Paediatric a i d Perinafal Epidemiology 1990, 4, 255-260

From our own correspondents

Fumes from the spleen

W e live forwards, but w e understand backwards. William James

More than 80 years ago, William Fletcher, a district surgeon stationed in Kuala Lumpur, conducted a controlled clinical trial’ to demonstrate that a staple article in the Malaysian diet-white (Siamese) rice-was not, as claimed by some observers, the cause of beriberi. In a recent discussion of moral problems that arise in the conduct of such clinical exercises,* Vollrath examined Fletcher’s critical experiment carried out during the second year of an epidemic of beriberi that began in 1905 at the Kuala Lumpur Lunatic Asylum. The asylum was considered to be an ideal location for the controlled trial, Vollrath notes, because the lunatics were a captive population whose living conditions could be altered at will.

The district surgeon, having obtained permission from the government to conduct the experiment, lined the residents up and numbered them in consecutive order; those with odd numbers were assigned to the east ward, even-numbered residents were sent to the west ward. Subsequent admissions were assigned to the two wards in alternate order. For 1 year, beginning on 5 December 1905, all the residents received identical rations except for the type of rice offered: the standard fare prior to the trial (which included Siamese white rice) was served in the east ward; residents in the (experimental) west ward received only Indian brown rice in the usual diet. Fletcher was surprised to find that his prior expectation of no difference in outcome was not supported by the results. Beriberi occurred in 34 of 120 residents (18 of the affected died) on the ward receiving the standard (white rice) diet; among 123 fed the brown rice diet, there were no deaths and only two cases of beriberi (both of these residents were suffering from the disease when admitted to the asylum).

Just as Vollrath’s account of the unexpected outcome in the old, almost forgotten trial in Kuala Lumpur was published, news of the abrupt termination of a modern large-scale controlled clinical trial with surprising interim results made headlines in American newspaper^.^ The present-day investigators were testing the efficacy of two drugs (flecainide and encainide - antiarrhythmia agents which slow conduction in cardiac tissue) accepted as proper treatment to suppress mild to moderate irregularities of cardiac rhythm. The drugs were in current use to treat more than 200 000 Americans with these conditions. In the formal Cardiac

255

256 From our own correspondents Arrhythmia Suppression Trial, outcomes were compared in enrolled patients who were allocated, in random order, to either an antiarrhythmia-treatment group or to a control group (the latter received ’dummy’ pills). The trial, scheduled to continue through 1992, was stopped 3 years early when the safety monitoring committee overseeing the trial was convinced that mortality was unexpectedly higher (56 deaths) among 730 patients receiving specific-drug treatment as compared with 22 fatalities in the group of placebo-treated controls.

A comparison of the Kuala Lumpur and the American clinical trials provides supporting evidence for the claim that there has been considerable improvement in the safeguards to protect the rights of patients enrolled in such therapeutic experiments over the intervening period of more than 80 years. But we have found no easy answers to the many questions discussed by Vollrath. Much of the difficulty he describes is related to a widespread failure to take into account the highly variable nature of evidence gathered at the bedside. There appears to be, for example, remarkably little appreciation of the interpretive difficulties that arise when relatively few patients become sick or die after exposure to some harmful influence (e.g. the majority of patients who ate white rice in Fletcher’s experiment did not develop beriberi; the majority of the treated patients in the present-day cardiac arrhythmia suppression trial did not die).

The misunderstanding about variability leads to a poorly defined notion of a doctor’s moral obligation to his/her patient in the conduct of clinical trials that test new therapies. As has been noted previously in this space, one version of the profession’s duty (termed the ‘doctor’s therapeutic obligation’: always prescribe the best treatment) requires that doctors must not allow their patients to be enrolled in a controlled trial as soon as interim results show that a trend has developed in favour of one of the compared treatment^.^ But this view is as confused as that of a demented racing fan who demands that a horse race be stopped the moment one horse inches ahead of the pack to take the lead. Outcome of illness, like outcome at the track, is the result of a multitude of influences -the inescapable problems of interpretation related to variability cannot be solved without pre-planned stopping rules in the design of clinical trials (and in pre- agreement on the length of the course in a horse race!).

Results in both trials under discussion make the point that doctors need to recognise that they do have a ‘study-design obligation’ in the conduct of clinical trials. Patients’ best interests are served when investigators take precautions needed in trial design to improve the chances of making sense out of information. For example, a glimmering of the notion of ‘study-design obligation’ can be seen in Fletcher’s conduct of the trial so many years ago in Kuala Lumpur. (Perhaps the action was related to the fact that he began the trial as a sceptic: ’at the commencement of the experiment the opinion was held by myself that rice was neither directly or indirectly the cause of beriberi’.) Four months after the diet experiment was under way, Fletcher noticed that beriberi was occurring only in

From our own correspondents 257

asylum residents receiving white rice. Acting on the possibility that brown rice might be protective, he began a crude cross-over modification of the experiment: if a resident survived an initial attack of beriberi, the convalescent was transferred to the brown-rice ward. Ten such residents were transferred: all had no further symptoms. Since the admission of these patients caused some overcrowding in the brown-rice ward, four residents were transferred to the white-rice section of the asylum; two developed beriberi, one of whom died.

