- Email: [email protected]
CLINICAL TRIALS
1150
incentives now confronting clinicians. Professor Kirby of the University of Washington, in an inquiry into the effects of the new American Food and Drug Administration regulations on investigators in 75 medical schools, CLINICAL TRIALS showed that they are a strong deterrent. 73% of 650 Some Constructive Suggestions * investigators admitted reluctance to carry on or to initiate T. B. BINNS new projects.2 In Britain at least one regional board has M.R.C.P., M.R.C.P.E., D.C.H. insisted on approving all schemes. When approached OF GLAXO LABORATORIES, GREENFORD, MIDDLESEX; CLINICAL ASSISTANT, about a trial, an industrial company recently demanded DEPARTMENT OF MEDICINE, WEST LONDON HOSPITAL, W.6 that the drug firm should indemnify it against all eventualiW. J. H. BUTTERFIELD ties, including legal costs of fighting any claims that might O.B.E., M.D. Johns Hopkins, B.M. Oxon., F.R.C.P. arise. The great, and in some ways alarming, ethical 3-! PROFESSOR OF MEDICINE, and legal 5-7 responsibilities of the clinical investigator are GUY’S HOSPITAL MEDICAL SCHOOL, LONDON, S.E.I not new, but in the past year or two they have been IN the development and application of new drugs, the repeatedly. The whole subject has been much work of academic departments overlaps with that of emphasised in the limelight and this cannot fail to have its effect. medical advisers to the pharmaceutical industry. The Finally, the enthusiasm of many young investigators is figure illustrates this. The vertical column shows suc- damped by the difficulty of securing publication. cessive stages at which the medical adviser has to help We should remember that as soon as procedures of this to make judgments, while the overlapping interests of kind are formalised they become much more complex. academic departments are shown by the broken line. Moreover, it is difficult to control the unscrupulous, Interchange of information and discussion occurs at whereas the conscientious need no control, only guidance. almost all points in the two dimensions of the diagram. Ultimately, then, it is the calibre of people that matters We therefore decided to present this paper jointly. most. The right sort of doctor will be attracted to this Perhaps our decision will also emphasise our conviction work only if the right atmosphere is created and some of the present frustrations are removed. And this means putting the same effort into the organisation of clinical research as already goes into laboratory research. At present there is a gross disparity.
Special
Articles
QUALITY
Interrelation between medical work in and in the pharmaceutical industry.
an
academic department
challenging problems we want to discuss call for a cooperative effort.
that the
THE PRESENT SITUATION
clinical trials have revolutionised therapeutics. They have become the criterion by which the previous research is judged. But they are only one step in the continuous process of providing the doctor with more effective means of treatment and with the information necessary to use them to the best advantage. When an industrialist plans a factory or a process, he tries to eliminate bottlenecks and ensure a smooth flow of production. It is abundantly obvious that clinical trials are a bottleneck in the development of drugs, but so far next to no attempt has been made to study, let alone cater for, this new situation. This is primarily the medical profession’s responsibility. As Professor McCance has said, " the medical profession has a responsibility not only for the cure of the sick and for the prevention of disease, but for the advancement of knowledge on which both Since the
war
depend" .1 One byproduct of any form of control of new drugs will be a reduction in the number of preparations offered for trial. However, this alone will not offset the many dis*
Read at a symposium on drug evaluation held at the Royal Society of Medicine, under the chairmanship of Sir Derrick Dunlop, by the Association of Medical Advisers in the Pharmaceutical Industry, Tan. 22, 1964; see Lancet, Feb. 1, 1964, p. 263. 1.
McCance,
R. A. Proc. R. Soc. Med.
1951, 44,
189.
