TESTING OF NEW DRUGS

HL Deb 03 March 1964 vol 256 cc53-96

4.44 p.m.

LORD TAYLOR rose to ask Her Majesty's Government to consider the establishment, under the Medical Research Council or elsewhere, of a central agency to organise the clinical testing of new drugs. The noble Lord said: My Lords, I beg to ask the Unstarred Question standing in my name on the Order Paper. Because this is an Unstarred Question, I shall not have a chance to reply to it, and that means that I shall not be able to thank noble Lords who are going to take part in the debate after they have done so. May I therefore do so in advance, and thank all noble Lords who will be taking part in this debate, and say how grateful I am for their help?—I cannot say "support", because I do not know what they are going to say.

LORD LINDGREN

That is bad organisation.

LORD TAYLOR

My noble friend suggests it is bad organisation. Perhaps my organisation is better than it seems.

My Lords, the successes of commercial and academic pharmacology during the past twenty years have been quite extraordinary and have changed the lives of many millions of people all over the world, but as a result of these successes medicine and the public are now facing a situation which is really without precedent. I think it is fair to say that medicine has never had a finer lot of drugs available for the cure and relief of disease. But there is another side to the penny. Not only is more good done by drugs than ever before, but also more harm. I think this is recognised by all serious students, certainly not least by Professor Alastair Macgregor, the Regius Professor of Materia Medica and Therapeutics in the University of Aberdeen, who recently gave a lecture in Glasgow called a Maurice Block lecture, which was reprinted in the Listener: and if any of your Lordships are interested in the technical side of this problem I strongly recommend this lecture, entitled Drugs and the Community.

Now I said that drugs have done harm, but I do not think we should overestimate this. I think we want to keep the matter in proportion. We are all aware of the tragedy of thalidomide; but two years ago there was a severe epidemic of German measles, and if your Lordships will look in this week's Lancet you will see that the first letter is from a pædiatrician who describes five ghastly cases of congenital defects, similar to but not identical with those of thalidomide babies, which had occurred during the year, following German measles in the mothers. This pædiatrician goes on to calculate that the total number of malformed babies—these particular babies went blind, were mentally defective, and so on—from this cause in that year may well have been greater than the total crop from thalidomide. But that does not make the situation any better: it merely gives us a little picture of the risks and difficulties we run, and enables us to see that, while we cure many more people, some suffer as a result of our efforts.

In between the great number of good drugs and the dangerous ones, there is a vast penumbra of new drugs of marginal advantage—some useful, but not very much more useful, or perhaps no more useful, than their predecessors; and some, on balance, useless. In this country we are struggling towards a national method of dealing with the effects of all this pharmaceutical and pharmacological activity, and here I should like to pay a tribute, first, to my noble friend Lord Cohen of Birkenhead, who, on a series of committees, has done great work in this particular respect. In particular, one of his committees has been concerned with the classification of drugs for the benefit of doctors, and year by year his committee has classified new drugs, as they have come out, into five categories.

These categories are designated by letters. The trouble is that I can never remember which letter is which, but in fact they are as follows: "N" are the jolly good ones—"N" for "new" drugs of proved value. My noble friend will correct me if I am wrong, I know. Then, "S" drugs are those similar to standard pharmacopoeia preparations; and "P" are new drugs which look good but are not yet fully proved. So "P" is for "possibles", one might say. Then, "O" are new drugs of little or no value; and "H" are mixtures of "O" with other things: so you can say that the "O's" and the "H's" are really out. This has not prevented the successful, although usually temporary, sale of certain drugs in the "O" and "H" categories, but I think it is fair to say that when drugs have an "O" or an "H" after or before their names, this, in the long run, has meant a death blow to those products. Although I understand my noble friend has retired from this particular Committee, I think this work is going on—at least, I hope so, because the value to the medical profession of this simple classification of new drugs has been very great.

My second tribute is to something the Ministry of Health have done to help. They have prepared a little journal called the Prescribers' Journal. This little book goes out to every doctor throughout the land in the National Health Service—and others can buy it—and it gives us absolutely unbiased information about the new drugs. It is first-class material, and has been going out since 1961. I value it immensely, as I am sure do most of my colleagues. I hope they all read it. Each month this journal takes three or four new drugs or conditions and gives us helpful advice about what is really useful. So my second tribute would be to the Prescribers' Journal and to the Ministry of Health for producing it.

The third tribute (and here, perhaps, not all my noble friends will agree) is to the pharmacological industry itself. Noble Lords will know of Professor Alastair Macgregor, the gentleman who gave the lecture at Glasgow, and who reminded us that, of all the valuable antibiotics now available to doctors, only two—penicillin and streptomycin—came out of a university, or noncommercial, laboratory. All the rest came out of commercial laboratories, and were the achievement of the commercial pharmacological industry. So I do not think we should belittle the industry, even if some of us may sometimes criticise its commercial methods.

There are at least five stages in the development of new drugs. First, there is the chemical elaboration or extraction of the new compounds. This is the pure laboratory work and may involve testing the compounds against germs in vitro in the laboratory. The second stage is to test the new drug on animals, first to ascertain its pharmacological activity (that is to say, what it does to the animal, whether it makes its stomach more or less acid, and so on) and, secondly, if the animal be infected with a disease, what effect the drug has; and, at the same time, whether the drug is poisonous to the animal and, if so, how much is required to produce a poisonous effect. It is worth while remembering that almost every substance can be poisonous if enough of it is taken. Even water can be poisonous, if you take enough of it; and certainly common salt can quite easily be so. So there is an optimum amount of everything; and while "a little of what you fancy" may do you good, too much can prove fatal. That is the second phase: the testing of drugs on animals.

The third phase when a new drug is produced is to test it on ordinary human beings for toxicity, to see whether it is poisonous to them. This test is usually carried out on the laboratory staff. The fourth phase consists of the clinical trials to assess whether the drug has any use as a cure and, if so, whether it is superior to existing drugs. It is to this phase of the process that I am drawing particular attention this evening. In the course of this phase the doctors watch out for any further sign that the drug is toxic and dangerous; and, if it is, they will at once deal with this. The final phase is the assessment of all the information made available by the results of the chemical tests in the laboratories, the animal tests, the human tests, and the tests on patients which lead to the recommendations to the industry and the profession on the therapeutic value and safety of the new drug.

I do not know how many of your Lordships have read Robert Burton's Anatomy of Melancholy; but those who have will recall that he once said that "Marriage is a lottery with twenty blanks to one prize". Well, my Lords, pharmacological research is a lottery where the ratio is approximately 4,000 blanks to one prize. Probably 4,000 new drugs are synthesised for every one that emerges as really useful in medical practice. Of that 4,000, about 400 pass stage "B"; that is, the stage of the testing on laboratory animals. And of the 400 that have some apparent value and are ready for human experimentation, only one will prove worth while. So, behind each successful drug, there are 3,999 which have failed to make the grade. This is some measure of the labour, disappointment and heartbreak that goes on behind the scenes in the scientific pharmacological industry.

Of the five stages which I have described, only the last one—the assessment of all the experimental findings—is a committee job. To do this (I think I am correct in saying this; but no doubt the noble Lord, Lord Cohen of Birkenhead and the noble Lord, Lord Newton, will correct me if I am wrong), there are at least two Committees currently engaged in this process. First of all, there is the Cohen Committee, or its successor—I do not know the name of the chairman of the successor committee, or its correct title. Secondly, there is the new Dunlop Committee on the Safety of Drugs. I think I am right in saying that this Committee issued its first report on the safety of a group of drugs only this week.

This Committee has sub-committees to review certain matters. First of all, it looks at drugs before they are used for clinical treatment; in other words, it assesses the toxicity as a result of the animal tests and tests on normal human beings before allowing the drug to be used on patients. My Lords, I have said "before allowing it to be used". But, of course, this is a voluntary committee, and therefore it is not absolutely mandatory on the drug industry to submit their drugs to the Committee. However I think they will increasingly do so—at least, I hope so. Secondly, it has a subcommittee for assessing the results of clinical trials; and, thirdly, it has a sub-committee for studying the reports of adverse reactions to drugs after they have been released. Some people felt that this should be a compulsory process; that all drugs should compulsorily go through this Dunlop Committee. But the Government have decided otherwise, and at the moment I am not going to criticise that particular decision. I am going to say that I think the weak link in the chain is the organisation for clinical testing, for the actual testing of a drug on patients. I propose to elaborate this matter a little to show why I think this is the weak link in the chain.

Your Lordships will recall the Hinchliffe Report of 1959. Paragraphs 261 to 266 deal with the question of clinical trials of drugs, and the Report says, among other things: The present arrangements for the organisation and interpretation of independent clinical trials and for the publication of results are inadequate. That indicates the importance of early clinical trials, the testing of new drugs on patients as quickly as possible. That is obvious because, first of all, if they are any good, we want to get them going as quickly as possible; and, secondly, if they get going, the manufacturers want to start making them and selling them as quickly as possible because they have spent a lot of money on research and development.

