The committee on the safety of medicines (1995)

foreign figures in the early days of regulating new drugs in the United Kingdom was Professor Bill Inman sadly he had bad polio when he was a medical student and he now has to spend all his time in a wheelchair and so I went down to see him at his home outside Southampton talk about the beginnings of the committee on the safety of drugs so can you tell us how it all started well I suppose Stephen the the first indication of trouble was 1956 when Dr mukta and Ryan came in grunden tell invented thalidomide and it was marketed in this country the following year as this develop in Germany as cons again and uh two or three years passed really before it's alleged that bill McBride in Australia spotted today yeah association between solidomide and congenital melodies and uh with the lens in the same year said he'd seen 52 babies in in Germany with the with these limb problems uh and following on that I I was at that time working with ICI in the medical department and almost out of the blue uh I had I had discussed this uh at meetings of a map here which you may remember as the association of medical advisors in the pharmaceutical industry and so it was known that I was interested in setting up some sort of a scheme to monitor new drugs and out of the blue A letter came from uh said Eric Dunlop in the end of 63 inviting me to show an interest in the in the new committee he was forming the committee had been set up by then it had established as far as adverse reactions were concerned the total number of yellow cards was in the contents of one shoe box literally yeah when I joined and I would in fact have been in right at the beginning had I not been late starting I was Ill yeah so what was your background how did Dunlop Choose You well it's rather obscure because the letter from him came completely out of the blue but I had been at the time I was working in ICI in their medical departments and I had been showing an interest at various meetings in the possibility of setting up some sort of a monitoring system you're working for RCI how long you've been there for uh I'd been there for about five years I suppose by that time yes and this was because of your polio or because you're interested that wasn't my choice of career was really dictated by the facts I had Polio as a medical students yes and uh it seemed that it was skinned in the Psychiatry or something laboratory work which didn't appeal to me and you didn't of course have quite an icr background uh has it been in the family for since the early 20s yes my father was a father member of the company yes yeah so you get to the committee in 1964. and uh what What's eventually arrived in years in the in 1964 by which time yellow cars were just beginning to trickle in and yes there were various bits of publicity to encourage that Derek Dunlop himself wrote a letter to all doctors yeah circulated it with yellow cards and they started to come in I can't remember the exact rates but I mean a thousand a month easily and maybe more than that yeah who was the chairman of the committee uh the chairman of the main committee was Derek Dunlop himself and he operated three subcommittees the first was a subcommittee on toxicity which was uh the chairman of that was uh Professor Fraser the second was the clinical trials committee Robert Hunter Bob Hunter yeah and the third was adverse reaction was Leslie wits yes this was really the subcommittee that the attention was focused on um I think it was um it certainly could be the most dramatic when things went wrong as with the pill and Asthma deaths and so on yes we got most of the press attention yep Leslie wits was the distinguished professor at Oxford he was a specialist in blood this crazy isn't it okay that was felt to be one of the target uh areas we might get involved in yes and was he an easy person to get on with and well I liked him very much and yeah he was very quiet very considerate uh a perfect gents in fact I was very fond of him yes and who else was working there on the uh the names I can recall uh it's now over 30 years um Becky kernsberg who was the GP in advance Irwin Wade who at that time was in Belfast um Bill motion from Cardiff he was a professor yes um Michael Lynette well I believe was was the Queen's general practitioner yep yes uh who else um on adverse reactions I think that was about the well Roy Goulding put in an occasional appearance from the poison information center yep yes how exactly did you work well the Keystone of the whole operation was the yellow card which is a a very simple business reply card folded double and glued around the edge for security and confidentiality and these were issued periodically to doctors with a uh who are encouraged to report any suspected reaction to a New Drug and any serious reaction to any any drug however old or knew it was and it was an entirely a voluntary system they didn't get paid for it and on the hill I think they responded very well but of course the yellow cards really grossly underestimated the probable numbers of events which were occurring give us some examples of uh the first drug that uh struck us as dangerous was a drug called benzyledrine there's a drug use and heart disease and it quite obviously caused Joe and jaundice and the company was persuaded to remove that voluntarily without any any pressure all that was kept Under Wraps there wasn't much publicity well that's right I mean we didn't seek publicity the uh another good example is di transcend which was the precursor of brufen which is known still on the markets that did the same thing two waves adjourned this one over the issued it to hospitals the second one went initially the general practitioners yes and uh boots had no difficulty taking that one off the market straight away yes so firstly the drug was taken off the market did you also issue sort of warnings uh several times I can't remember the we had a thing called the um adverse reaction series which the company is called the yellow Peril yeah and the first one we issue was monoam and oxidase Inhibitors we put out one on chloramphenicol which wiped out a plastic anemia virtually except for the odd patients who'd use the stuff in France or Spain while in Costa Brava and got a cold and came back to die of aplastic anemia yes in England yes yeah and then there was a particularly High spot or low spot with the pill oh yes the pill first impacted about 1965. uh and um they've been odd anecdotes in various journals I think the first man ever to produce one was a man called Jordan who described three cases somewhere down in the west country these were cases of what family members I think I think they were public permanent embolism yeah uh and by about the beginning of 1966 it was obvious that um if we'd had 100 reporting the the estimated incidence was about what you'd expect from the national the registrar General's figures yeah and clearly you couldn't have um believed that we were getting 100 reporting and so we had a prima facie case that the pill was possibly causing thrombosis and with some difficulty I am managed to organize a national study picking out all deaths of women of child bearing