In the design of the recent antiarrhythmia trial, the inclusion of an untreated control group improved the chances of obtaining interpretable results; and, no small accomplishment, the concurrent control design reduced the number of patients exposed to the completely unexpected harmful consequences of the widely-used drugs. Like Fletcher's hopes for the standard white-rice diet, the present-day investigators expected that standard drug treatment would be vindicated by the trial results. (A small pilot trial conducted in 1982 had indicated that patients having problems with asymptomatic or moderate heart-beat irregularities might be protected from a subsequent heart attack or death by controlling irregular cardiac rhythm with antiarrhythmia drugs.) A member of the steering committee for the trial said he 'was truly stunned and shocked' when given the interim results by the safety monitors.

Anyone can see, with the clear vision of hindsight, the safety and the fairness of the hedging strategy used in both trials: one-half of the enrolled patients were protected from the unfortunate consequences of what their doctors did not know about the treatments they prescribed. There must be increased public recognition that it is just this risk-limiting feature which makes concurrent control design a socially responsible exercise. (Medical positivists to the contrary notwithstanding, knowledge about treatment effects is never complete.) Moreover, for all enrolled patients in a comparative trial the unknown risks and hoped-for benefits are distributed impartially, as they are in everyday life, by chance. In response to reporters' questions about the practical value of the truncated antiarrhythmia trial, one of the participating investigators said, 'Absolutely, unequivocally, this trial was a success because we have identified two drugs of a type that are more dangerous than the disease they are supposed to treat'.

Another issue stands out in an examination of the 1905-1906 and the 1989 trials: the problem of who can, should, or must participate in these clinical exercises has not yet been solved. There has been some progress since the days of the Lunatic Asylum trial, insofar as there is general agreement that it is unconscionable to enroll institutionalised or mentally incompetent patients without obtaining explicit and informed consent from individual guardians. But the knotty problem of who is a proper enrollee is not completely solved by the now generally-accepted rule that only fully informed volunteers may participate. The informed-volunteers-only approach overlooks the dubious moral position of those who refuse. Do they have the right to insist, in effect, that others must

258 From our own correspondents

undertake the risk on their (the refusers) behalf? What should we say about those who, as one critic has ~ r i t t e n , ~ are content ‘to possess the end and yet not be responsible for the means, to grasp the fruit while disavowing the tree, to escape paying the cost until someone else has paid it irrevocably’. Chalmers has made a plea for an accounting of the public obligation:6 ‘we must face up to the fact that testing treatments is everyone’s business’.

MALCONTENT

References

1 Fletcher, W. Rice and beri-beri: Preliminary report on an experiment conducted at the Kuala Lumpur Lunatic Asylum. Lancet 1907; i:1776-1779. 2 3 New York Times 26 April, 1989. 4

5 with Human Beings, Editor: J. Katz. New York: Russell Sage Foundation, 1972. 6 clinical experimentation, Controlled Clinical Trials 1987: 8388-391.

Vollrath, J. Experiments and rights. Bioethics 1989; 3:93-105. Leary, W.E. Warning issued on 2 heart drugs after deaths of patients in a test.

Marquis, D. Leaving therapy to chance. Hustings Cenfer Report 1983;

Cahn, E. Drug experiments and the public conscience. In: Experimentation

Chalmers, I., Silverman, W.A. Professional and public double-standards on

13~40-47.

So what?

The prophet in his own home

How can we win the respect and admiration of our children? This is something that has puzzled me for nearly 30 years and I am no nearer to finding a satisfactory answer. When my son was little, the only way to get status at his primary school was to have a mother who was a dinner lady. Getting a second degree or a teaching job or a parliamentary seat went for nought: being a dinner lady was the ambition he had for me, and I failed him.

I once discussed this with a professor of social medicine, world famous for his unrivalled expertise in medical statistics, and much in demand for government committees. His son would not stop talking enviously about a new school friend whose father played football for a fourth division football team.

Trying still, after 30 years, to win my son’s approval I sent him a couple of reprints from my little articles in Paediatric and Perinatal Epidemiology. (I could not send him a copy of all of them as the publisher sometimes sends me reprints and sometimes not; I cannot be sure whether it means that the person deciding whether or not I deserve reprints is making a judgement of the article or feeling