453

done, but staunch resistance comes from the nursingauthorities, who insist on a casualty centre for trainingpurposes; it comes too from the surgeons who fear a

greatly increased work-load in the hospital providing thecentre; and, not least, it comes from the community,who fight to keep their doorstep service. (More peoplewould be willing to spend a few extra minutes in theambulance if they knew that their local casualty officerwas an unsupervised preregistration house-physician.)Such are the difficulties of the administrators.In 1957 the Willink Committee reported that there

was likely to be a surplus of doctors in the 1970s. Theestimate was based on the number of doctors the countrywas likely to afford, rather than on the number for idealmedical care; but in making the estimate the committeealso assumed that, by then, medical manpower would beemployed more efficiently, and with maximum use ofancillary services. The existing difficulties in staffing theService stem, at least in part, from its failure to progressto more efficient methods. But, whatever the reasons,about half the hospital junior staff now come from over-seas. Many of these can only obtain posts which offer aminimum of training in return for a maximum of work,and it is increasingly realised that British postgraduatediplomas are of little value to them when they get home.Possibly for this reason there are now signs that themore able graduates are staying at home, and that manyof the doctors now coming to Britain are academically,intellectually, and linguistically less gifted than theirpredecessors. So it is of great importance now for theService to resist the temptation to fill every post: qualitymust be maintained or improved.Some of the difficulties with overseas graduates stem

from the anomalous system of temporary registration. 2The General Medical Council endeavours to assess thecandidate’s suitability for a post in the light of hisqualifications and experience, but, because temporaryregistration is normally given on condition of selectionfor a given post, a good deal of the onus falls on theappointing body. Certainly confusion arises betweenthe bodies: it is not unknown for an inexperienced over-seas graduate to be appointed to a post normally openonly to candidates who have completed preregistra-tion training. Overseas doctors, whether junior or

senior, often need advice when they arrive in Britain;some need instruction, particularly in the working of theNational Health Service, and most need help in obtain-ing suitable appointments. The B.M.A. has for twentyyears been providing such a service with its Common-wealth and International Medical Advisory Bureau,which has given much assistance, but a major advancewas the Ministry of Health’s scheme for clinical attach-ments started in 1966 (see p. 474). In the course of amonth or so in an approved unit, overseas graduatescould be introduced to medical work in Britain, assessedon clinical and linguistic ability, and advised on furtherwork and studies. Such schemes, which are now usuallyorganised by postgraduate deans, have encountered

many difficulties: there is evidence that they are useful,1. See Lancet, 1957, ii, 1043.2. Lancet, 1967, ii, 1192, 1200.

but it is clear that many candidates would have been welladvised to stay at home in the first place. These findingsunderline the view of the Royal Commission on MedicalEducation that appointment of overseas candidatesshould be restricted to those with postgraduate experi-ence in their own countries. In addition, at a time whenmedical schools are more and more adapting theircurricula to local rather than European needs, theGeneral Medical Council will need to keep an evencloser eye on the qualifications regarded as acceptablefor practice in Britain. Assessment schemes should

certainly remain voluntary for most candidates, but theymight be of great value to the Council, or to appointingbodies, in establishing the merits of borderline cases.

British doctors will always be grateful for skilled helpfrom abroad. In the past they have rewarded such helpungenerously, and perhaps the newer arrangements forpostgraduate education will do better justice. But earlyin the days of the Health Service the profession made itclear that whatever the staffing difficulties, standards ofpractice were to be maintained; and it seems that thisprinciple must now be reasserted.

Annotations

CLINICAL TRIALS: THE STATE OF THE ART

" WE want to learn distinctly what is the action of

drugs ... to me it has been a lifelong wonder howvaguely, how ignorantly, how rashly, drugs are often

prescribed." These words, uttered in 1868 by a formerpresident of the Royal College of Physicians of London,Sir Thomas Watson, are by no means out of date. Hewould doubtless have approved, therefore, when today’spresident, Sir Max Rosenheim, took the chair at theopening of a symposium, organised in London onFeb. 12 and 13 by the Association of Medical Advisersin the Pharmaceutical Industry, on the principles andpractice of clinical trials.One theme which emerged prominently was the

increasing size, complexity, duration, and consequentlycost of the process of developing a drug from its genesisto full appraisal. As a result, economic considerationsare increasingly influencing drug research. The processin the laboratory takes at least five years, and in thelater stages critical path analysis is used to integrate thework of the many departments involved. Laboratoryscreening has become highly refined, but it is very hardto simulate various types of human disease. Partly forthis reason and partly in order to correlate the metabolichandling of a drug in man and animals, there are strongarguments for early, restricted, and carefully controlledtrials in man. Speakers at the meeting commended thereport of the Royal College of Physicians 2 and the W.H.O.report on Principles for the Clinical Evaluation of Drugs 3as valuable statements on the ethics and conduct ofhuman experimentation.

