Hark, hark, the fictitious dogs do bark

S I D E E F F E C T S O F D R U G S E S S A Y 1987

Hark, hark, the fictitious dogs do bark Graham Dukes One of the most delectable descriptions of the English Sunday which I know is that by D a a n van der Vat, a Dutch journalist whose sympathy for the English is rivalled only by his astonishment that they still survive. ' A t about ten thirty in the morning', he writes (and I quote him from memory), 'a million front doors open just a fraction. A pyjama-clad arm emerges from each and takes hold, first of the milk bottle which has been delivered on the doorstep in the small hours, and then o f the collection o f Sunday newspapers which lies beside it. Then each d o o r closes again, not to open until well beyond noon.' English Sunday newspapers are well attuned to that situation. However solemn their pretensions, they vie with one another in sheer juiciness, filling their bulky mass with tales which will titillate the jaded Sunday morning palate, throwing the dreadful state of the world into stark perspective, and convincing at least the male reader that a warm bed with tea, fried eggs and an understanding woman is the only safe place to be. It was under those conditions that England was first made aware, on Sunday, September 18th, 1986, of what was presented as the despicable wickedness of Professor Michael Briggs. 'The Pill: professor's safety tests were faked' read the headline on the front page of The Sunday Times: ' E X P O S E D ' shouted the three-inch headline on page 27, superimposed on a portrait of the miscreant's unshaven face, intended no doubt to portray due remorse. But let us leave the story to the journalists of that venerable newspaper themselves: Deakin University lies just outside the small town of Geelong, an hour's train journey west of Melbourne on Australia's south coast. Road traffic is light and the squat modern buildings of student, arts and science blocks barely disturb the peaceful Victoria countryside. It is not the sort of place where one expects to find major research going on. But it was to Deakin's little campus that Professor Michael Briggs came in 1976. His background was beyond reproach. The British scientist, now aged 51 . . . . assumed the post of professor of human biology and head of the sciences school. His teaching duties were extensive, mainly coaching Ph.D. students in biochemistry, but he was able to continue work he had begun in Zambia four years previously on one of the most remarkable series of research publications that has ever been produced. Under his authorship, or jointly with his wife, Dr Maxine Briggs, he produced over 10 years some 55 research papers, and almost as many detailed reports in letters to science or medical journals. Most were on various aspects of contraceptive safety. Briggs' particular specialty was in subtle blood changes that might predict long-term risks from the pill. He was also a special advisor to the World Health Organization ... If The Sunday Times is to be believed, Professor Briggs' reputation continued to rise until around 1982. And then? Rivals began to wonder about some of his results. Not only were a number of his findings questioned, but so were the means by which he so swiftly published them. 'It was incredible, unbelievable, the things he was reporting' says Dr Dryan Hudson, who ... was at the time president of both the Royal Australasian College of Physicians and the International Society of Endocrinology. Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 ElsevierSciencePublishers B.V., 1987