The Hinchliffe Report went on: Early clinical trial not only for those for which new therapeutic effects are claimed but also for minor improvements on existing drugs". And Hospital authorities should encourage clinical trials. Then they discussed how these should be organised and made two suggestions, on page 82. The first was that the trials should he done by or through the Medical Research Council, which in fact does do some clinical trials but not very many; and, secondly, that they should be done through various professional bodies—the Royal College of Physicians, the Royal College of Surgeons, the College of General Practitioners and the British Medical Association. The Report did not come out firmly in favour of either of these methods and left it at that.

I think that I am right in saying that not much has happened about this particular problem. On January 23 of this year there was a symposium in London of the Association of Medical Advisers to the Pharmaceutical Industry, which repeated the plea that something should be done about this problem of clinical trials. They said that it was five years since the Hinchliffe Report was published, and asked why no move had been made to help them to make certain that clinical trials were done.

Why are clinical trials necessary, your Lordships may ask? Why cannot we just do them on animals? The answer is that they just do not work on animals. Sometimes animals give the wrong results, which may be even misleading and certainly can be quite unreliable when it comes to studying safety. For instance, one of the safest drugs is penicillin. Yet if penicillin had been tried only on guinea-pigs we should have reached the conclusion that it was an extremely dangerous drug because it happens to be toxic to guinea-pigs. Your Lordships are familiar with thalidomide. No amount of clinical testing on pregnant dogs, cats, rats, mice or hamsters would show any adverse effect. It does not produce what are called teratological effects, which means changes in the embryo, in these animals. It produces such changes in the embryo only if fed to a pregnant rabbit or a pregnant human being.

This problem of drugs which affect the human embryo is virtually insoluble at the moment because we do not know whether a drug is liable to do this if it is administered during pregnancy. We have had some pretty stern warnings administered to the medical profession by those in authority about trying out new drugs early in pregnancy, and I think that we should be very careful about this. There is a drug called hydroxyurea, which is a simple sort of compound, but which turns out to be one of the most teratogenic of the lot. Yet hydroxyurea is a very simple compound, which is extremely harmless and which can he taken in enormous quantities. We just cannot tell, even with clinical testing, because it would be quite impossible to do clinical tests on pregnant human beings. We have just to be very careful indeed about what is used in the early months of pregnancy.

There was a spendid example of the fallacy of animal tests as compared with human tests in The Times on February 28. It is a description of how a doctor set out to find a short-acting barbiturate which would produce unconsciousness and then, when one stopped giving the drug, the patient would come round. He found such a drug. He tried it on a doctor and it worked perfectly. The article says: The sequel is best told in the author's own words. ' With high optimism, and the collaboration of the department of anæsthesia, the new barbiturate was given by slow infusion to a doctor volunteer until anæsthesia was achieved. We then sat back and waited for signs of anæsthesia to disappear. 'Two days later we were not really concerned except that the subject was not yet awake and was expected home for dinner. … We had discovered the most long-lasting barbiturate of all time—in man '. It is just impossible to predict from animal experiments what can happen to a human being. There is no escape from the necessity of clinical trials.

Clinical trials present considerable organisational difficulties. It is easy enough with diseases that are fatal, because we can tell how long a patient lives and can compare that with other patients who do not have the particular drug. But it is much more difficult for non-fatal conditions, where improvement is subjective, is in the feelings of the patients or in complaints, as of rheumatism, which are hard to measure. The answer has been found out. It is the use of matched controls—that is to say, the use of two lots of patients in every way similar, one group of whom receives, not the drug, but something that looks exactly like it, and the other group who receive the drug. Moreover, the testing must be by what is called the double blind technique; that is to say, neither the patients nor the doctors who are giving the drug must know which patients are getting which, otherwise the power of suggestion comes in and the whole test is valueless. So this double blind technique with controls series is essential, with the statistical assessment of results.

All this is technically easy enough, but it takes a lot of organising, and in a majority of cases the results are bound to be negative and therefore it is rather dreary work. Without this elaborate organisation, clinical trials are valueless. It is fair to say that, if a drug is worth testing at all, it is worth testing properly. There are three factors necessary. The first is the willingness of the patients to co-operate in the test. And let me say that the enormous majority of patients are willing to co-operate in these tests, if the thing is fully and properly explained to them. The second is a sufficient number of patients suffering from the appropriate complaint. The third is willingness on the part of the doctor.

Relatively few doctors are in fact willing to undertake these double blind, properly controlled, therapeutic trials because of the extra volume of work involved, because they have not the assistance and because of lack of time. Still fewer of them have enough patients to make the results worth having. So the drug firms have to set out and find doctors who are willing to do this. I am assured that the hunt becomes ever more difficult, though not apparently so difficult in Scotland as in England.

The first suggestion which I would make is that there should be a panel of doctors who are both competent and willing to carry out such tests. The size of the panel, I think, will depend on there being some financial reward for the work done, because in some cases it may need the employment of extra secretarial or extra medical help. In the United States, I gather, it is usual to pay doctors to have these therapeutic trials, and the payment per trial, I am told, is of the order of 10,000 to 15,000 dollars—that is, £3,000 to £5,000. Here we should say it is quite wrong for the payment to be made from the drug firm to the doctor, and this would at once introduce an element of bias into the situation which might upset the results. That is one of the reasons why I feel there needs to be some impartial buffer body between the drug firms and the doctors. I suggest that such a body might be called a Therapeutic Trials Board, and comprise a board of scientific integrity.

I do not see why on earth the drug firms should not pay to have this work done for them, and pay reasonably and properly, rather than make small donations to hospitals, which I cannot regard as a proper return for doing this work; and they should pay either individually or by levy. I suggest that such a body should build up a register of a panel of doctors and institutions where these tests can be done, to receive the drugs for testing; that they should allocate them, pay for the test, and publish the results.

At the moment, the initial toxicity of the drug is assessed by the Dunlop Committee. That could continue perfectly well, and a drug would not normally go for clinical trial unless it had been to that Committee. Whether this should be done compulsorily or should be available as a voluntary service, I do not know. I personally would prefer to know that all drugs were properly tested in this way, but I can see objections to it, at any rate at first.

I am not sure—and the nature of my Question makes it clear that I am not—whether this organisation which I have suggested should be located under the Medical Research Council or under the Ministry of Health. The Medical Research Council has, I think, carried out the best clinical tests that have been done anywhere, but they have been very slow indeed about it. They have been most thorough, but slow. Here we want something which will operate with businesslike efficiency, and would be a fair return to the pharmaceutical industry for financing the thing. But there was under the Medical Research Council for 21 years an organisation which operated with businesslike efficiency, and in fact still does under the Ministry of Health: I refer to the Public Health Laboratory Service. That grew up during the war, and a few years ago we participated in its transfer to its own board under the Ministry of Health. I should very much like to see the Therapeutic Trials Board under the Medical Research Council at first, and then perhaps being transferred to the Ministry of Health. I do not mind how it is done, so long as it is done.

There are certain technical problems. The first is the problem of secrecy. When a manufacturer has a new drug he does not want all his rivals to know about it, particularly until it has been tested. Once it has been tested and he knows it is good and he is starting to market it, then they are bound to know about it. There is a legitimate secrecy. So clearly the doings of such a board would have to be conducted discreetly vis-à-vis the different manuacturers. The second thing is the volume of drugs which would be produced and tested. My own guess is that if we had a really good organisation for carrying out these clinical tests, which everybody knew was absolutely and ruthlessly honest, then this would itself reduce the number of drugs submitted for tests. Although there may he 500 new preparations coming forward every year now, I think that relatively few absolutely useless products would be submitted, particularly if there were a fair fee; and certainly, if the procedure were compulsory, they would not be submitted at all.

I know that some of my noble friends think there is no problem here and that genuine advances can always get tested. Well, I think there may be something in that view; but I also feel there is something in the view that I have advanced. It is true that when one pharmaceutical firm strikes a winner, as it were, by finding some good new drug, its rivals start trying out minor variants by just altering the OH group here or the CO group there, trying to find something which just is not covered by the patent, but is equally effective, or even slightly better. That is a game called in the trade "molecular roulette". There is no harm in it. It may not be very valuable, but they may strike something even more remarkable, so one must not discount "molecular roulette".

I myself am fairly satisfied (I know that if I am wrong I shall be told so in the course of this debate) that there is a real and substantial problem here, and I think we ought to be looking at it and doing something about it, particularly because I am sure that as this century goes on we are going to get more and more of these complicated new drugs coming forward for testing. The sooner we get a good machine for doing it quickly, the better. If we do not do this, we are going to waste great volumes of human effort by using drugs which have been improperly tested; we are going to add to human misery by using drugs which have been improperly tested and which may be less efficient than existing drugs; and, incidentally, we are going to reduce the efficiency of our own doctors and add to the nation's drugs bill. So I am not at all diffident in asking my Question, and I hope that we shall receive from the noble Lord, if not a complete answer, at least a helpful answer for the future.

