- Email: [email protected]
Monitoring the physical forcing of resuspension events in the Thermaikos Gulf—NW Aegean during 2001–2003
152
G.p.-assuage the G.P.’s feeling of isolation, introduce objectively than the drug salesman the advances in therapy, serve as a real link between hospital and community doctor ? If we are successful in obtaining a Royal Commission to investigate the N.H.S. this is an area they might well look at. I have not mentioned the Plowden recommendations. Most are already well known. Perhaps the most important is that part-time nursery education should be available for all who want it. It will be long coming-so long that the question of its cost generated the only really sharp division of opinion and emotions on the Council. The members who believed themselves most Tory and most Socialist respectively joined together in advocating (with several more
Special Articles TRIALS AND TRIBULATIONS The Lancet has been
talking to some of those doctors in the who coordinate clinical research, to get pharmaceutical industry some idea of the background to their final product-the clinical trial. THREE and four years ago, the safety and evaluation of drugs, and new drugs especially, was subject to much discussion in Parliament, in the Press, and by both the medical profession and the pharmaceutical industry. In this there were two, non-opponent camps: there were those whose main concern was safety, and whose arguments drew strength from the thalidomide tragedy, and those who were urging a better-equipped milieu for the conduct of clinical trials. In the event, the Committee on Safety of Drugs provided one answer; but coincident interest in the discipline of human (clinical) pharmacology and in some form of mediating body between the industry and the potential trialist has produced little of substance. The effects of this lack of productive interest seem to pervade the whole atmosphere in which clinical trials are conducted. Medical advisers* are seeking clinicians with the time, informed enthusiasm, and the right clinical material -and they find this a rare combination. Ideally clinical trials would be done in academic departments in teaching hospitals, but in practice the medical adviser must often look elsewhere-to non-teaching hospitals, special clinics, or general practice-areas in which trialists will be doing the work as a secondary interest. HUMAN PHARMACOLOGY
The " proper study of mankind ", initially at least, is the medical adviser himself. Taking a minute dose in the office with a colleague to hand is rarely a dangerous exercise, nor is it particularly scientific, but it can be more than just a demonstration of confidence. Two medical advisers took a very small quantity of one new drug, the product of many years of laboratory research, only to find that it produced visual disturbances and atropine-like toxicity, and was quite unsuitable for clinical trial. At this point, as with most new drugs, some 80% of the planned budget had already been spent. The laboratory did not feel that their brainchild had had a fair trial; but rejected, after a conflict, it was. Trialists, at least the pioneers, expect details of the absorption, metabolism, and excretion of a new drug in man-and in any case the Dunlop committee requires this information-but in the U.K. there is no standard way of going about this. For one thing there is relatively little experience: only 8°o of the *
Only a minority of the doctors who work full-time in the pharmaceutical industry are concerned with clinical trials, but, since no simple alternative term comes to mind, medical adviser in this article refers to this minority. "
"
pay; the educationists, true believers in the unified State service they had fought to create and maintain, opposed this bitterly, and won the majority to their side. The Press is predictably making much of the dissension about religious education; in fact this was fought with the greatest good will and sincerity on all (not both) sides. (It was an illness and not the religious issue, as some papers said, which made the report come out three months late.) I shall miss the visits to primary schools, miss the stale biscuits and earnest conversation, miss the intellectual stimulus of a chairman and secretariat whose expertise exceeded that of any other committee I can recall. I suppose now I shall have to get on with some work.
others) that parents should
submissions new
to
the
Dunlop
committee in 1965
were
for wholly
drug substances, and of these the human pharmacological
work for many will have been completed in the country of origin (i.e., by the parent or licensing company). This work may need to be repeated or extended, but this is rare when it has initially been done in the U.K., the U.S.A., Scandinavia, or Switzerland. Starting from scratch, many methods are used: one company relies on paid factory staff under day-time supervision of the factory doctor; one leaves the work wholly in the hands of an academic department; another has a panel of volunteers who can be admitted to the company’s surgery for 48 hours with medical attention and resuscitative equipment to hand; and there is talk that companies might " admit" their volunteers into fully paid-up private beds.