In the process of evaluation, the initial clinical phar-macology could be a sound basis for further studiesin both animals and man, but no ready extrapolation is

1. Lancet, 1868, i, 76.2. ibid. 1967, ii, 357.3. Wld Hlth Org. techn. Rep. Ser. 1968, no. 403.

454

possible from healthy volunteers to diseased patients,in whom, for example, the half-life of a drug might bemuch longer or more variable. Lasagna was quoted assaying that therapeutic trials, if successful, should beconfirmed by different investigators in different centreson other populations and under other conditions. Trials

designed to demonstrate efficacy are insufficient to

establish safety and, too often in the past, serious adverseeffects have emerged only after drugs have been in usefor several years. Some system of

" monitored release "was advocated whereby both the numerator and denomin-ator of such effects would be recorded more accuratelyand, if necessary, compared with the spontaneousincidence. Hence the final assessment of a drug’s clinicalvalue might also take four or five years.As for the practicality of the trial itself and the need

for careful judgment of the optimum conditions, themanufacturer’s medical adviser probably has the bestoverall knowledge of the drug, of what needs to be done,and of what others are doing. Whatever plan is ulti-

mately adopted, he will provide the material and thestandard drug or placebo for comparison, suitably packedand labelled. Before any formal trial starts, it is wise to"

get the feel " of a drug and to spend plenty of time oneliminating snags from the protocol and record form.Many studies are perforce preoccupied with measuringthings that may only be incidental, such as blood-levelsof lipids or sugar, when the real problems are the com-plications of atherosclerosis or diabetes. But the limita-tions of our capabilities and resources have to be accepted.As drugs become more similar to each other and perhapsalso to natural substances, increasing sophistication is

necessary to demonstrate a statistical difference. Quiteoften, it was said, we should be prepared to accept a10% probability level, rather than the usual 5%. It was

important to realise that the statistician could onlyeliminate or allow for assignable causes of variation andindicate probabilities based on the data provided. Inthe end, it was for doctors to judge the clinical significanceof the findings, and subsequently to apply these to theindividual patient, who might differ from the groupthat had been studied in one or more respects. Trialswere having a profound effect on clinical medicine andclinicians have been dragged to the very brink of

numeracy ".The discussion turned to the importance of psycho-

logical factors and human frailties. More than ever,successful trials are the product of teamwork, in bothorganisation and execution. Those conducting the trialmust be convinced that the job is worth while and thatit is ethically justified. This applies not only to the

clinicians, but to the laboratory, nursing, pharmacy, andsecretarial staff and whoever else may be involved. The

techniques of measurement should be validated and

reproducible, and observer error should be reduced tothe minimum. " There is more error and bias at thestage of data editing than at any other time," one of thestatisticians remarked. These pitfalls can largely beavoided by careful planning and by ensuring that judg-ments are made before decoding.

Patient motivation is equally important. One of thefunctions of the Dunlop Committee is to raise standards,including those of public understanding. It was saidthat there is a natural tendency for public reaction to thedevelopment of drugs to be: " I want drugs to be avail-able-cheap, safe, and well tested-but don’t try them

out on me." In fact, in the long run, it is the public whoas taxpayers or patients stand to gain or suffer.The placebo effect is well known, even if its power

never ceases to amaze, and the difficulties it causes arenever successfully eliminated. The " de-placebo " or" anti-placebo " effect may become an increasing prob-lem when symptom-free patients are singled out bio-chemically and dragooned into prophylactic trials.Even among apparently willing patients, the incidenceof tablet defaulters is high. One speaker said he believedthat most were honest enough to admit it; other speakerswere less sanguine, but specific urine tests are rare andnon-specific ones generally unsatisfactory. Hence someform of tablet counting is usually the best check available.

Apart from this, individual variability in response wasattributed to: (1) lack of homogeneity in the trial group,in either the nature or severity of the disease (but somecompromise is usually necessary to avoid the groupdwindling away); (2) variation in rate of drug meta-bolism, causing wide differences in plasma level betweenand sometimes within patients, so that at one extremethey experience an excessive effect and, at the other,none at all; (3) social factors-for example, marriedpatients tend to be discharged sooner.Too few trials include different or variable dosages;

too few allow a sufficient run-in period when one isindicated (blood-pressure may continue to fall spon-taneously for several weeks); most trials are short-term,and too few are done to demonstrate the continuingbenefit of any therapeutic regimen. Either throughhabituation or induction of metabolising enzymes theeffect may wear off. On the other hand, minor side-effects may also wear off, if the patient can be persuadedto persist for a few days. When two drugs are beingcompared, patients may base their preference on lackof side-effects rather than on efficacy, and they may bemore impressed by the speed of response than its ultimateextent. Moreover, if they are to continue with one ofthe preparations, they may choose the second of a pairin order to avoid another change. The crossover trialis a useful device, but so often the baseline is not strictlycomparable in the two periods.Dunlop 4 remarked that the modem controlled trial

might be claimed to be the greatest therapeutic advance inthe last quarter of a century, but that there is a desperateshortage of physicians with training adequate to the taskof evaluating the large number of new drugs beingconstantly introduced. Certainly students and doctorsare being encouraged to take a more critical attitudetowards drugs; but it is doubtful if this warning has yetbeen sufficiently heeded, and only a very small minorityare prepared to play an active part.Many people at the meeting must have come away

with mixed feelings: most of the preaching was to theconverted; our standards and sophistication are con-

tinually rising, but must not be allowed to outrun ourcapacity to meet them; in spite of all the problems,drugs are now being evaluated more accurately andmany studies are, in fact, quite simple. Finally, somemay have reflected that in little more than ten years theAssociation of Medical Advisers in the PharmaceuticalIndustry has done a lot to stimulate a wider interest inthese matters and to promote a greater degree of pro-fessionalism in the new subspecialty it represents.4. Dunlop, D. M. in 2nd Symposium on Advanced Medicine (edited by

J. R. Trounce); p. 343. Bath, 1966.