5.18 p.m.

LORD AMULREE

My Lords, the noble Lord, Lord Taylor, has covered the ground so fully that there is not a great deal for me to say, but I should like to follow him on one or two points, and add just a few words about them. First, I would say how much I agree with the things he said to start with. I am particularly pleased that he mentioned the Prescribers' Journal, because the editor is one of my colleagues at the medical institution where I work and an old friend of mine.

I should like to talk about the difficulty that the ordinary doctor has in carrying out clinical trials; because at one time, when I was younger and not so experienced as I am now, I undertook several of these trials for various pharmaceutical firms. With the normal staff one has working at a hospital one finds such trials quite impracticable. I found, in the first place, that it took a long time—several months. But had one wished, it could have taken even longer. It depended on the number of patients available. An enormous amount of time was spent by the various members of my staff doing the extra work for me, and when it came to the end one was still not satisfied that the job had been done as well as one would have liked. So I am afraid that what I do now, if I am approached by one of the pharmaceutical industries to carry out a therapeutic trial, is to say that it is quite impossible, and I turn the offer down. That seems to me a great pity, because one would like to do what one can to help people who are manufacturing drugs which may further the end towards which one is working.

Therefore, I should like to support what the noble Lord, Lord Taylor, suggested: that the money for these trials might come from the pharmaceutical industry itself. The industry wants the trials done, and it will be greatly to its advantage if they can be done properly. I would favour a different method from that adopted in the United States. I do not think I would pay the doctor who is in charge of the trial anything at all: the work would be part of the normal work he is doing at his hospital. But because he would need to engage extra staff for the work, money should be provided for that staff. Here again, I think it would not be possible for the hospital itself to undertake the bother of engaging the staff, and I believe that it would be a good thing if it were possible for the pharmaceutical industry to run some kind of a pool of staff, of trained and experienced people who could visit various hospitals where these trials were to be done. That, I think, would be one way—I do not say the only way —of solving a certain number of the big problems involved.

Then the second point comes up: what are we going to do to spread the knowledge we have? Because the point about these trials is that people should know whether these drugs are effective and safe—not only whether they are safe, but that they are also effective. That, I think, is where the new Dunlop Committee could do quite a lot. The noble Lord, Lord Taylor, said that they produced one little report on a group of drugs—a report which seemed to me to be very well done— to explain, quite shortly, what are the dangers associated with the drugs in question. One of the troubles for the average doctor with these new drugs is that, as has been said often enough before, we have an enormous amount of advertisements sent to us. I am afraid that some people just tear them up before opening them. I at least used to look at the cover on taking it out of the envelope before tearing it up, but I can quite see that one might well miss some warnings that were given, unless they were in a form which enabled one to recognise immediately that they came from an authoritative body such as the Dunlop Committee. Such a document would be immediately recognisable on opening one's mail in the morning. One would say, "That is something I must read", whereas the others could go straight into the waste paper basket. That seems to me to be one way of getting the knowledge of these drugs spread rather more widely.

I do not want to go into details about various drugs. There has been some correspondence about various drugs at the present time, but I do not think it would serve any purpose if I were to repeat it to your Lordships. It merely goes to show that in dealing, as we are now, with strong, powerful and dangerous drugs, which have been made in increasing numbers and are being supplied to patients in increasing numbers, unless clinical trials are undertaken with care and skill, we must expect the occasional catastrophe to arise. That is why I should like most strongly to support this plea for the clinical trial. As the noble Lord, Lord Taylor, has rightly said, trials cannot be done by laboratory work or animal work. You can do preliminary work on them, but if you are going to deal with patients the final need is to try the drug upon the human patient. You should not, if you are careful in your laboratory and animal work, get a great deal going wrong with your trials; but even then, with the best will in the world and in the best possible conditions of all, you may find the occasional catastrophe happening, because we do not know what is going on. Therefore, the sooner we can have some proper machinery made available by the Medical Research Council and the pharmaceutical industrv—I do not mind what it is, but done, I think, by the reputable doctors themselves, working in reputable institutions—the sooner we shall be sure that these totally unnecessary but, at the present moment, almost inevitable tragedies do not occur.

5.26 p.m.

LORD COHEN OF BIRKENHEAD

My Lords, may I, at the outset, express my gratitude to the noble Lord, Lord Taylor, for his graceful and generous tribute to the Joint Committee on the Classification of Proprietary Preparations which, during the last fourteen years, I have had the privilege of chairing? I shall tell the noble Lord a little later what is its successor. I fully realise that the noble Lord's Question is intended to try to ensure that the maximum safety of drugs will he achieved when they are used for therapeutic purposes. He therefore suggests in his Question that the responsibility for clinical trials should rest with the Medical Research Council or with a Central Agency which will organise the testing of these new drugs. He referred to the Dunlop Committee. Perhaps I might be permitted to recapitulate the history of the Dunlop Committee.

Your Lordships may remember that the public unrest which followed the thalidomide tragedy led to the establishing of a Committee called the Safety of Drugs Joint Committee by the Central Health Services Council in this country and the Scottish Health Services Council, to advise the Government on what measures might be taken to try to ensure the safety of drugs. I was Chairman of that Committee, which recommended that there should be a parent or main Committee which would have three subcommittees, the first dealing with pharmacology—that is, the animal reactions to drugs and the toxicity of drugs in the laboratory; secondly, clinical trials to indicate immediate safety of a drug and its therapeutic efficacy, and, thirdly, a Committee on adverse reactions, because we know that many drugs which appear to be safe, do in the course of time reveal certain undesirable reactions in patients which must be taken into account in prescribing the drug.

The Safety of Drugs Committee, which established the Dunlop Committee, recommended—and I shall deal with this a little later—that the Clinical Trials Sub-Committee of the Dunlop Committee should assess clinical trials, the organisation of which the Safety of Drugs Committee thought should be left (as indeed it had suggested in its Interim Report) together with the toxicity trials, as a responsibility of the manufacturers. The noble Lord, Lord Taylor, will know the composition of the Clinical Trials Sub-Committee, and I think he will agree that it has an unrivalled expert membership. I do not wish to detail this now: it has already been published. The noble Lord referred to the lecture by Professor Alastair Macgregor, who was a member of the original classification committee. I am sure the noble Lord will be reassured to hear that in relation to the recommendations of the Safety Drugs Committee, under my Chairmanship, this is what Professor Macgregor said in his lecture: These are eminently sensible recommendations and the majority of the Committee have felt that although these arrangements will ultimately require legislative sanction they should, nevertheless, be introduced as soon as possible without waiting for legislation, although these interim measures should not be regarded as any justification for delaying a comprehensive review of the whole legislative field. If the recommendations of the Safety of Drugs Committee are to be comprehended, I think it is necessary for me to stress certain basic facts. The first relates to the concept of the safety of a drug. No drug is wholly free from any hazard. The noble Lord, Lord Taylor, has referred to the fact that water itself is capable of producing toxic effects in man, and many of the most commonly used drugs may, in certain susceptible individuals, show significant deleterious effects. The homely aspirin can produce stomach bleeding and can give rise to asthma. Only six weeks ago there was a report of a coroner's inquest in Dereham, in Norfolk, in which an unfortunate individual who had been prescribed two tablets of aspirin by his doctor had succumbed. He was a known sensitive aspirin subject, but, unfortunately, the doctor was new and was not fully aware of this sensitivity. Phenacetin, which I suppose over the last 20 or 30 years has been a regular constituent of practically every headache powder or tablet, is now known to cause, when administered continuously, significantly serious effects on the kidney, which can lead to kidney failure. The ordinary bicarbonate of soda that one takes for wind can produce grave renal damage leading to uraedemia.

These are dangers that might follow the use of any drug, and therefore it is important to stress that no drug is without some hazard; that the safety of a drug is a relative and not an absolute quality of the drug, and that whether a drug is safe for human use depends on many factors. It depends on the constitution of the individual. Many of us are curiously constituted and we react abnormally to simple drugs. It depends on the dose. The noble Lord, Lord Taylor, will remember that prussic acid was once used in the treatment of gastric disorders. Your Lordships know that it can be used for other purposes. The fact is that it is the dose which determines whether or not a drug is a poison, and that is why slogans about certain preparations, such as "Fluoride is poison", are significantly misleading; because it depends entirely on the amount which is taken. For these reasons we think in terms of a "margin of safety" for drugs. There is the dose which will produce a therapeutic effect, and the dose which is toxic; and the wider the margin of safety, the more reliable the drug is for human use.