There are ethical difficulties whenever volunteers are involved in research, and these are enhanced when the work is on a new drug. In the U.S.A. prisoners may volunteer for this purpose, but in the U.K. this practice is not allowed (in one known exception the material was not strictly speaking a drug); furthermore, some clinical pharmacologists regard work done on prisoners as suspect, because the motives which prompt a man to volunteer under such circumstances may colour any subjective responses noted. THE PROGRAMME
Clinical evaluation is a very lengthy business. Some idea of the stages may be gained from the following programme (with future stages filled in from past experience) for a new chemical substance: January, 1965.-Manufacturing and laboratory work completed and written up. April.-Three trialists contacted and agree in principle to do preliminary clinical work as soon as approval has been obtained from the Dunlop committee. yMKe/M/y.—All data and names of prospective trialists sent to the Committee on Safety of Drugs. AugustfSeptember.-Permission for clinical trial granted, provided that work is accompanied by certain specified laboratory checks. (The type of patient who may be treated can also be restricted at this point: this is important because a limited scope here can lead to restrictions being imposed on indications and availability at a later stage.) October/December.-Preliminary work started. Some pharmacology may have to be repeated or extended if the early findings do not accord with the animal work. January, 1966.-Most of the preliminary findings from the three centres will be in, and requests for more, and more extensive, trials can now be made. February!April.-Up to 10 trials may be started; and, for these, record forms and trial plans must be approved by the trialists, and drugs must be matched and packed (perhaps according to a randomised plan). December.-The results start to come in. February, 1967.-The first trial to be completed will now be analysed and a report sent to the clinician for write-up. April/May.-Draft paper written and discussed.
153 do it conscientiously in the busy environment of a hosward is difficult, especially since matrons and sisters may be reluctant to let their staff take part. Many firms get round December.-The first major trial is published. this problem by paying for registrars to work full-time in the hosSo between initial submission and permission for marketing and a an be a two half less for will of about there years: pital and devote part of their time to clinical trials. On the gap antibiotic used in acute illnesses but more for a drug of potential whole, this idea seems to work well, but there may be difficulties as the practice becomes more widespread: certain hospitals in the prophylaxis of cardiovascular disease. For reformulations or mixtures most of the delays up to January, 1966, will be may get a reputation for doing work for one company, and the avoided. registrar, because of his seemingly different status, may not fit in well. Even where interest is stimulated all down the line THE APPROACH at first, it is not easy to keep enthusiasm fired for longer than Laurence,l commenting on the transition of a drug from three to six months, and staff changes are likely to make inlaboratory to patient, said that " ... there is seldom any patient assessments of a year or more extremely difficult. difficulty with new compounds of obvious theoretical or The control drug.-Companies want to test their brainchild particular practical interest "; and certainly no-one would against the so-called " market leader ", and their statistician expect problems with a chemically novel antibiotic or with will wish to include a placebo at some stage if only to test his an oral formulation of insulin. But novelty and interest method. But the trialist may not like the market leader, or he are in the eye of the beholder: the description " a new may feel that to test one unknown against starch or lactose is X-azide " which seems apt in the laboratory may be not in the best interests of his patients. Nor is the making of received with " not another X-azide ! " in the hospital. identical-looking tablets or ampoules always as easy as it sounds. The medical profession is becoming opposed to mixtures, One firm wishing to test its product against a well-established and this opposition is shared by some, but not all, medical drug found that it was not allowed to reformulate the marketed brand so that the test and control drugs would be identical. advisers; but the commercial attractions, for example, of Concurrent laboratory work.-The human pharmacology will X plus aspirin when one has spent 1:3/4 million on X are not have given information on possible long-term effects of the so strong that few medical advisers wholly avoid them. drug in illness. And routine testing of blood-picture, urine, Sometimes a company may meet with opposition to a and liver function during a clinical trial adds a heavy load to certain type of compound-one had great difficulty with a an already hard-worked pathology department. In one crossmucolytic agent, perhaps because there was little to over trial involving some 40 patients these tests were done once before the trial and twice for each of the three regimens being measure. Since pharmacological advance is made by small hops tested: 500 complex record forms had to be completed and rather than impressive leaps, medical advisers are reluctant then checked by an independent consultant pathologist. One firm makes use of the Emergency Volunteer Service-leatherto prejudge their material; but experience does show that who rush samples from the hospital to there is one pattern of interest for the excitingly probable jacketed motor-cyclists the company’s laboratory-but it is still thought desirable for and another for the unexcitingly possible. For the first the work to be checked elsewhere. Private laboratories undergroup there are a small number of workers to whom one take this work, but they are rather expensive, and the difficulties " and retire confident that of collection and transport remain. can say " Please test this for us the work will be well done. Of these trialists, 90% will Follow-up.