have died unnecessarily. They wouldn't all have been vaccinated once, but of course the new vaccines will take time to come in too. So if there were no other reason for doing something about this, this is one of them. The reason for all this is an unfortunate practice in the law that they recognise a distinction between harm caused by action and harm caused by inaction. This doesn't just apply to vaccines, which we are talking about, but also active and passive euthanasia. You can't give people drugs to help them on their way, but you can starve them or refuse to give them drugs. Ethically, whether there is a difference between omission and omission in doing harm is very contentious, and you can read cases on both sides. I wouldn't wish to take a strong course on this, particularly because I know that Neil believes there is a difference. But in the context of a doctor's duty of care to patients, I think there is no doubt that there is no difference. We did once have a vote of this in a medical meeting, and at least 90% of the people present agreed. In this particular context, to have this distinction is meaningless. I will take the opportunity of quoting to you from one of your late colleagues. Lord Donaldson, who wrote a letter to The Times in 1974, which is worth quoting, says, What has become of the age-old medical commandment thou shalt not kill but needs not strive efficiently to keep alive? What's happened to the well-known distinction between boredom, treatment, et cetera, et cetera? I wrote an answer at the time that didn't publish it, so you are seeing it here. Lord Donaldson is wrong in writing thou shalt not kill but needs not strive efficiently to keep alive is an age-old medical commandment. It is neither. It's neither old and certainly not a medical commandment. It's a quotation from Arthur Clough's clergyman and the Victorian poet who wrote very memorable poems. Deeply ironic rendering of the Ten Commandments known as the latest decilog. And if you don't believe that that is meant to ironically try the next two couplets, thou shalt not steal an empty feet when it's so lucrative to cheat. Thou shalt not covet, but tradition approves all forms of competition. He goes through all ten of the Ten Commandments this way. And though I didn't know Clough, I imagine he would be mortified to have this used as a legal precept for how to treat people. So what do we do? I think, I do hope we'll take a list with you, you should require proof of direct causality before compensation is due. It shouldn't be just on the basis of statistical association. No win, no fear arrangements will really be abolished as they once were. They do encourage things like people who set up these funds for actually profiting out of this. Indemnities should be made legally binding and I understand that this means abolishing strict liability and replacing it with a tort of negligence in respect of myths and so that risk benefit can become central to making decisions as is entirely sensible. And try to abolish at least in part the distinction between harm caused by commission and omission. And finally, and this is slightly different and more for our government than its lawyers, is to ensure the NHS is adequately financed to provide necessarily care for all, including those who suffer dried effects, but even those where there's nobody to be blamed. And it is just worth pointing out that a lot of this litigation culture is imported from the United States. And in the United States the situation really is totally different. Having no national health service and a large part of the population are not adequately insured, the financial consequences of illness are a great disaster and the attempt to try to recoup this whenever you can, even if it does harm on the side, is more understandable than it is here and we're in a much better position to do without this. And finally, my last slide, the thought of which I'll leave you, is a modern rendering of Hippocrates' famous dictum, premium non-notary. And I thank you for your attention.