The duration of treatment, of course, also affects the action of drugs. Some drugs accumulate in the body and can be used for short periods only. Some drugs must be used in excessive doses to try to reverse a disease process, but if continued may prove to have serious adverse effects. Again, the safety of a drug is related to the purpose for which it is being used. You must not tolerate any toxic effect in a mild hypnotic or a mild antacid tablet, but you can tolerate a toxic effect in a drug which is used for a very grave disease. For example, before the advent of chloramphenecol (chloromycetin), the death rate from typhoid was about 20 per cent. We know that chloramphenecol does, in certainly not more than one in 10,000 patients, produce a grave anæmia but we still use chloramphenecol in the treatment of typhoid, because the hazards of the disease are much greater than the hazards of the drug.

This is, after all, what Hippocrates taught us over 2,000 years ago: that desperate diseases require desperate remedies. That is why, when anyone is assessing the therapeutic efficacy of a drug, he must take into account also the indication for the drug. I might remind your Lordships that the reason why thalidomide was introduced was that thalidomide was a relatively non-toxic drug, so far as its action on animals and human beings was concerned; the ordinary person can take 50 or 60 times the hypnotic dose of thalidomide without its producing any deleterious effects. When there were in this country hundreds of cases each year of suicide from barbiturate poisoning, there was no wonder that thalidomide (or Distaval, which was its proprietary name) caught on and was extensively used. It was dropped as soon as its deleterious effects were recognised. I think the noble Lord, Lord Taylor, has spoken quite objectively about the effects of thalidomide, that they could not be avoided, although I think that, with our present mechanism of recording adverse reactions, we should recognise them sooner.

The noble Lord then referred to the question of new drugs. The Committee which I chaired had to deal, on an average, with about 300 new drugs per annum; but, of course, 75 per cent. of these are not new drugs in any strict sense of the word "new". They have no novelty about them; they are slight modifications of existing drugs. The noble Lord spoke of "molecular roulette". The fact is that these can also well be called "me-too" drugs, because the manufacturer who has produced a very good drug soon has on his heels other manufacturers who wish to produce something similar. As the noble Lord said, they make slight modifications, to avoid certain litigation on patent law, and they then produce the drug. That is why I suppose there are to-day about 25 anti-histamines, 45 tranquillisers and 30 diuretics, all of the chlorothiazide group. It is not because each one of these is an absolutely new, satisfactory drug, but because one repeats the other. And I am doubtful whether we shall see any reduction on the lines suggested by the noble Lord, unless a recommendation that I shall make a little later is adopted. The fact is that only 6 or 7 per cent. of new drugs have some chemical structure which is without precedent in therapeutics or have a promising novel therapeutic action, and only half a dozen of these are significant advances in therapeutics each year. As the noble Lord, Lord Taylor, said, some of these drugs have undergone clinical trials by the Medical Research Council. I have taken part in several of these trials, and I have, in fact chaired the Committees which have dealt with all the cortisone series, which the noble Lord will know; others were penicillin in sub-acute bacterial endocarditis; streptomycin in tuberculosis, and streptomycin associated with other anti-tuberculous drugs to try to diminish the likelihood of the emergence of resistant strains of tubercule bacilli.

It is proper that the Medical Research Council should undertake this work, because it requires co-ordination of a very large number of centres, and not infrequently some of the facts are in dispute. But do not let the noble Lord, Lord Taylor, think that this will necessarily increase the rate of turnover of new drugs or diminish the rate at which we shall have replies to our questions about new drugs. I would only remind the noble Lord that anti-coagulants are still the centre of a great battlefield; that there are strong proponents of anticoagulants, and there are the antagonists who regard anti-coagulants as rat poison and the like. The Medical Research Council has had its own committees on this matter. The result really is that no definitive view can be expressed at this stage; it will doubtless appear that the drug might have a value in certain cases but not in others, and the difficulty has clearly been the selection of appropriate cases. My view—and I will explain in a moment why the Safety of Drugs Committee came to this conclusion—is that although the Medical Research Council might undertake them at times, organised trials are not a proper function of the Medical Research Council; nor do I think, indeed, that it is practicable.

LORD TAYLOR

My Lords, my noble friend is not, I take it, referring to the organised trials which he has just mentioned as having been done by the Medical Research Council?

LORD COHEN OF BIRKENHEAD

I am referring to all organised clinical trials—that is to say, the clinical trials about which the noble Lord has spoken in relation to all drugs, and I say that it is not a proper function of the Medical Research Council to undertake this: the Council's function is essentially research. And it is impracticable, because of the amount of work involved and because it is not the best way of doing it, as I hope to convince the noble Lord in a moment.

May I just read what the Safety of Drugs Committee's proposals were'?—I am quoting paragraphs 20 and 21. Paragraph 20 says: The responsibility for arranging clinical trials should lie with the manufacturer. In some special cases the Medical Research Council might be prepared to arrange these trials; in others university or hospital departments or individual consultants may accept responsibility for the trials. Then paragraph 21 says: There should be an independent objective assessment of clinical trials. That, of course, is the independent assessment which will he undertaken by the Dunlop Committee's Clinical Trials Sub-Committee. The noble Lord is prepared to allow toxicity and pharmacological tests to remain with the manufacturer and to allow the Dunlop Committee to assess them.

LORD TAYLOR

My Lords, the noble Lord is muddling me a little, because he has been concerned far more with toxicity than with therapeutical efficiency. I have been all the time stressing that what I wanted assessed was therapeutical efficiency. Toxicity is admittedly important, but I am perfectly happy to have toxicity assessed by the Dunlop Committee on the result of animal tests and on the result of therapeutic trials. My concern is to get proper therapeutic trials for the assessment of therapeutic efficiency.

LORD COHEN OF BIRKENHEAD

I hope I shall be able to satisfy the noble Lord's impatience. If he wishes, I will deal with what I think the organisation of clinical trials should be. The Safety of Drugs Committee recommended (and this was accepted by the Government) that the organisation of clinical trials, like the organisation of toxicological and pharmacological tests, should remain with the manufacturers. I wonder whether the noble Lord would allow me to elaborate what he said of the stages of a clinical trial. The clinical trial is not a simple thing. It is true that an early stage is that after the drug has passed its appropriate toxicological tests in the laboratory it should be given to human volunteers not only to see whether it is toxic but to examine in man the metabolism of the drug; that is to say, to examine through what changes it passes in the body of man, because this is often a very good indication of the similarity of the changes in man and animal.

The second stage is a pilot trial, and this is of the utmost importance. It is a trial, rightly, as the noble Lord has said, carried out with the knowledge of the patients who are in the trial, and it is on a very limited number in order that we may establish the probable safety of the drug in disease, and its possible therapeutic promise. The results of this pilot trial may indicate that there should be further animal tests—in the laboratory of the manufacturers who have undertaken the original toxicological and pharmacological tests. It may indicate that there is a need to modify the drug, to modify its formulation, to try to ensure that it does not deteriorate in a relatively short time, and so forth. In other words, the whole armamentarium of the pharmacological laboratories of the manufacturer must be brought into use during this pilot trial and there must be repeated and frequent communication and consultation between the clinicians carrying out the trial and the manufacturers themselves. This is vital to the success of the pilot trial, and that is why it is necessary to leave that in the hands of the manufacturer also.

In relation to the full-scale clinical trial, here again the Safety of Drugs Committee, I think rightly, recommended that early clinical trial on a full scale should be carried out only at a couple of centres or so. Nowadays there is too often a tendency to disseminate the drug widely and let it be tried on a wide scale, but in that way you might encounter too many hazards, you might have taken too great a risk. After all, in the United States some 1,270 doctors were provided with thalidomide and over 20,000 patients were given the drug because the drug was disseminated in that way. Then, provided you have a promising pilot trial and an adequate clinical trial with proper controls, clearly you can have a more extensive trial with adequate numbers. There is another reason why it is important to leave this with the manufacturer—it is a point which the noble Lord mentioned—and that is that we should minimise delay. It is much quicker to communicate directly with manufacturers than it is with any central organisation.

Is there any real difficulty in arranging for clinical trials? I have had a long experience of this matter and I will tell your Lordships of it. I am sure manufacturers would agree there is no difficulty in arranging for clinical trial of a product which has promise of a major, significant therapeutic advance. And it is no use having a panel as the noble Lord, Lord Taylor, suggested for this, because the drug must be tried by those who are most expert in a particular field, and your panel may not include such an expert. For example, if there is a drug for use in a grave disease, such as cancer of the uterus, you want an expert in that field.

There may be, for reasons which I shall mention in a moment, some difficulty about the clinical trials of those marginal products to which the noble Lord has referred in his "molecular roulette", because doctors do not want to waste time undertaking clinical trials of drugs which are of only marginal significance. But if the noble Lord would look at the Hinchliffe Report again he will find that the Hinchliffe Committee recommended that there should be a body to which manufacturers might turn in order that they might have advice, if they wished to seek it, on the organisation of clinical trials and where they might be carried out.