-A full-scale clinical evaluation can take a long undertake work and 90% will produce a useful report-a time and, as the industry begins to think more in terms of chronic illnesses and long-term treatment, these times will get success-rate of, say, 80%. Help, financial or technical, longer. But however short the period of observation is to be, may be given but otherwise the evaluation has a refreshing follow-up is always necessary for the success of the spontaneity. For the rest, the position is less satisfactory. continuous trial. Although " never do clinical trials " is a rare response, Publication.-Permission to market the drug can be obtained most companies would reckon to have done well to get a before publication of the results of clinical work, but there is Typical no doubt that publication in a widely read journal is the ideal helpful reply in two approaches" out of every three. " reasons for refusal might be: too busy "; doing a trial end-point of any clinical trial. Editorial rejection and delays in for someone else "; or, nowadays, " gone to U.S.A." the press can add substantially to the time spent in clinical Those who cast their bread upon the waters will expect a evaluation, and this is most dispiriting for the clinician-a degree of pulp among the returns, and a characteristic registrar, for example, who wants to get into print. One sound, pattern of response to 10 approaches might be: 6/7 accept- though admittedly substantial, report spent the best part of two years in typewriters, editorial baskets, mailbags, and the ances, 2/3 trial failures, and 1 unusable report-a successpress. One way round this delay is to precede publication by rate of 20-40%. holding a symposium at which trialists read their papers-but THE TRIAL this does not have quite the same impact. Statistical analysis It is easy to design the ideal trial to suit a given question; of results can be a complex business, and usually the firm but it is what is practicable in the hospital that must, in provides an explanatory write-up to accompany the sometimes abstruse mathematics. Although few companies would be the event, govern the shape of the work. Since medical advisers know that they will rarely, if ever, be able to happy to go much further than this, multicentre work and G.P. trials do need different handling; the medi,:al adviser may proorganise the perfect trial they also know in advance what vide the trialist with much more than a short write-up, and fullcriticisms are likely to be made. They feel that some of the scale " ghost writing " is not unknown. critics who make academic points can have little idea of the
June July.- The journals.
paper starts the round of the medical
but
practical difficulties that have
to
ATMOSPHERE
be solved and the
compromises that have to be made. DMn
to
pital
Laurence, D. R. Lancet, 1964, i, 1173.
Binns and Butterfield2 claimed that: " The right sort of doctor will be attracted to this work only if the right atmosphere is created and some ofthe present frustrations are removed ". The right doctors are few, and there are many frustrations but what about the less concrete contribution, the atmosphere ? There is general agreement that the existing atmosphere is not satisfactory, but it 2.
Binns, T. B., Butterfield, W. J H. ibid. p. 1150.
154
is difficult
pinpoint what is wrung. The N.H.S., especially at registrar level where much of the work is done, is in a delicate state, and the industry itself is very conscious of constant surveillance-it already has two to
committees on its shoulders and a third is even now investigating it. But while these problems wilt sort themselves out there are other areas in which the air might be cleared. Motives It is impossible, when organising clinical trials, not to be aware of the motives which induce a doctor to cooperate. (One must exclude here the super-trialists who are rarely found outside academic departments). Motives, all liberally mixed with a desire to help, may be: (1) a departmental head starved of the means to provide a research interest for his staff may welcome the opportunity to do clinical trials; (2) registrars, who at some stage are expected to produce papers, may find trials an easy way of doing this; (3) there is considerable kudos in being associated with the early days of a new wonder drug, but this is a gamble with such long odds that it cannot be a common motive; and (4) there are a very few who do work on " " a rate-for-the-job basis. Finance It is not true that money, in cash or kind, changes hands during all clinical trials; and when it does the idea is usually raised by the company. Quite a common practice is for the company to provide a piece of equipment which is needed for the trial and which is then left with the hospital. A company may pay registrars or part-time technicians and secretaries. At a lower level a gift may be made to a department’s travel fund or a firm may agree to pay the costs of a clinician’s visit to a symposium; the trialist may be pleased to receive a book-token or be wined and dined; or he may neither expect nor receive anything. It has been suggested that all transactions should be disclosed, and most medical advisers agree that such a practice would clear the air. But they do foresee difficulties. Such disclosures would encourage the " rate-for-the-job approach and by insisting on them one would seem to imply that trialists are capable of deliberate bias. On the other hand, in discussing results most trialists go out of their way to find something helpful to say about the test drug-clinicians may say " A is very slightly better than B " rather than " A is no significant advance on B which, like half full " and " half empty ", is a subtly different way of saying the same thing. Some medical advisers feel that where such distinctions or the occasional quite unwarranted eulogy are possible (for in the long run they can only damage drug, trialist, and industry) it would be salutary for the writer to know that his interests were to be declared. "
before going ahead. Sales departments like to time marketing with the publication date of some major trials; but medical advisers can have no control over publication, and occasions where the two have come together are purely fortuitous. Clearly, the medical adviser must shield his trialists from these pressures when they arise. This has been only one side of the coin but it is one that or
so
is seldom
seen
by the practising doctor.