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Doubt or not, Professor Briggs pressed on, heavily backed financially by the (European) Schering Company for which he had once worked, and by other pharmaceutical firms. But? But much of the research work as described and presented by Briggs never took place. He did not do tests on which the papers appeared to present results, some of his reported tests were impossible to conduct and in one paper he wrote up a study of dogs that he had not done. In a four-hour interview in Spain, Briggs admitted to The Sunday Timesthat he had collected from other people unpublishable, small-scalefindings and generalized them into apparently big and convincing trials .... The story goes a great deal further. Deakin University 'did not have the elaborate and costly equipment for the work Briggs had described ...' His papers were published, not in the eminent journals which employ referees to vet the papers they publish, but at symposia and in companysponsored books. Finally, in October 1984, a meeting to discuss his work was held in Berlin; there appears to have been a great deal of agreement that it would have to be set aside. Professor Briggs left Deakin and retired to a villa in the south of Spain. And that, until The Sunday Times decided to exhumate and pillory the poor man, was that. At this point, let me move from our Englishman, shaking his head over all these iniquities as he chews on his morning toast, to the Englishwoman in bed beside him. She is fortyish, running a little to fat and this morning, as most other mornings, she has spread her toast thickly with butter. Lipids, you understand, saturated fats and all that. But she has taken a precaution. The contraceptive tablets on the table beside her came from Schering. The prescription came from her doctor. Her doctor prescribed them because they had 'No significant lipid impact up to 18 months of use'. And who told the doctor that? Schering. And who told Schering that? Apparently Professor Michael Briggs. Up to this point, and assuming that what The Sunday Times wrote was all factually correct, the whole thing looks horrendous; that is indeed the word used by a colleague who knows the ins and outs of the affair. Dr Briggs is said to have falsified data, performed studies on non-existent dogs and generally let down the school; he will never be on the Queen's Birthday Honours List, if that was his ambition. But the story also has to be looked at in a broader perspective. What, to put the old question, is truth? In the field of drug safety at least, truth is an uncertain and even a malleable commodity. To say that is not to be cynical. The Side Effects of Drugs Annuals were created 11 years ago for dealing with precisely that problem; time and again one can see how these volumes have been obliged to define and redefine truth as the evidence grows, changes, is called into doubt or shifts its balance. We have changed our minds several times on an issue such as 'breast cancer and oral contraceptives'; even such a hoary old problem as halothane hepatitis is still causing us to wonder. One thus has to be reluctant about presenting any conclusion about drug safety as if it will hold good for ever. All the same, one has to say something; one cannot be silent merely because the data are incomplete, or constantly take the most cautious approach in the interests of safety; decisions have to be taken all the time, and the information available is rarely all that one would wish it to be. It can be positively dangerous to ignore even flimsy evidence of serious risk. And so one is constantly weighing up the balance of probabilities and seeking to provide the sort of commonsense judgement which will help the practitioner to prescribe in a responsible fashion. That brings me directly back to the case of Dr Briggs. In his own defense, he argues that as a rule he simply took the small-scale findings of various investigators and welded them together into something usable; it was these analyses which he seems to have presented at industry-sponsored symposia. However righteously the experts raise their epidemiological eyebrows, that approach can, within strict limits, be useful. I well remember attending a meeting in Warsaw in January, 1962, where I did virtually the same, with the best of intentions. The industrial research group to which I then belonged had recently gone into the clinic with an original oral contraceptive and had received the first sketchy reports from rather more than a dozen investigators on no more than 1500 cycles of treatment. By piecing them together it was possible to form a picture of the way things seemed likely to go; that preliminary impression was a very useful guide to the work which still needed to be done, and it provisionally answered some of the questions which were being asked. Some of the investigators proved to have delineated, almost uncannily and by virtue of sheer clinical acumen, a number of the things about oral contraceptives which were not firmly proven until several years later. I still look back on that paper with some affection, but the limits

Hark, hark, the fictitious dogs do bark

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of the approach are evident; one has to emphasize the fragility of the starting material, discount the weakest data, beware of building statistical houses on clinical quicksand, and be very guarded in one's analysis. If, subject to those restrictions, the method proved useful in sketching for the first time the apparent clinical properties of 'the pill' in 1962, I am not surprised that anyone used something similar to gain an impression of the effects of some newer oral contraceptives on blood lipids 20 years later. The clinical results which Dr Briggs presented, apparently largely distilled from the fragmentary work of others, do not seem to have been very much at variance with the reports subsequently published by other centres, but they were rather more readable and they formed a good basis for discussion at meetings. Where Dr Briggs and his industrial sponsors may well have slipped up was in advancing preliminary impressions, pieced together in this way, as if they were rock-hard data, and perhaps also in failing to say exactly whose data had been used, why and how. And if he positively asserted that he had done work himself rather than borrowing other people's results, then he was very seriously off the rails. As to Schering: the company seems to have concluded that one of their current products had no unfavourable effect on blood lipids when taken for a year and a half, and to have used this conclusion emphatically in their advertising; if in doing that they relied primarily on Dr Briggs' approach (and if they had never taken the train out from Geelong to check up on things), then they were being very incautious. One should add, in fairness, that the technique of pooling and editing other people's data, often with curious results, is a habit which has been positively encouraged by drug regulators. Look for a moment at the requirements set by a drug regulatory agency such as the Federal F o o d and Drug Administration in the United States. The way in which data on drug efficacy and safety have to be submitted for official assessment is specified in much detail; it is rigidly standardized and complex. It means in effect that the report of an investigator who has done some honest work on a small scale and gained some preliminary impressions is hardly eligible for submission; and if a dozen investigators have worked according to a common protocol, all that the F D A will want to study is a common report written at some central point. Working myself in drug regulation, I have often had to examine those common reports, generally compiled by people in the regulatory departments of pharmaceutical companies, who, I suppose, as a rule had never met the investigators whose work they were supposed to edit. It is rather as if, rather than studying the works of Shakespeare at first h~nd, one were to read only an analysis of their style and content. The contact with the original is lost; one does not know how the investigator felt, what he or she thought, what hunches and premonitions he or she may have developed in the course of the study; nor does one get a picture of the qualities of the various investigators as critical practitioners. But these large pooled analyses are what the regulators demand and are supposed to like; and it is hardly surprising that at a given moment a company may send a package of small studies to people like Professor Briggs, asking for them to be dealt with similarly and perhaps made more digestible at the same time. In other words: I can summon up a lot of comprehension for the fact that things like this happen, and for the fact that they can be useful for limited purposes. But the temptations to overreach oneself, and the absolute need to resist those temptations, are all too clear. I am not quite sure that I believe even The Sunday Times when it comes to reports on fictitious dogs. Creating credible reports on non-existent animal studies is not a sinecure; I have on occasion created some entirely fictive reports on drug investigations which could serve as exercise material for students, and it proved about as difficult as actually doing the studies; an electronic tin whistle is far more complicated than the real thing, and the deceit soon shows through. A liar, they say, needs a good memory; in this field he also needs such a solid knowledge of epidemiology, statistics and biochemistry that he should be able to find his way in the world without lying at all. Animal studies have nevertheless been fabricated on occasion; there was the celebrated case of Biometric Testing Inc., back in 1979, when two former vice-presidents of that American company pleaded guilty to charges of conspiring to falsify reports of animal tests on certain drug products in order to show them harmless when in fact the tests had not been carried out at all. Periodically, one also finds that small biochemical laboratories involved in such studies have been pouring their samples down the drain and then inventing the analyses. What I suspect, however, is that Professor Briggs borrowed his dog studies, as he borrowed his patient studies, from unwitting lenders elsewhere. If he did, it was naughty and unethical but not disastrous for the user. However much hullabaloo may be raised about cases like that of Michael Briggs, I do not get very excited about them unless the community gets truly misled as regards drug safety. Some