The Ministry of Health in its wisdom, or otherwise, extended the terms of reference of the Joint Committee for the Classification of Proprietary Preparations which had long experience, so that this Committee would be prepared to advise manufacturers on clinical trails. That was in 1960. Until the time when I retired from the chairmanship of the Joint Committee, which was three years later, there were only three requests from manufacturers for advice on clinical trials; they were all for preparations which had had earlier clinical trials in which it had been found that these preparations had no proved therapeutic value. So I am still a little dubious as to whether there is a grave difficulty in finding opportunities for the carrying out of clinical trials, except on drugs which have, it may be, only marginally significant differences; and we in fact know—the noble Lord will, I am sure, agree—that most of these marginal differences do not add to the value of the drugs.

May I mention also that when these trials are carried out, the reports come to the Dunlop Committee's sub-committee on clinical trials, and it is that Committee's responsibility to ensure that the trial has been properly organised by experts, that it is of the right size, of the right duration, covering a sufficiently adequate section of the population and so forth. They may then find that there is evidence of hazards, of complications, of side effects, and they may wish that the trial be held for a further period of time, or the drug used only in hospital or on special prescriptions, rather than freed to the general public. I can assure the noble Lord, Lord Taylor, that this is a big, but it is not an insuperable, task.

Over the fourteen years for which I have chaired the Joint Committee we assessed 8,000 drugs, because in the early days we had to deal with many which were on the market and so our task at that time was gigantic. In the last six or seven years we have assessed approximately 300 drugs each year. There is only one of those drugs—I would challenge the noble Lord, if he knows of others, to tell me of them—in which the assessment went wrong and that was because we had inadequate information. That drug was, of course, thalidomide. In 1958, thalidomide was issued in this country. Its protocol was presented to the Cohen Committee which assessed it, and they said that this was a drug of proved therapeutic value. It was in 1962, after the effect of thalidomide in the production of neuritis and of fœtal deformities had been published that the Food and Drugs Administration of the United States did not agree to the release of the drug. But I can tell the noble Lord if he so wishes, that there were certain drugs that the Food and Drugs Administration of the United States—this vast organisation costing millions of dollars a year which leaves the organisation of clinical trials to the manufacturers—passed which the Cohen Committee refused to pass as of proved therapeutic value.

Having said that, may I just make this quite clear. The Dunlop Committee will, and I think rightly, not express a view on the relative values of drugs; it will only say whether the drugs are or are not of proved therapeutic value, and it relies on the doctor's own judgment in prescribing for individual patients what he feels is necessary for them. After all, this is a fundamental tenet of the National Health Service. One of the earliest Committees over which I presided said that doctors should be allowed to prescribe any drug which they wished for their patients, provided that they can justify its prescription. It seems to me that this is proper.

EARL ALEXANDER OF HILLSBOROUGH

How, without test?

LORD COHEN OF BIRKENHEAD

I am sorry; I did not hear the noble Earl's intervention.

EARL ALEXANDER OF HILLSBOROUGH

I was wondering how, without test?

LORD COHEN OF BIRKENHEAD

I did not hear it even then, I am afraid; it may be my fault. But this, of course, does carry a corollary. It means that the doctor must keep himself aware, in these days of virtually explosive changes in his therepeutic armamentarium, of the uses and abuses of drugs. That is why the Prescribers' Journal, and the British Medical Journal with its weekly treatment article, are giving such valuable service, and why there must be more Chairs for clinical therapeutics and clinical pharmacology in our universities, because what is important is the educational aspect. Drugs which are of inestimable value in the prevention of crippling, and indeed in saving life, can themselves be extremely dangerous, indeed lethal, if they are improperly used.

Now I come to the point which I think is of the utmost importance. Your Lordships may recall that the Safety of Drugs Committee had two dissentient members. They were both pharmacists, who said that it is useless relying on voluntary controls; we must have legislation. The Safety of Drugs Committee itself said that there must be legislation as soon as possible, that this is urgent and no interim measures will justify unnecessary delay; but that voluntary measures can help, provided that the pharmaceutical manufacturers and the doctors are prepared to play. I am delighted to say that the pharmaceutical manufacturers, as represented by the Association of British Pharmaceutical industry and the Proprietary Association of Great Britain, who together are responsible for about 90 per cent. of all the drugs which are manufactured and marketed in this country, have agreed that they will accept the advice of the Dunlop Committee and will act upon it.

That leaves 5 to 10 per cent. of drugs produced by the "black sheep" of the pharmaceutical industry, and of course it takes no account of the drugs which are imported, say, from North America or from Europe. That is why the Safety of Drugs Committee said there must be legislation, that legislation on the whole subject is urgently required, and they emphasised that its proposed interim measures should not be regarded as a justification for delaying this essential measure.

It is well known amongst those who are interested in this subject that there has been an Inter-Departmental Working Party considering this "tortuous and ungodly jumble" of the laws which are concerned with pharmacy and therapeutic agents, and that this Inter-Departmental Working Party has not issued a Report. It seems to me that the most urgent task of prime importance of Her Majesty's Government in this field is to complete their proposed consolidation of, and improvement in, the legislation to embrace the Safety of Drugs Committee's recommendation that there shall he these Committees—such as the Dunlop Committee now on a voluntary basis—that shall be made statutory; that the quality of drugs and their purity, now the responsibility of the British Pharmacopœia Commission, should be made a statutory responsibility of Government, and that indeed there shall be continuing surveillance to guard against long-term, adverse reactions and such matters as deterioration in quality, the regulation of promotional literature, the labelling of containers and the like. I believe that such legislation will prevent the marketing of drugs, wherever they are manufactured, which have not been approved for quality, safety and efficiency, and that therefore we shall have established an effective control. But there will still remain the responsibility, and it is a heavy one, which lies with the practitioner who prescribes these drugs.

6.0 p.m.

LORD FERRIER

My Lords, this Unstarred Question set down by the noble Lord, Lord Taylor, has performed a most useful function; but whether its timing is quite right is open to doubt. I say this in the light of what has been said in this Chamber about the development of the effect of the Dunlop Committee. As time goes on, it is clear that its effect will become more pronounced and easier to assess. As to the timing of this debate, it is fair that I should say that I am sorry that the Question was moved forward from last Thursday, because I know of at least one other noble Lord who would have been present on that occasion and who would have liked to take part in it to-day. Be that as it may, any step that will contribute to an advance in the field of medicine is a step worth taking. I should like to congratulate the noble Lord on avoiding an attack on the pharmaceutical industry—an attack which has become almost a ritual in some quarters. It makes my task easier and, your Lordships will be glad to hear, my speech shorter.

I am not abashed that I should be one among technicians to address your Lordships on this subject, because, although the issue is a narrow one and very largely a medical one, the industry is involved, as, indeed, has been mentioned by the noble Lord, Lord Taylor. Consequently, I feel that the debate would be unbalanced without a contribution from someone with experience such as mine. This leads me to make the declaration which I usually do on these occasions: my interest as chairman of a group of pharmaceutical companies which form part of a larger group. And again, as usual, I would add the fact that, although I am not a pharmacist or chemist, I take pride in being concerned with this reputable, important and vital industry, despite the current mode for abusing it which one sees in some quarters. I do not speak for the industry; and, if I did, I have the feeling this would not be the place to do so. All I wish to do is to make a contribution to your Lordships' deliberations from my own experience.

The noble Lord, Lord Taylor, said something which I feel he did not mean: did drugs do harm in the past? The implication was that in the good old days nothing went wrong with drugs. But I would not go all the way with the noble Lord in that, because, of course, the fact remains that when they did go wrong nobody heard about it. There was no Press to start a hue and cry and to highlight the tragedies and the mistakes which took place. We need not go back very far to find these—to cortisone, antiseptics, and back to Galenicals when medical experimentation must have brought about tragedies such as we find in our time.

I should like to thank the noble Lord for his tribute to the industry, but there have been misunderstandings in some quarters. Perhaps, in the light of what has been said, the time is coming—I make this suggestion in all seriousness—when we should have a debate in this House on the relations between the National Health Service and the pharmaceutical industry. It might provide a better platform for the expression of a number of opinions which need not be expressed to-day.

To turn to the subject of clinical research, my own interests are probably exceptionally well-placed in Edinburgh. Lord Taylor has made reference to the position in Scotland. Each of the three companies with which I am concerned has well over 100 years of history of close association with the medical schools in Scotland. Indeed, the founders of these companies contained doctors of medicine. In other words, we have little or no difficulty in arranging clinical trials. I would emphasise and confirm what the noble Lord, Lord Cohen of Birkenhead, said: that the more meritorious the product, the easier it is to arrange a clinical trial. After all, the number of new drugs which reach the stage of clinical tests is comparatively small, and of that number only a comparatively small number are really meritorious. Our own research departments screen and discard hundreds of items before the stage of clinical examination is reached. Incidentally, be it noted that one of the functions of the Dunlop Committee is to ensure that only such drugs as these come for ultimate trial. That is a point worth emphasising, and it is one that has already been made.