Medicine and the Law
"
"
"
Hierarchy Undoubtedly there was a time when the clinical-trials unit of a company (if it had one at all) occupied a lowly level in the management pyramid and when a doctor knew that to get on he had to leave the research side and move into sales or administration. But the past five years have seen a big change, and in most companies the clinical-research organiser, if not himself a director, is responsible to a research-oriented doctor on the board. Internal Pressures Commercial pressures ? Never without them; but then, who in industry is not in the same position ? " Such pressures first act at the moment of entry of a drug into clinical trial, but they mount as the work progresses. They are rarely unpleasantly imposed or foolishly motivated, but five years of laboratory and clinical work is a considerable investment, and companies have to start to get a return some time. Typical questions might be: When is so-and-so’s trial due to finish ? "; Surely you have enough data for a second Dunlop submission ? "; What can we quote from X’s paper ? There is a tendency also to think that permission to market means you must market; but the Dunlop committee, although it takes account of efficacy, is primarily concerned with safety. A full picture of the clinical applications of the drug may not emerge until all the clinical work is completed, and it is better sometimes to wait six months "
...
"
"
"
"
Subnormality
and Unsoundness of Mind
BY A LEGAL CORRESPONDENT
THE
of
Woolley
Woolley1
raises
important and have rarely had occasion to consider: can the husband A)r wife of a "subnormal " or " severely subnormal " person (defined in the Mental Health Act, 1959,2 as, to a lesser or greater degree, "in a state of arrested or incomplete development of mind ") obtain a decree of divorce on the ground that his or her spouse is incurably " of unsound mind " within the meaning of the Matrimonial Causes Act, 1965 ? " Of unsound mind " is not defined in the 1965 Act. The courts have been set the task of interpreting the term which, of course, is not a medical one. There are only two reported cases in which the term has been considered in the context of the " subnormal " spouse. In 1964,3 Cairns J. defined " unsoundness of mind " as the incapacity of a person to manage himself and his affairs, including the problems of society and married life, without reference to the cause of the incapacity. He derived assistance from an earlier decision,4 in which the patient was indisputably insane (a paranoid schizophrenic) and the only question was whether he was now recovered. Cairns J. held that a defective was " of unsound mind," although he refused a decree on other grounds. In a more recent decision,I Park _7. refused to follow the reasoning of his brother judge, whose jurisdiction is parallel " to his own. In deciding that a subnormal" or severely subnormal," person was not " of unsound mind," Park J. referred to the Statutesdealing with the care and treatment of the mentally disordered and held that the law had consistently distinguished the " unsound " of mind (the term substituted by the Mental Treatment Act, 1930, for the " lunatic " of the 1890 Act) from the mental defective. In the Matrimonial Causes Act, Parliament included the mentally defective specifically in the provisions relating to nullity; but no mention is made of mental deficiency in the divorce provisions of that Act. Parky. inferred that the omission was a deliberate one. The question is therefore open. A future court may decide to follow either of these decisions-or neither of them. Perhaps the decision of Park. is likely to prevail. Cairns J.’s broad interpretation of unsoundness of mind as the inability of the patient to manage himself and his affairs is not based on established principle. Having found the patient " of unsound mind," the courts have used the test of inability to manage to decide whether the nature of the patient’s condition is such as to bring him or her under the provisions of the Matrimonial Causes Act.4 The phrase " inability to manage ..." has never before been used to define " unsoundness of mind " itself. The courts have sought, sympathetically, to aid the husband " or wife of a subnormal " patient and in the two recent cases have indeed pronounced decrees of divorce; one,’ on the ground of adultery; the other,3 on that of cruelty. It would appear, however, that in the absence of evidence to support an alternative ground, a marriage where one spouse is a defective case
v.
interesting point of law, which the
an
courts
"
"
must
remain,
so
long
as
the
seeming lacuna in the
"
law is open,
indissoluble. 1. [1966] 3 W.L.R. 1117; see Lancet, 1966, ii, 1358. 2. Section 4 (2) and (3). 3. Robinson v. Robinson [1964], 3 All E.R. 232.
4. 5.
Whysall v. Whysall [1960], p. 52. Esp. Lunacy and Mental Treatment Acts, 1890-1930; Mental Deficiency Acts, 1913-27.