OF TRIALS
It is true that the quality of many so-called clinical trials is still below what can reasonably be expected; but any trial is easy to criticise, and some of the most severe critics seem to speak from a purely theoretical standpoint that makes one wonder whether they have had any practical experience themselves. By contrast, most people who have distinguished themselves in clinical trials are moderate and constructive in their opinions. Having been associated with numerous trials, we cannot recall any that have been entirely satisfactory. All have entailed some compromise short of the ideal. Perhaps the greatest difficulty in designing a trial is to decide the optimum conditions. If you wait until you can do it perfectly, you will probably never do it at all. We should not set our sights unrealistically high, but should seek continued improvement. When sights are lowered, it is almost always because of the doctor and his practical difficulties. On the part of a drug firm the commonest reason is the necessity for speed. This is something that is arguable, and few clinicians understand or sympathise with the reasons why a company may be in such a hurry. Conversely, the firm’s executives find it equally difficult to understand why the doctors take so long to reach any conclusion. Good judgment and better understanding are needed on both sides. FACILITIES
Practical difficulties should be identified and overcome by all possible means. Many will be insurmountable, but careful study would probably show ways of obviating some It
is, for example, a world-wide experience that the supply of case-material is in inverse proportion to the facilities for studying it. In this country
recurrent
problems.
2. Med. Trib. 1963, 4, 15. 3. Hill, A. B. Brit. med. J. 1963, i, 1043. 4. Brit. med. J. 1963, i, suppl. p. 238. 5. Hatry, P. Clin. Pharmacol. Therap. 1963, 4, 4. 6. Schreiner, G. E., Bogdonoff, M. D. Clin. Res. 1963, 7. Bowker, W. F. Canad. med. Ass. J. 1963, 88, 745.
11, 127.
1151
few of
our
big hospitals
seem to
be
willing and able
to
undertake trials, though it has been pointed out many times that the standard of care does not suffer but is
usually improved by the spirit of inquiry that is created. A small minority of hospitals has tried to encourage these activities and some have appointed a subcommittee to foster clinical research. Much could be learnt by inquiring what success they have achieved or why they have failed. Present methods of obtaining physical and financial help, at least in regional hospitals, seem to be much too cumbersome and discouraging.8 Specialist associations are in some ways well placed to carry out coordinated trials, which are difficult but increasingly necessary. An outstanding example of the constructive approach is the declaration by the British Tuberculosis Association’s subcommittee on clinical trials that it was " formed to try to provide a service for pharmaceutical firms in the organisation and conduct of clinical trials of their products. Drugs are still being marketed without adequate clinical assessment; and this is by no means always the fault of the manufacturers, who have to rely on the clinicians themselves to do the investigations."9 Certain specialties undoubtedly lend themselves better than others to such studies; but it would bear investigation why some associations are more successful, and what could be done to help activity of this type. It would be a pity if any of them shied away simply from lack of staff or because of a too-perfectionist approach.
experience of clinical trials. A possible system would be to appoint a new fellow annually. He would spend two-thirds of his time on trials and a third on departmental duties. In the following year he would become the (N.H.S.) departmental registrar, and give only one-third of his time to trials and twothirds to departmental duties. This arrangement would give continuity and put the fellow back on the conventional ladder with valuable experience behind him. A smaller number of fellows could be at senior-registrar level at a suitable area centre, preferably in an academic department. These would be longer-term appointments, and, apart from teaching, the holders could supervise and coordinate the work of junior fellows and possibly general practitioners.
salary cost of 50 junior and 10 senior fellows would roughly equivalent to 1%of what the industry now spends on research, and less than 0-2% of what the State pays for its drugs. By any criterion it should prove a The
be
sound investment. Most of the fellows would doubtless return to other branches of medicine, but a few would find a permanent career in therapeutics. Such training would be a great asset to a medical adviser in the pharmaceutical industry, especially if he could retain some association with the area centre after his appointment. MEDICAL ADVISERS
STAFF
The success of these collective efforts ultimately depends on the enthusiasm of individuals. For too long clinical trials have been a spare-time hobby for the dedicated few. The rest of the profession and the public do not seem to realise what an enormous debt they owe these enthusiasts, even for evaluating the good drugs; and still less for eliminating the bad. We should try to find out why so small a proportion of doctors take an active interest in trials. It has been estimated as 5 % 10 but is probably considerably less even in hospitals. The gospel should be spread by more determined undergraduate and postgraduate education. In view of its obvious importance, the teaching of therapeutics is surprisingly patchy. The number of academic departments is lamentably small, and clinical pharmacology is hardly recognised as justifying departmental status, whereas there are at least twenty such departments in the United States.11 We should also do more to see that ancillary staff, including nurses, are taught at least to appreciate the reasoning behind clinical trials, so that the investigator can rely on them for the help he increasingly needs. They are likely to respond by becoming more useful members of the team, and by helping to correct the guineapig image of clinical research that is being projected by the popular press.