There is another side to the question. I could tell of medicaments approved by the F.D.A. and already marketed abroad which have been rejected by companies in this country even before they have reached the stage of clinical examination here. I sometimes wonder whether it ever occurs to the critics of the industry that such things do happen. Our Scottish tradition of co-operation between the medical authorities and the industry is something which has grown up over the years and cannot be replaced. But can it be augmented? That is what the noble Lord is asking. Are improved facilities for clinical trials possible of development? These are questions which, in a measure, have been answered by the noble Lord, Lord Cohen of Birkenhead; but, as other noble Lords have said in their speeches, Sir Derrick Dunlop's Committee is well equipped and is the best source from which to seek advice, recommendation and instruction on how this can he done. It is already an "early warning" system, and it is really a question of whether more co-ordination and a greater pool of information can be achieved under its ægis.

As it is, the pharmaceutical industry's own skills, the established position of the Cohen Committee (if I may so call it) and the Dunlop Committee, are powerful safeguards. The value of having another organisation under the Medical Research Council seems to be doubtful, and it occurs to me that when the noble Lord added the words "or elsewhere" to his Question on the Paper to-day it was perhaps an indication that he felt, on examination, that that might well he the case. As I have said, the present safeguards are powerful, and it is left, and properly left, to the pharmaceutical companies, and their medical advisers up and down the country, to arrange clinical trials. I emphasise the point that the spread in terms of space and personnel is tremendous. This point was made by the noble Lord, Lord Cohen of Birkenhead. There is no one group of consulting physicians or registrars who could cover the whole field. The co-operation in clinical trials, which has been so willingly given to the pharmaceutical companies, has worked well, and I am one who agrees with the view that it should continue and, if anything, be embellished. Of course, this embellishment is all the easier since the creation of the Dunlop Committee.

The noble Lord referred to the fact that the Medical Research Council has already concerned itself with the organisation of co-ordinated and controlled clinical trials, through its advisory board in clinical research, but I think I am right in saying that this advisory board does not conduct trials of specific drugs. As to whether the existence of a further centralised body might add to the present difficulties in terms of speed, the importance of which has already been mentioned, and as to whether the existence of another centralised body would slow up development, I am inclined to believe that it might. It would not, I feel, add many workers in the field; and since it would exercise selection among comparable competitive drugs, progress would be delayed and chance observations overlooked.

My Lords, there seems to be an opinion held by some that pharmaceutical companies are anxious to get products on the market at all costs and without adequate trials. I say that such an opinion is held by some, because this is an opinion which is not shared by all. But it is an opinion which is very far from the truth. I would make the point that, from the purely commercial point of view, any company which marketed a product of dubious merit would be in a difficult position. Therefore, it does not do it. Proper clinical observation is, therefore, a commercial essential. It is well, too, to remember that, given always the need for maximum feasible security, speed is of importance. I would emphasise this not only as regards the problem of making new, meritorious drugs available to the sick, but also as regards keeping pace so far as possible with world competition and keeping up with our export trade. I noticed when the noble Lord suggested that 3,999 out of 4,000 shots were going to be misses that he referred to disappointment. But he did not refer to the cost in terms of pounds, shillings and pence which this enormous figure means.

Of course, Britain's ability to compete in world markets with our low prices—and our drugs are priced low—is seriously affected by the limited financial resources available for research compared, shall we say, with people like the Americans and the Swiss. I could not restrain a chuckle when the noble Lord talked about the pharmaceutical companies paying for this and paying for that, when I thought of the times we hear that drugs are too expensive and the price should come down. Now we hear that the industry will be able to pay for these plans. However, that may be, I think it is safe to say that the pharmaceutical companies will support any workable proposal. Of course, the noble Lord has referred to the fact that the associations representing the vast majority of the pharmaceutical companies in the country have assured the Dunlop Committee of their full support, and I am not surprised.

My Lords, before I conclude I would mention another factor in the industry's approach to clinical work. I refer to the ordinary pharmaceutical companies' force of representatives. These skilled and generally dedicated men are in some measure the industry's eyes and ears. Unfortunately, part of the ritual of decrying the industry has been to pour scorn upon its sales staff. But it should not be forgotten that they have a part to play in initiating, in promoting and in fertilising the exchange of clinical information. Through them news often reaches research departments of unexpected happenings or reactions, for G.P.s in busy practices will recount in conversation observations that they have neither the time nor the inclination to write about. Observations such as these can be followed up by research experts with minimal delay. To this extent the sales force of the pharmaceutical organisation is a useful, if small, adjunct to clinical research.

Before I sit down, I should like to make a point about the noble Lord's therapeutical trials board. What I have to say is very much what the noble Lord, Lord Cohen of Birkenhead, had to say. There is the problem in regard to the supply of trained clinicians and, of course, the supply of patients. It is for that reason that I made use of the word "spread" when I described the ramifications of the clinical research system as it exists at present. The noble Lord, Lord Cohen of Birkenhead, quite properly mentioned the problem of competition and secrecy, which were the commercial and industrial difficulties which would obviously spring from one of the suggestions which the noble Lord, Lord Taylor, has made. I feel myself that if speed is essential, and it is, then this problem of competition and secrecy would make such a board difficult to create. Surely, a stage might be to provide a sort of bureau of exchange through the existing Committee.

I see that I have made a note here of this word "meritorious", but I have written it beside a note I made when the noble Lord, Lord Taylor, said that we were going to get a lot of new drugs. Of course I am thrilled with the idea, but that is not so. I am quite certain that, it terms of available meritorious drugs of the future, there are going to be something like the half-dozen which the noble Lord, Lord Cohen of Birkenhead, mentioned.

The noble Lord, Lord Taylor, implied that he felt that some drugs were improperly tested to-day. I do not think he meant it; certainly, not in connection with the major pharmaceutical advances. As I said before, this is probably not the place to discuss complex industrial problems, some of which the noble Lord has raised. I should like to congratulate him on the presentation of his material, though I sympathised a little with a number of noble Lords who are not intimate with the industry or with the technicalities of medicine, in the detail into which he went. But I hope very much that my part in this debate has been a contribution to the end which we all seek.

6.20 p.m.

BARONESS SUMMERSKILL

My Lords, I should like to congratulate my noble friend for initiating this debate, because this most important matter which we are discussing to-night on this Unstarred Question concerns the welfare of the whole community, for, sooner or later, every one of us must be treated for a minor or a major complaint. Because of this, for many years we have pressed the Government to establish some kind of machinery designed to ensure that the new drugs, with their potential dangers, should be adequately tested. To emphasise that point, let me quote the noble Lord, Lord Cohen of Birkenhead, when he said that in the field of the drug industry we can only describe the situation as "explosive". What better word than that of the noble Lord can describe the importance of this matter?

At long last a Committee of eminent people has been set up, with Sir Derrick Dunlop in the chair. But its inherent weaknesses are these. First, it is not compulsory for the drug manufacturers to submit their products; and, secondly, the pharmaceutical industry, which profits from drug manufacture, has again been left to undertake a report on the toxicity tests and the clinical trials. Surely, that is a fundamental weakness of this new Committee. Although the manufacturers are given a memorandum and told what is required of them, how can the Committee assess the thoroughness of a clinical test unless an independent agency of the highest repute is responsible? That is what my noble friend is asking for, whether it is under the ægis of the Medical Research Council or some other professional body.

This raises the question—and do not let us be mealy-mouthed about it—of the trustworthiness of certain elements in the drug industry, and whether they have forfeited our confidence. That, shortly, is why we come to your Lordships to-night and ask that this independent agency should be set up. Tonight, I want to prove to your Lordships that certain elements of this industry have completely forfeited our confidence. Year after year the Public Accounts Committee comment adversely on the mounting cost of drugs and the individual prescription, and the disproportionate number of proprietary drugs prescribed. The drug industry completely ignore these strictures by applying more and more pressure on the doctors to buy proprietary products, although there is a non-proprietary equivalent at a lower price. In the last five years the cost of prescriptions has risen by 32 per cent., and the estimate for our drug bill under the National Health Service for 1963–64 puts the total cost at over £100 million.

The industry claim that it must have high profits for research; but after the cost of research has been met the profits are very high. Let me remind your Lordships of what some of the profits are. The Glaxo company, which of course produces a great many drugs and not only the old-fashioned milk powder, had a trading profit last year of nearly £10 million, and their dividend was 14 per cent. This firm also have a policy of issuing share bonuses. The Beecham Group had a trading profit of nearly £10 million, and their dividend was 30 per cent. for 1963. The British Drug Houses, a rather smaller concern, had a trading profit of £875,000, and the dividend for 1962 was 16 per cent. The Committee of Public Accounts for the Session 1961–62 were informed that the cost of advertising amounted to 9.7 per cent., or about £6½ million. The Ministry of Health said they knew of firms which spent substantially more than 10 per cent. of their sales receipts on promotion costs.