G.p.-assuage the G.P.’s feeling of isolation, introduce objectively than the drug salesman the advances in therapy, serve as a real link between hospital and community doctor ? If we are successful in obtaining a Royal Commission to investigate the N.H.S. this is an area they might well look at. I have not mentioned the Plowden recommendations. Most are already well known. Perhaps the most important is that part-time nursery education should be available for all who want it. It will be long coming-so long that the question of its cost generated the only really sharp division of opinion and emotions on the Council. The members who believed themselves most Tory and most Socialist respectively joined together in advocating (with several more
Special Articles TRIALS AND TRIBULATIONS The Lancet has been
talking to some of those doctors in the who coordinate clinical research, to get pharmaceutical industry some idea of the background to their final product-the clinical trial. THREE and four years ago, the safety and evaluation of drugs, and new drugs especially, was subject to much discussion in Parliament, in the Press, and by both the medical profession and the pharmaceutical industry. In this there were two, non-opponent camps: there were those whose main concern was safety, and whose arguments drew strength from the thalidomide tragedy, and those who were urging a better-equipped milieu for the conduct of clinical trials. In the event, the Committee on Safety of Drugs provided one answer; but coincident interest in the discipline of human (clinical) pharmacology and in some form of mediating body between the industry and the potential trialist has produced little of substance. The effects of this lack of productive interest seem to pervade the whole atmosphere in which clinical trials are conducted. Medical advisers* are seeking clinicians with the time, informed enthusiasm, and the right clinical material -and they find this a rare combination. Ideally clinical trials would be done in academic departments in teaching hospitals, but in practice the medical adviser must often look elsewhere-to non-teaching hospitals, special clinics, or general practice-areas in which trialists will be doing the work as a secondary interest. HUMAN PHARMACOLOGY
The " proper study of mankind ", initially at least, is the medical adviser himself. Taking a minute dose in the office with a colleague to hand is rarely a dangerous exercise, nor is it particularly scientific, but it can be more than just a demonstration of confidence. Two medical advisers took a very small quantity of one new drug, the product of many years of laboratory research, only to find that it produced visual disturbances and atropine-like toxicity, and was quite unsuitable for clinical trial. At this point, as with most new drugs, some 80% of the planned budget had already been spent. The laboratory did not feel that their brainchild had had a fair trial; but rejected, after a conflict, it was. Trialists, at least the pioneers, expect details of the absorption, metabolism, and excretion of a new drug in man-and in any case the Dunlop committee requires this information-but in the U.K. there is no standard way of going about this. For one thing there is relatively little experience: only 8°o of the *
Only a minority of the doctors who work full-time in the pharmaceutical industry are concerned with clinical trials, but, since no simple alternative term comes to mind, medical adviser in this article refers to this minority. "
"
pay; the educationists, true believers in the unified State service they had fought to create and maintain, opposed this bitterly, and won the majority to their side. The Press is predictably making much of the dissension about religious education; in fact this was fought with the greatest good will and sincerity on all (not both) sides. (It was an illness and not the religious issue, as some papers said, which made the report come out three months late.) I shall miss the visits to primary schools, miss the stale biscuits and earnest conversation, miss the intellectual stimulus of a chairman and secretariat whose expertise exceeded that of any other committee I can recall. I suppose now I shall have to get on with some work.
others) that parents should
submissions new
to
the
Dunlop
committee in 1965
were
for wholly
drug substances, and of these the human pharmacological
work for many will have been completed in the country of origin (i.e., by the parent or licensing company). This work may need to be repeated or extended, but this is rare when it has initially been done in the U.K., the U.S.A., Scandinavia, or Switzerland. Starting from scratch, many methods are used: one company relies on paid factory staff under day-time supervision of the factory doctor; one leaves the work wholly in the hands of an academic department; another has a panel of volunteers who can be admitted to the company’s surgery for 48 hours with medical attention and resuscitative equipment to hand; and there is talk that companies might " admit" their volunteers into fully paid-up private beds.