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instances of major and minor f r a u d - particularly involving the use of other people's d a t a - merely enrich the miscreants, bolster their unworthy reputations, and inflate the files. These Annuals have referred briefly on 3 occasions to the conclusions published by Dr and Mrs Briggs - in 1977, 1979 and 1982 - but they were entirely overshadowed by much more extensive work published by others. A lot of petty misdemeanours - and I mean a lot - are picked out by the better drug regulatory agencies. I have, for example, several times seen bioavailability and tolerance data clumsily forged by a minor importer. No major company with a reputation to lose is likely to do that. It may (and very often will) edit its data carefully to make the best possible impression, and in doing that it can also overstep the limits of caution, but it will not knowingly create false data; and a sound company will drop a fraudulent investigator like a hot brick. Schering seems to have dropped Dr Briggs like that after its Berlin meeting in 1984, nearly two years before The Sunday Times belatedly picked up the story. There are, of course, marginal cases on which it is more difficult to pass judgement. Take my favourite clinician, Dr XX of Bad Nauheim. He has for many years worked with what his variously industrial sponsors call a 'factor 10'; having studied three patients he will report on thirty. The trouble is that he is one of those people with the clinical acumen which I referred to just now; he is very likely to extract from his three patients as clear an impression as you could wish of what the drug does in man. And if he inflates things a little for the sake of the per capita payment, his mentors will simply sigh a little, set aside the 27 wraiths, and gladly pay up. In the early phases of clinical investigation he is just the sort of person one needs; but woe betide the company which relies on him to go beyond that. Have we really been misled, on any major drug safety issue, by positive fraud? Personally, I doubt it. Negative fraud - the suppression of worrying data is a very much greater problem, but that is not the subject of this essay. In the case of Professor Briggs, the way he worked and the use made of his publications, may have had an influence on the market, inducing physicians to choose, in the hope of reducing the risk of a deranged lipids spectrum, the contraceptive products about which he wrote. In actual fact, however, all the medium and low-dose oral contraceptives now on the market are much of a muchness; one may in the course of a generation prove to have a slightly better (or less unfavourable) effect on blood lipids than another, but the evidence is all flimsy, and the Tweedledum and Tweedledee battle going on between their various promoters does not need to be taken very seriously. It was that petty scenario to which Professor Briggs made some contribution, and it will soon be forgotten. The Englishwoman with her Sunday Times can safely swallow her pills, eat her toast and let serum lipids take care of themselves - provided, that is, she eats a little less butter. Copenhagen January 7th, 1987