One way of overcoming the shortage of staff is the creation of research fellowships. Some drug firms and other agencies already sponsor fellows, but we should like to see a more ambitious scheme, preferably financed from a central fund and administered by independent trustees. Prof. Graham Wilson has said that a few more chairs in clinical pharmacology and therapeutics would ultimately produce more talent than many fellowships.12 We endorse the need for more chairs, but we also need 8. Lancet, 1963, i, 1039. 9. Tubercle, Lond. 1961, 42, 373. 10. Brit. med. J. 1963, i, 872. 11. Carr, E. A. Clin. Pharm. Therap. 12. Wilson, G. M. ibid. p. 255.
fellowships, because these serve a different purpose. Indeed, we believe that there should be fellowships at both registrar and senior-registrar levels. The majority would be at registrar level in large general hospitals. The fellow could be attached to clinicians with
1963, 4, 587.
In clinical trials the medical adviser is a key figure. Though he rarely does the clinical work himself, he may be concerned with: Conception and development of research project.
Laboratory work and documentation. Choice of investigator. Design of trial. Provision of materials in most appropriate form. Coordination of work in several centres. Analysis and interpretation of results. Writing for publication. Reporting to management.
Even if his role is usually more restricted than the full list would imply, his influence is important. In their report on the clinical testing of drugs, the New York Academy of Medicine recommended that the status of medical advisers should be raised, so that they may be better able to discharge their responsibilities. 13 Clearly, the higher their status, the greater their value is likely to be both to the industry and to the profession. This report recommended that a medical adviser should be a good clinician, have an adequate knowledge of pharmacology, be competent in trial procedures, and know suitable clinical investigators. It might well have added that the investigators must be able to trust him completely. Occasionally, it has been possible for a doctor or a technician to be seconded from a firm to work as a member of a clinical department during a trial. This admirable arrangement should be encouraged for several reasons: for example, it solves the problem of temporary help and makes collaboration much closer. Alternatively, it may be sufficient for specimens to be sent to the firm for analysis. The continual variation in requirements calls for a flexible
approach. However, apart from finance, perhaps the greatest contribution the industry could make would be to refine the laboratory screening of drugs, so that only probable winners are offered for clinical testing. Undoubtedly, 13. Bull. N.Y. Acad. Med.
1962, 38, 415.
1152
there is still scope in this direction-for example, in the development of methods for measuring micro or submicro amounts of drug in body-fluids, so that its disposition and fate in animals and man can be more accurately followed.14 AN INSTITUTE OF THERAPEUTICS
In 1959 the Hinchliffe Committee said: " The present arrangements for the organisation and interpretation of such (clinical) trials and for the publication of results are inadequate." 15 Five years later the situation is worse and is continuing to deteriorate. There are several ways in which it might be improved; but every cause needs a champion, and it is difficult to see how any of the changes could come about of their own accord. A positive effort is needed, but at present it is no-one’s job to make it. For some years one of us has canvassed the idea of an Institute of Therapeutics. Several of the functions originally proposed for it have since been taken over by other newly created organisations, but there still seems to be a need for a body to support therapeutics as a scientific
discipline. Foster
Such
an
institute could:
in and clinical therapeutics investigation. Support studies on methodology, including operational research. Advise individuals, institutions, and if necessary the Government, on training, on the best method of using available facilities, and on future trends. Raise money and allocate grants-e.g., for fellowships. Although at the moment it seems to’ lack a lead, the
undergraduate .and postgraduate training
drawn up. In particular, those who actually do the work should be asked what their problems are. To organise this research with sufficient authority, and to ensure that the results and recommendations carry enough weight to be put into effect, we recommend that a small committee of the highest standing should be created,
SUCCESSFUL REATTACHMENT OF A COMPLETELY SEVERED FOREARM A COMMENTARY
J. S. HORN M.B.
Lond., F.R.C.S.