There are ethical difficulties whenever volunteers are involved in research, and these are enhanced when the work is on a new drug. In the U.S.A. prisoners may volunteer for this purpose, but in the U.K. this practice is not allowed (in one known exception the material was not strictly speaking a drug); furthermore, some clinical pharmacologists regard work done on prisoners as suspect, because the motives which prompt a man to volunteer under such circumstances may colour any subjective responses noted. THE PROGRAMME
Clinical evaluation is a very lengthy business. Some idea of the stages may be gained from the following programme (with future stages filled in from past experience) for a new chemical substance: January, 1965.-Manufacturing and laboratory work completed and written up. April.-Three trialists contacted and agree in principle to do preliminary clinical work as soon as approval has been obtained from the Dunlop committee. yMKe/M/y.—All data and names of prospective trialists sent to the Committee on Safety of Drugs. AugustfSeptember.-Permission for clinical trial granted, provided that work is accompanied by certain specified laboratory checks. (The type of patient who may be treated can also be restricted at this point: this is important because a limited scope here can lead to restrictions being imposed on indications and availability at a later stage.) October/December.-Preliminary work started. Some pharmacology may have to be repeated or extended if the early findings do not accord with the animal work. January, 1966.-Most of the preliminary findings from the three centres will be in, and requests for more, and more extensive, trials can now be made. February!April.-Up to 10 trials may be started; and, for these, record forms and trial plans must be approved by the trialists, and drugs must be matched and packed (perhaps according to a randomised plan). December.-The results start to come in. February, 1967.-The first trial to be completed will now be analysed and a report sent to the clinician for write-up. April/May.-Draft paper written and discussed.
153 do it conscientiously in the busy environment of a hosward is difficult, especially since matrons and sisters may be reluctant to let their staff take part. Many firms get round December.-The first major trial is published. this problem by paying for registrars to work full-time in the hosSo between initial submission and permission for marketing and a an be a two half less for will of about there years: pital and devote part of their time to clinical trials. On the gap antibiotic used in acute illnesses but more for a drug of potential whole, this idea seems to work well, but there may be difficulties as the practice becomes more widespread: certain hospitals in the prophylaxis of cardiovascular disease. For reformulations or mixtures most of the delays up to January, 1966, will be may get a reputation for doing work for one company, and the avoided. registrar, because of his seemingly different status, may not fit in well. Even where interest is stimulated all down the line THE APPROACH at first, it is not easy to keep enthusiasm fired for longer than Laurence,l commenting on the transition of a drug from three to six months, and staff changes are likely to make inlaboratory to patient, said that " ... there is seldom any patient assessments of a year or more extremely difficult. difficulty with new compounds of obvious theoretical or The control drug.-Companies want to test their brainchild particular practical interest "; and certainly no-one would against the so-called " market leader ", and their statistician expect problems with a chemically novel antibiotic or with will wish to include a placebo at some stage if only to test his an oral formulation of insulin. But novelty and interest method. But the trialist may not like the market leader, or he are in the eye of the beholder: the description " a new may feel that to test one unknown against starch or lactose is X-azide " which seems apt in the laboratory may be not in the best interests of his patients. Nor is the making of received with " not another X-azide ! " in the hospital. identical-looking tablets or ampoules always as easy as it sounds. The medical profession is becoming opposed to mixtures, One firm wishing to test its product against a well-established and this opposition is shared by some, but not all, medical drug found that it was not allowed to reformulate the marketed brand so that the test and control drugs would be identical. advisers; but the commercial attractions, for example, of Concurrent laboratory work.-The human pharmacology will X plus aspirin when one has spent 1:3/4 million on X are not have given information on possible long-term effects of the so strong that few medical advisers wholly avoid them. drug in illness. And routine testing of blood-picture, urine, Sometimes a company may meet with opposition to a and liver function during a clinical trial adds a heavy load to certain type of compound-one had great difficulty with a an already hard-worked pathology department. In one crossmucolytic agent, perhaps because there was little to over trial involving some 40 patients these tests were done once before the trial and twice for each of the three regimens being measure. Since pharmacological advance is made by small hops tested: 500 complex record forms had to be completed and rather than impressive leaps, medical advisers are reluctant then checked by an independent consultant pathologist. One firm makes use of the Emergency Volunteer Service-leatherto prejudge their material; but experience does show that who rush samples from the hospital to there is one pattern of interest for the excitingly probable jacketed motor-cyclists the company’s laboratory-but it is still thought desirable for and another for the unexcitingly possible. For the first the work to be checked elsewhere. Private laboratories undergroup there are a small number of workers to whom one take this work, but they are rather expensive, and the difficulties " and retire confident that of collection and transport remain. can say " Please test this for us the work will be well done. Of these trialists, 90% will Follow-up.