The Chairman of the Public Accounts Committee in another place referred to the anxiety which the Committee felt over the prescribing of proprietary drugs as against the unbranded equivalent, and to the "cold war" which existed between the Ministry and the pharmaceutical industry. My Lords, those are strong words coming from a responsible man like the Chairman of the Public Accounts Committee. The Public Accounts Committee, with regard to the promotion of drugs, said this: The National Health Service, as the main purchaser of drugs in this country, bears the bulk of the sales promotion expenditure incurred by the drug manufacturers. Part of this expenditure is incurred in promoting the sale of proprietary preparations in competition, not only with similar proprietary preparations but with unbranded standard equivalents which are frequently available at a lower price. This may involve a two-fold extra charge to the Health Service: first, for the sales promotion expenditure itself, and secondly for the excess of the cost of the proprietary preparations over the cost of unbranded standard equivalents". In view of the high cost of drugs the Ministry of Health decided to buy drugs from a cheaper market abroad, and we must congratulate the Ministry of Health for trying to do their best to counter this mounting drug Bill. The drug firm Pfizer's had the affrontery to challenge in the courts the Ministry of Health's right to try to cut down the expenses of the Health Service. The Court of Appeal overruled the High Court and upheld the legality of the Ministry's right to buy in cheaper markets. This is an appalling background, and I think that when I said that the drug industry has forfeited our respect that was not an overstatement. The pharmaceutical industry makes no attempt to put its own house in order. It seems incapable of controlling that element which is devoid of ethical considerations, and which regards the National Health Service solely as a source of wealth.

The industry produces an unending flow of drugs for mental depression. This, of course, is a commercially remunerative field, because nearly 40 per cent. of complaints are functional, and the introduction of the so-called tranquillisers offers a huge market. Indeed, the very nature of the complaint—let us take the neurotic—lends itself to the production of different products with substantially the same ingredients but under different names. That is what they want. The neurotic has one prescribed, and then says, "This doesn't do me any good, doctor; give me something else". The doctor, willing to oblige, and pressed always by the commercial representatives of the drug houses, then prescribes something else. There is a fortune, of course, as they know, in selling these tranquillisers to the neurotics of the world. In America, colossal sums are made. The Practitioner of January 1 said: The very multiplicity of these new preparations has proved a handicap to the medical practitioner. And the Dunlop Committee (we have already heard of the Dunlop Committee) made one recommendation last week. The Dunlop Committee warned doctors of the country of the possible side effects from eleven of these drugs, many of which contain amphetamine, an ingredient of the so-called "Purple Heart" pills. Some of these drugs have been responsible for a rare liver disease which may be fatal; others are associated with changes in the blood pressure and strokes.

But the significant thing about this last week, when the doctors were warned about eleven drugs, is that the industry has been responsible for ensuring clinical trial of these drugs, most of which have been prescribed for years. Yet only now that this Committee has been set up has a warning been issued. Nardil has been widely advertised in every medical paper for years. Yet only now are the doctors warned against it. This drug has been used since 1959. Parnate has been available since 1960. It has been completely withdrawn in the United States of America because there is evidence that it can produce fatal brain seizures. Let me tell your Lordships the other eleven. Parstelin has been available since 1960; Drazine has been available since 1961; Actomol since 1962. Then there are Cavodil, Eutaryl, Marsilid, Niamid, Tersavid, Marplan. Many of these contain the same basic constituents but masquerade under different names to increase sales. The noble Lord, Lord Cohen of Birkenhead, called them "modifications". This is a delightful understatement of the situation, but it is absolutely accurate.

The noble Lord opposite talked about ritual. He really should not be so cynical. He accused me last time of doing a "ritual dance". I would call it a minuet; but at least I have been doing a minuet with the Public Accounts Committee and the Ministry of Health. Here are eleven drugs on which last week the doctors were warned that there was a risk. The Dunlop Committee feel that it is sufficient to inform the doctors of the risk of serious side effects; but the United States Food and Drug Administration have decided that it is dangerous to leave the valuation of drugs to the individual practitioner.

I would remind your Lordships that a few weeks ago when there was a debate in your Lordships' House on the position of the general practitioner, one-third of the general practitioners of the country petitioned the Government to grant them relief from day and night working, bad conditions and underpayment. These are the people who are now to be asked to do the most detailed research work, to keep carefully a record of day-to-day reactions from a wide variety of drugs. Then they have to compile and send the findings to a central register. This is a fact, The general practitioners were told last week that the use of these drugs carried wide risks; and yet here are these busy men—exhausted, worn out, actually agitating at the door of Parliament for relief—given this work to do.

I can think of no scheme more welcome to the worst elements in the pharmaceutical industry. They can put drugs on the market without clinical trial and then, if things go wrong, can throw the blame on to the doctors for not reporting that certain drugs caused danger to their patients. Striking proof of what I say was given at Salford last week at an inquest of a woman who died from the combined effect of Nardil and another anti-depressive drug. The manufacturers said there was a warning in one of their pamphlets. The poor, busy doctor said that he may have read it three years ago; but, as he gets about 20 circulars from the drug manufacturers every day, he has no time to read them. Another pathologist, in Yorkshire, questioned a general practitioner after the death of another woman who had taken Nardil. He said, according to a Report: It is obvious doctors just have not got the time to read everything that is sent to them. They cannot possibly do that, run surgeries, visit patients, keep up with their medical Press and have a normal home life as well. These changes we are asking for tonight, that a new individual authority should be set up, will be resisted by the pharmaceutical industry. When the United States Food and Drug Administration ordered the withdrawal of Parnate, the president of the manufacturing company, Smith Kline and French, said that although they were withdrawing the drug they did not agree with the United States Food and Drug Administration. Though they would order the withdrawal of it in the United States, they challenged the Food and Drug Administration. Yet I would remind your Lordships that the Food and Drug Administration of the United States was responsible for refusing to allow thalidomide to be prescribed. The manufacturers called the woman doctor who was responsible "ignorant" and "stupid" when she repeatedly refused permission to allow thalidomide to be distributed. We are moving into a period when this matter becomes so serious that the British Medical Journal on January 25 printed an article, under the heading Drugs and The Embryo, but it concerned men and women. It said: We now have to recognise that the increasing complexity of drugs may result in increasingly subtle interference with the intricate biochemical mechanisms of the dividing cell. In future, therefore, a doctor who prescribes a new drug to a patient of either sex may unwittingly be testing its ability to produce genetic mutation, with eventual deformity and disease in future generations. Sometimes the seriousness of this matter is so great that I find it difficult to understand how the public can accept the situation as it is to-day, and the irresponsibility of certain drug houses—for instance, in distribution of oral contraceptives. It is outrageous that British Drug Houses should advertise these products to harassed, ignorant and innocent women. Last week a doctor showed me a sample brought in by the latest commercial traveller. It was a box of oral contraceptives, beautifully packed, to go to some woman who might come in. I looked at the pamphlet which was with the package. British Drug Houses, in advertising these products to the doctors, sought to allay the doctors' fears by printing under the heading, "Evaluation of testing", the words: Before release it was necessary to establish the safety and efficacy of this product". This is a deliberate distortion of the truth. Many eminent doctors have warned of the possible danger of oral contraceptives. The Times of March 2, in an article under a heading, "Caution over Oral Birth Control", said: Cautious individuals very reasonably question the advisability of the use of such a potent group of hormones for a purpose which may be satisfactorily handled otherwise. The Times to-day thinks it necessary to quote the Lancet on the same subject. The Lancet said: Despite the lack so far of evidence in the human of harmful permanent effects, their use"— that is the use of oral contraceptives— for long periods cannot be contemplated without considerable trepidation, for it may be dangerous to interfere with rhythmical processes … Twenty years may go before we can he sure about the safety of the present oral contraceptive". Yet doctors throughout this country will be sent beautifully packed parcels of oral contraceptives for their poor women patients with large families, who are desperately anxious to do something, irrespective of what it might do to their health. The firm have written in these pamphlets: Before release it was necessary to establish the safety and efficacy of this product. We are asking your Lordships to-night to agree to the setting up of an independent agency, absolutely independent of the pharmaceutical industry. There is no doubt that the control of the testing of drugs is now an international problem. For this reason, we were pleased that a symposium on the toxicity of drugs has just taken place in Moscow, attended by delegates from nine European countries, among whom, I was delighted to see, Britain was represented by the Principal Medical Officer of the Ministry of Health. The Ministry of Health did not feel that he had to echo the interests of the pharmaceutical industry. Not a bit of it. Among other things he recommended in Moscow was that all new drugs should be clearly marked, warning people of adverse side effects.

One does not need to have any medical knowledge to know that one can go into a chemist's to get a prescription made up and is given a box or bottle without any name on it or any indication of what it contains, whether it is something simple or something very dangerous. In his opening remarks, my noble friend said that any prescription can be poisonous, if you take enough of it, but the dangers to children are obvious and they are faced every day of their lives with all these bottles and boxes containing mixtures and tablets.