OF THE INSTITUTE OF ORTHOPÆDICS AND CHI SHUI TAN
HOSPITAL,
TRAUMATOLOGY,
PEKING
SALVAGE of incomplete traumatic amputations has been reported,occasionally 12 but, so far as I know, no cases in which a completely amputated extremity was reattached, survived in its entirety, and regained good function. A full account of the following case appeared in the Chinese Medical Journal.3 CASE-REPORT
On Jan. 2, 1963, a male factory worker, aged 27, caught his right hand in a machine and sustained a clean traumatic amputation just proximal to the wrist (fig. 1). He was immediately sent to the nearest hospital-the Shanghai Sixth Municipal
pharmaceutical industry has offered financial help to improve trial facilities,Io and there is no reason why money should not be raised elsewhere. Others facing the same problems are thinking along similar lines. In Canada a Foundation has been created " to stimulate the improvement of drug evaluation procedures". It will be concerned primarily with granting funds for training and research.16 17 Still more recently the United States National Academy of Sciences has appointed a drug research board to " foster the orderly progress of therapeutic research in the development and evaluation of drugs". The board will act in an advisory capacity and will attempt to reconcile the needs of investigators, industry, and the Government.18
Fig. I-Stump and amputated hand on arrival of patient at hospital.
is the usual type of 400-bed general hospital be found in most of the large cities of China, possessing no
Hospital. This to
No-one can feel complacent about the present quality or scale of clinical trials. They are an increasingly serious bottleneck in the development and effective use of drugs, but no real attempt has yet been made to tackle the
out-of-the-ordinary equipment or facilities. The amputated extremity was wrapped up in clean cloth and was also sent to the hospital. On arrival, the patient’s blood-pressure was 130/80 mm. Hg. The patient was not in a state of shock, and, although no tourniquet had been used, there was no active bleeding from the stump. Dr. Ch’en Chung-wei and Dr. Ch’ien Yun-ching operated on him and were responsible for his subsequent
problem.
treatment.
CONCLUSIONS
Better use could be made of resources already available. The following questions deserve study: How to match facilities and case material. How to overcome practical difficulties. The value and limitations of specialist associations and hospital research committees. Methods of providing physical and financial support. Why so few doctors undertake drug research; what motivates those who do.
We probably need additional resources: more academic departments, a fellowship scheme, and an Institute of Therapeutics. To allocate priorities in terms of men, materials, and money, a programme of operational research should be Brodie, B. B. in Absorption and Distribution of Drugs (edited by T. B. Binns). Edinburgh, 1964. 15. Ministry of Health. Cost of Prescribing. H.M. Stationery Office, 1959. 16. Canad. med. Ass. J. 1963, 88, 1299. 17. Murphy, C. W. ibid. 1963, 89, 1298. 18. Med. Trib. 1963, 4, 6. 14.
Operation Treatment of the amputated extremity.-The amputated extremity was thoroughly washed with sterile soap and saline solution, and the exposed soft tissues were carefully excised until only healthy-looking tissue remained. A slice of bone 0-5 cm. thick was sawn off from the severed ends of the radius and ulna. Large quantities of 10% heparin in physiological saline were instilled into the cut end of the radial artery, and the blood-vessels of the hand were irrigated until the fluid returning from the severed veins was clear.4-7 Treatment of the proximal stump.-Under brachial-plexus 1. Salesses, Moussu, Aupecle (Rapport de M. R. Soupault) Mém. Acad. Chir. 1962, 88, 32. 2. Kleinert, H. E., Kasdan, M. L., Romero, J. L. J. Bone Jt Surg. 1963, 45A, 788. 3. Ch’en, C. W., Ch’ien, Y. C., Pao, Y. S. Chin. med. J. 1963, 82, 632. 4. Breidenbach, L., Lord, J. W. Amer. J. Surg. 1948, 76, 578. 5. Ferguson, I. A., Sr., Byrd, W. M., McAfee, D. K. Ann. Surg. 1961, 6. 7.