-A full-scale clinical evaluation can take a long undertake work and 90% will produce a useful report-a time and, as the industry begins to think more in terms of chronic illnesses and long-term treatment, these times will get success-rate of, say, 80%. Help, financial or technical, longer. But however short the period of observation is to be, may be given but otherwise the evaluation has a refreshing follow-up is always necessary for the success of the spontaneity. For the rest, the position is less satisfactory. continuous trial. Although " never do clinical trials " is a rare response, Publication.-Permission to market the drug can be obtained most companies would reckon to have done well to get a before publication of the results of clinical work, but there is Typical no doubt that publication in a widely read journal is the ideal helpful reply in two approaches" out of every three. " reasons for refusal might be: too busy "; doing a trial end-point of any clinical trial. Editorial rejection and delays in for someone else "; or, nowadays, " gone to U.S.A." the press can add substantially to the time spent in clinical Those who cast their bread upon the waters will expect a evaluation, and this is most dispiriting for the clinician-a degree of pulp among the returns, and a characteristic registrar, for example, who wants to get into print. One sound, pattern of response to 10 approaches might be: 6/7 accept- though admittedly substantial, report spent the best part of two years in typewriters, editorial baskets, mailbags, and the ances, 2/3 trial failures, and 1 unusable report-a successpress. One way round this delay is to precede publication by rate of 20-40%. holding a symposium at which trialists read their papers-but THE TRIAL this does not have quite the same impact. Statistical analysis It is easy to design the ideal trial to suit a given question; of results can be a complex business, and usually the firm but it is what is practicable in the hospital that must, in provides an explanatory write-up to accompany the sometimes abstruse mathematics. Although few companies would be the event, govern the shape of the work. Since medical advisers know that they will rarely, if ever, be able to happy to go much further than this, multicentre work and G.P. trials do need different handling; the medi,:al adviser may proorganise the perfect trial they also know in advance what vide the trialist with much more than a short write-up, and fullcriticisms are likely to be made. They feel that some of the scale " ghost writing " is not unknown. critics who make academic points can have little idea of the
June July.- The journals.
paper starts the round of the medical
but
practical difficulties that have
to
ATMOSPHERE
be solved and the
compromises that have to be made. DMn
to
pital
Laurence, D. R. Lancet, 1964, i, 1173.
Binns and Butterfield2 claimed that: " The right sort of doctor will be attracted to this work only if the right atmosphere is created and some ofthe present frustrations are removed ". The right doctors are few, and there are many frustrations but what about the less concrete contribution, the atmosphere ? There is general agreement that the existing atmosphere is not satisfactory, but it 2.
Binns, T. B., Butterfield, W. J H. ibid. p. 1150.
154
is difficult
pinpoint what is wrung. The N.H.S., especially at registrar level where much of the work is done, is in a delicate state, and the industry itself is very conscious of constant surveillance-it already has two to
committees on its shoulders and a third is even now investigating it. But while these problems wilt sort themselves out there are other areas in which the air might be cleared. Motives It is impossible, when organising clinical trials, not to be aware of the motives which induce a doctor to cooperate. (One must exclude here the super-trialists who are rarely found outside academic departments). Motives, all liberally mixed with a desire to help, may be: (1) a departmental head starved of the means to provide a research interest for his staff may welcome the opportunity to do clinical trials; (2) registrars, who at some stage are expected to produce papers, may find trials an easy way of doing this; (3) there is considerable kudos in being associated with the early days of a new wonder drug, but this is a gamble with such long odds that it cannot be a common motive; and (4) there are a very few who do work on " " a rate-for-the-job basis. Finance It is not true that money, in cash or kind, changes hands during all clinical trials; and when it does the idea is usually raised by the company. Quite a common practice is for the company to provide a piece of equipment which is needed for the trial and which is then left with the hospital. A company may pay registrars or part-time technicians and secretaries. At a lower level a gift may be made to a department’s travel fund or a firm may agree to pay the costs of a clinician’s visit to a symposium; the trialist may be pleased to receive a book-token or be wined and dined; or he may neither expect nor receive anything. It has been suggested that all transactions should be disclosed, and most medical advisers agree that such a practice would clear the air. But they do foresee difficulties. Such disclosures would encourage the " rate-for-the-job approach and by insisting on them one would seem to imply that trialists are capable of deliberate bias. On the other hand, in discussing results most trialists go out of their way to find something helpful to say about the test drug-clinicians may say " A is very slightly better than B " rather than " A is no significant advance on B which, like half full " and " half empty ", is a subtly different way of saying the same thing. Some medical advisers feel that where such distinctions or the occasional quite unwarranted eulogy are possible (for in the long run they can only damage drug, trialist, and industry) it would be salutary for the writer to know that his interests were to be declared. "
before going ahead. Sales departments like to time marketing with the publication date of some major trials; but medical advisers can have no control over publication, and occasions where the two have come together are purely fortuitous. Clearly, the medical adviser must shield his trialists from these pressures when they arise. This has been only one side of the coin but it is one that or
so
is seldom
seen
by the practising doctor.