age that would occur in 1966 I had to wait for them to occur yeah yeah and um following them up by that time I'd recruited a team of field workers we call them Derek's dolls and they were personable young mostly young doctors who would actually visit the general practitioners and get the information firsthand which the doctors appreciated they felt it's you did this some death certificates or hospitals through their certificates but I also use the same team to follow up the yellow card reports yes and so these girls went out and we collected I think from memory about three or four hundred cases and come the beginning of 1967. there looked like at least a six-fold maybe an eight-fold excess of pill users and we took controls living controls from the same practices yep and so this this was one first really a major first for the committee when was this published well that was eventually published in 1968 but there was quite a lot happened before there because in in way back in 65 before we'd even shown that there was a statistical evalion case against the pill I had already spotted a difference between Maestro and ethylene estradiol and I thought it was possibly a chemical difference I didn't do very much about it until quite considerably later so anyhow late in 1966 we um Leslie Whits and I went off to the MRC to try and encourage them to set up some parallel studies because one study isn't enough yeah and uh we did that with great difficulty they were persuaded to do a study which they did in Hospital admissions not deaths yes and we also persuaded the College of general practitioners to do the same thing and they did a study a small one mainly superficial Venous Thrombosis in general practice what was the difficulty you said you had some difficulty well they didn't really seem to be very interested in the family MRC wasn't interested not at first no we had to make two visits for them all together yes but once I got some data to show them they were a little bit more impressed and this basically was uh Richard doll and and Martin vessey who I hadn't met at that time so we um we got together and these three studies were supposed to be published early in 1967 yeah as a medical MRC report but the college gp's in the meantime jumped the Garden in order to be in first they published their little series and so we were forced to I think to publish the MRC report prematurely yes this was all happening just before Christmas I didn't remember no no no this is May 67 the Christmas business comes two years later I see um anyhow it's got a long story short the MRC paper and our paper miles University and I published on the same day same edition of bmj and um I then think it's quite database after the initial media response and I then went back to the yellow cards by which time I had about three or four thousand of them and they used to go home in a suitcase every night and were arranged in piles according to First the dose the chemical the age of the women how many children they'd had and suddenly the penny dropped that where the two hormones were equally distributed in the market and I got that data from InterContinental medical statistics it was a 52 48 split there was a huge excess relative excess of the larger doses irrespective of what chemical it was yeah and that um at that stage I hadn't looked at the progesterone and I advised the authorities not to publish anything until we'd had time to do that but Mr Crossman wanted something to say in Parliament and as you know just before Christmas in 1969 the um I would say in America to hit the fan and yes and the committee was heavily criticized can you tell us just a bit more about this because there was a leak wasn't there dude Chapman Pinscher I think is Gary Express uh yes I I had predicted that if we held a conference with the industry because they are legally obliged to inform their masters in America yes that the FDA would have to have the story within 24 hours yeah and I predicted then that there would be a an automatic leak to The Washington Post through Mr Morton Mintz who usually I think they used it as a sort of safety valve really to take the heat off some of these things sure but I was wrong because in fact Chapman Pinscher had it a day earlier and the doctors hadn't been informed and the doctors hadn't been informed now the committee then were forced to produce a an urgent yellow pill which was a piece of A5 paper typed by an ordinary typewriter yeah and tried to fob that off as a as one of their adversaries one of the leafits in their adverse reaction series and this fooled nobody they were even more insulted yes after receiving this pathetic little bit of paper yeah yes so along the end of the story there was I got the nickname of father of the mini pill in respectable circles and Bill a pill in in the eyes of the industry weren't too pleased about this a lot of women came off the pill didn't they I mean there was a lot of it's alleged that some did George gobbron I never knew whether he was fooling or not the following nine months later claimed that I'd caused a slight eruption in the in the population yes I said well you know I'm a man that I can still move around I probably the father of a lot more than I bargained for so this almost brings us to the end of the committee on the safety of drugs it's actually overlaps the end yes because the 1970 or something the the main paper on Eastern dose is published in 1970 yeah I mean soon after Christmas a few hours we could get it out by which time I'd I'd been to Switzer to Sweden and to Denmark and got all their data and it showed exactly the same yeah same thing yes and then we get the medicines done from that from that September 71 I think it was the medicines act yeah became operative yes and everything changed I see so finally what do you think the main lessons we learned from this period I think I learned three things first of all the value of Independence uh secondly the need for transparency the ability to communicate freely with people outside and thirdly the need for more information about the efficacy of drugs and I if I take the last one first I think that was a serious defect in the act probably initiated by pressure from the industry but many other countries now insist that a new drug has to have a margin of superiority or to be very considerably safer and you so in other words you've got to have the complete equation relative safety and relative efficacy and the medicine's ACT prohibits this really these considerations uh as far as the independence is concerned I always felt that it was a great mistake to expect doctors and other other scientists working in the department to be loyal to a scientifically independent committee on one hand and to the minister of the day on the other hand there may be perfectly good reasons why ministerial decisions Clash apparently with a scientific decisions and if they were separate these problems wouldn't arise I think the the doctors know about working at the department now find themselves more as medical advocates rather than being free to to communicate scientific scientifically thank you Bill very much it's my pleasure Stephen thank you very much thank you