Finally, it is astonishing that, while we have waited for months for the Dunlop Committee to be set up, the medical advisers of the pharmaceutical industry only last month decided to discuss the ways and means of effecting clinical trials. The report in the Lancet of February 1 fills me with misgivings. It said: In the past it was said clinical trials had been nobody's business but the hobby of a dedicated few. The noble Lord, Lord Ferrier, opposite told us how all drugs have been carefully tested. He has no difficulty at all in securing clinical trials.

LORD FERRIER

My Lords, does the noble Lady suggest that any drugs which go out from firms with which I am associated have not been tested?

BARONESS SUMMERSKILL

My Lords, I am always very careful to support any such statement I make by an authentic quotation. I am quoting now the noble Lord's industry at a meeting last month, of which results were reported on February 1, when they said: In the past it was said clinical trials had been nobody's business but the hobby of a dedicated few.

LORD FERRIER

May I interrupt the noble Baroness?

BARONESS SUMMERSKILL

My Lords, I did not interrupt the noble Lord; would he mind please sitting down? Sir Derrick Dunlop found it necessary to remind that meeting of a very elementary fact. The noble Lord ought to blush that it had to be said. Sir Derrick said: The deep-rooted, built-in ethics of the profession is the greatest safeguard, greater than any rules that could be drawn up by any committee. I say that the corollary of this is surely that we must establish an independent agency governed by the highest ethical standards to undertake the clinical evaluation of drugs if the public is to be afforded the fullest protection.

6.45 p.m.

THE JOINT PARLIAMENTARY SECRETARY, MINISTRY OF HEALTH (LORD NEWTON)

My Lords, I should like to begin by thanking the noble Lords, Lord Taylor and Lord Amulree, on behalf of my Department, for the kind words which they said about The Prescribers' Journal, which I personally was very glad to hear.

In view of the learned discourses to which we have listened this afternoon, your Lordships will not, I hope, expect from me a judgment of Solomon upon this difficult and complex matter. It is not just a matter of organising an efficient piece of machinery. The professional ethics of doctors are involved and, so far as I am aware, there is in the profession no general consensus of opinion that a central testing agency is desirable. Indeed, from what has been said this afternoon by my noble friend Lord Cohen of Birkenhead, it is clear that there is a powerful weight of professional opinion on the other side. So, my approach is cautious.

Though we have sometimes strayed rather far from the theme, the noble Lord, Lord Taylor, is mainly concerned with the value or efficacy of new drugs, and, indeed, the expression "clinical testing" or "clinical trial" is normally taken to refer to the administration of drugs to patients, under controlled conditions, for the purpose of testing their therapeutic efficacy, as opposed to tests for determining toxicity—and, therefore, safety—which are performed in the laboratory and on animals and sometimes on human volunteers. Things would be simpler if toxicity and efficacy could be treated as wholly separate aspects of a drug's nature, but, unfortunately, they cannot be. I follow my noble friend Lord Cohen of Birkenhead in saying that for any worthwhile drug, judgment about hazards must depend on judgment of what the drug will do therapeutically. In a drug that could be relied on to cure cancer, for instance, a much higher risk of side-effects could be accepted than in a drug for curing headaches. So toxicity and efficacy must be looked at together in order to assess safety.

In October, 1962, after the thalidomide tragedy, the Medical Research Council reviewed their responsibilities over the whole field of toxicity testing and clinical trials. They confirmed the principle, which had developed down the years, that responsibility for routine toxicity screening of new drugs should remain with the manufacturers and that the Council themselves ought not to become involved in it. It is a matter of history, as your Lordships know, that following the Report of Lord Cohen of Birkenhead and his Committee—a Report which was endorsed by the Standing Medical Advisory Committees in England and Wales and in Scotland—the Government appointed the Dunlop Committee on Safety of Drugs, after receiving assurances of co-operation from the pharmaceutical industry and the medical profession. As your Lordships know, the Committee began their functions on January 1 this year.

The arrangements for submission of new drugs to the Committee ensure that such drugs are not offered by their manufacturers for clinical trial without adequate toxicity testing. Furthermore, the Committee decide whether or not the results of the clinical trials of a new drug justify that drug being put on the market. This, I should think, is as effective as the proposed board of the noble Lord, Lord Taylor, in reducing the number of insufficiently tried drugs coming on to the market.

The Medical Research Council have given advice on the conduct of clinical research and of clinical investigation generally, with special reference to the interests of patients. Nevertheless, my Lords, the individual doctor's judgment as to whether a particular drug should be administered to a particular patient is still crucial and it always will be. His personal responsibility is, and always will be, an important safety factor.

I turn now from safety to efficacy, and, first, the attitude of the Medical Research Council. In their review of their responsibilities in this field, which they made in 1962 and to which I have already referred, they concluded that clinical trials which are clearly desirable on medical grounds ought to be arranged directly between the manufacturer and the individual physician. They further decided that they should be concerned only if there were a necessity for full-scale co-operative trials which involved issues of major importance to medical practice; and even then they considered that they should retain the freedom of deciding whether or not to undertake the trial of a particular drug. That, I am advised, is the view of the Medical Research Council. My right honourable friend the Minister for Science supports the contention of the Council that they should not become responsible for routine testing, as it is not an appropriate task for a research council.

As I understood it, part of Lord Taylor's argument is that manufacturers find it difficult to get trials done; and the noble Lord, Lord Amulree, said, from his personal experience, that he considered it difficult for an individual doctor to carry out clinical trials. On the other hand, my noble friend Lord Ferrier has said that his pharmaceutical firm have no difficulty in getting trials done; and, moreover, the Committee on the Safety of Drugs, presided over by my noble friend Lord Cohen of Birkenhead, said they had been informed that the pharmaceutical industry had little difficulty in arranging for clinical trials of new drugs which showed promise of marked therapeutic advance, although there was difficulty over drugs of probable marginal advantage over existing remedies; and my noble friend more or less repeated that in his speech this afternoon. If this is so, it seems safe to conclude that at any rate the priorities to-day are not wrong.

I suppose it is possible that a doctor might be more willing to undertake the clinical trial of a new drug if requested by an official agency rather than by the manufacturer. But might he not feel that an official overture was derogatory of his professional status and of his personal responsibility for the care of his patients? I do not much like Lord Taylor's suggestion that doctors might receive a special payment for undertaking clinical trials; and I think I have the noble Lord, Lord Amulree, with me on that. I do not believe that that sort of inducement would be acceptable to the profession generally, and I am reasonably certain that it would not be acceptable to the general public, because many of the general public do not like being treated as guinea-pigs by the medical profession.

LORD TAYLOR

My Lords, this is a very fair point, and I stand corrected. I would accept what the noble Lord, Lord Newton, has said. But the difficulty arises where a doctor is in hospital and cannot do it but could employ a part-time registrar, for example, to do it, and the question of paying him might arise. However, on principle, I think I would agree with the noble Lord, and I withdraw my previous suggestion.

LORD NEWTON

I am obliged to the noble Lord for saying that.

The noble Lord's idea of a central agency is certainly, at first sight, an attractive one. It might well secure that available resources were used to the best advantage and save manufacturers and doctors the trouble of harassing and being harassed. The agency would need to be very knowledgeable; it would have to concentrate in a few people all the knowledge in depth about the whole range of drugs which is at present spread among manufacturers, each of whom tends to specialise in a particular range. That might be feasible, but not obviously so. The manufacturer knows the clinicians who are interested in his particular line. It would not be easy for a central agency to acquire that information for the whole range of new drugs, although I am not saying that it could not do so.

As a matter of historical interest, in the 'thirties the Medical Research Council operated a therapeutic trials committee to supervise a scheme for the clinical testing of new substances which had given promise of therapeutic value in laboratory tests, but it was not reconstituted after the war because the rapid increase in the number of new drugs made it impossible for a single committee to cover the whole field. On the other side of the coin, the prevailing system, unco-ordinated though it may be, has the advantage that it makes for the closest personal contact between manufacturer and clinician; and my noble friend Lord Cohen of Birkenhead said that, in his opinion, that contact is vital. This enables the clinician to obtain expeditiously all the information he needs before making up his mind about undertaking trials in the interest of his patients; it also enables him to exchange information with the manufacturer while the trials are in progress. A central agency would, rightly or wrongly, come between the two and affect the responsibilities of each in relation to the other.

The noble Lord, Lord Taylor, has asked in his Question that the Government should consider the establishment of a central agency. We have considered it, and we will consider it. But I have felt it right to sound a note of caution, and I warned your Lordships that I would. I have done so mainly for this reason: that the doctor, unlike any other scientist, has to care about what ultimately happens to the physical matter upon which he carries out his experiments. He cannot just chuck the hits into the dustbin and start again, because the bits are human beings, and nothing must ever be done, in my view, which would limit the responsibility of a doctor for the treatment of his patients.

So I would sum up my position like this. After listening carefully to the debate, I am not convinced that the present arrangements are so defective that, notwithstanding their advantages—which I have mentioned—it is imperative to discard them and set up new machinery.