Medicine and the Law
"
"
"
Hierarchy Undoubtedly there was a time when the clinical-trials unit of a company (if it had one at all) occupied a lowly level in the management pyramid and when a doctor knew that to get on he had to leave the research side and move into sales or administration. But the past five years have seen a big change, and in most companies the clinical-research organiser, if not himself a director, is responsible to a research-oriented doctor on the board. Internal Pressures Commercial pressures ? Never without them; but then, who in industry is not in the same position ? " Such pressures first act at the moment of entry of a drug into clinical trial, but they mount as the work progresses. They are rarely unpleasantly imposed or foolishly motivated, but five years of laboratory and clinical work is a considerable investment, and companies have to start to get a return some time. Typical questions might be: When is so-and-so’s trial due to finish ? "; Surely you have enough data for a second Dunlop submission ? "; What can we quote from X’s paper ? There is a tendency also to think that permission to market means you must market; but the Dunlop committee, although it takes account of efficacy, is primarily concerned with safety. A full picture of the clinical applications of the drug may not emerge until all the clinical work is completed, and it is better sometimes to wait six months "
...
"
"
"
"
Subnormality
and Unsoundness of Mind
BY A LEGAL CORRESPONDENT
THE
of
Woolley
Woolley1
raises
important and have rarely had occasion to consider: can the husband A)r wife of a "subnormal " or " severely subnormal " person (defined in the Mental Health Act, 1959,2 as, to a lesser or greater degree, "in a state of arrested or incomplete development of mind ") obtain a decree of divorce on the ground that his or her spouse is incurably " of unsound mind " within the meaning of the Matrimonial Causes Act, 1965 ? " Of unsound mind " is not defined in the 1965 Act. The courts have been set the task of interpreting the term which, of course, is not a medical one. There are only two reported cases in which the term has been considered in the context of the " subnormal " spouse. In 1964,3 Cairns J. defined " unsoundness of mind " as the incapacity of a person to manage himself and his affairs, including the problems of society and married life, without reference to the cause of the incapacity. He derived assistance from an earlier decision,4 in which the patient was indisputably insane (a paranoid schizophrenic) and the only question was whether he was now recovered. Cairns J. held that a defective was " of unsound mind," although he refused a decree on other grounds. In a more recent decision,I Park _7. refused to follow the reasoning of his brother judge, whose jurisdiction is parallel " to his own. In deciding that a subnormal" or severely subnormal," person was not " of unsound mind," Park J. referred to the Statutesdealing with the care and treatment of the mentally disordered and held that the law had consistently distinguished the " unsound " of mind (the term substituted by the Mental Treatment Act, 1930, for the " lunatic " of the 1890 Act) from the mental defective. In the Matrimonial Causes Act, Parliament included the mentally defective specifically in the provisions relating to nullity; but no mention is made of mental deficiency in the divorce provisions of that Act. Parky. inferred that the omission was a deliberate one. The question is therefore open. A future court may decide to follow either of these decisions-or neither of them. Perhaps the decision of Park. is likely to prevail. Cairns J.’s broad interpretation of unsoundness of mind as the inability of the patient to manage himself and his affairs is not based on established principle. Having found the patient " of unsound mind," the courts have used the test of inability to manage to decide whether the nature of the patient’s condition is such as to bring him or her under the provisions of the Matrimonial Causes Act.4 The phrase " inability to manage ..." has never before been used to define " unsoundness of mind " itself. The courts have sought, sympathetically, to aid the husband " or wife of a subnormal " patient and in the two recent cases have indeed pronounced decrees of divorce; one,’ on the ground of adultery; the other,3 on that of cruelty. It would appear, however, that in the absence of evidence to support an alternative ground, a marriage where one spouse is a defective case
v.
interesting point of law, which the
an
courts
"
"
must
remain,
so
long
as
the
seeming lacuna in the
"
law is open,
indissoluble. 1. [1966] 3 W.L.R. 1117; see Lancet, 1966, ii, 1358. 2. Section 4 (2) and (3). 3. Robinson v. Robinson [1964], 3 All E.R. 232.
4. 5.
Whysall v. Whysall [1960], p. 52. Esp. Lunacy and Mental Treatment Acts, 1890-1930; Mental Deficiency Acts, 1913-27.