153, 980. Seidenberg, B., Hurwitt, E. S., Carton, C. A. Surg. Gynec. Obstet. 1958, 106, 743. Shaw, R. S. J. Bone Jt Surg. 1959, 41A, 665.
incentives now confronting clinicians. Professor Kirby of the University of Washington, in an inquiry into the effects of the new American Food and Drug Administration regulations on investigators in 75 medical schools, CLINICAL TRIALS showed that they are a strong deterrent. 73% of 650 Some Constructive Suggestions * investigators admitted reluctance to carry on or to initiate T. B. BINNS new projects.2 In Britain at least one regional board has M.R.C.P., M.R.C.P.E., D.C.H. insisted on approving all schemes. When approached OF GLAXO LABORATORIES, GREENFORD, MIDDLESEX; CLINICAL ASSISTANT, about a trial, an industrial company recently demanded DEPARTMENT OF MEDICINE, WEST LONDON HOSPITAL, W.6 that the drug firm should indemnify it against all eventualiW. J. H. BUTTERFIELD ties, including legal costs of fighting any claims that might O.B.E., M.D. Johns Hopkins, B.M. Oxon., F.R.C.P. arise. The great, and in some ways alarming, ethical 3-! PROFESSOR OF MEDICINE, and legal 5-7 responsibilities of the clinical investigator are GUY’S HOSPITAL MEDICAL SCHOOL, LONDON, S.E.I not new, but in the past year or two they have been IN the development and application of new drugs, the repeatedly. The whole subject has been much work of academic departments overlaps with that of emphasised in the limelight and this cannot fail to have its effect. medical advisers to the pharmaceutical industry. The Finally, the enthusiasm of many young investigators is figure illustrates this. The vertical column shows suc- damped by the difficulty of securing publication. cessive stages at which the medical adviser has to help We should remember that as soon as procedures of this to make judgments, while the overlapping interests of kind are formalised they become much more complex. academic departments are shown by the broken line. Moreover, it is difficult to control the unscrupulous, Interchange of information and discussion occurs at whereas the conscientious need no control, only guidance. almost all points in the two dimensions of the diagram. Ultimately, then, it is the calibre of people that matters We therefore decided to present this paper jointly. most. The right sort of doctor will be attracted to this Perhaps our decision will also emphasise our conviction work only if the right atmosphere is created and some of the present frustrations are removed. And this means putting the same effort into the organisation of clinical research as already goes into laboratory research. At present there is a gross disparity.
Special
Articles
QUALITY
Interrelation between medical work in and in the pharmaceutical industry.
an
academic department
challenging problems we want to discuss call for a cooperative effort.
that the
THE PRESENT SITUATION
clinical trials have revolutionised therapeutics. They have become the criterion by which the previous research is judged. But they are only one step in the continuous process of providing the doctor with more effective means of treatment and with the information necessary to use them to the best advantage. When an industrialist plans a factory or a process, he tries to eliminate bottlenecks and ensure a smooth flow of production. It is abundantly obvious that clinical trials are a bottleneck in the development of drugs, but so far next to no attempt has been made to study, let alone cater for, this new situation. This is primarily the medical profession’s responsibility. As Professor McCance has said, " the medical profession has a responsibility not only for the cure of the sick and for the prevention of disease, but for the advancement of knowledge on which both Since the
war
depend" .1 One byproduct of any form of control of new drugs will be a reduction in the number of preparations offered for trial. However, this alone will not offset the many dis*
Read at a symposium on drug evaluation held at the Royal Society of Medicine, under the chairmanship of Sir Derrick Dunlop, by the Association of Medical Advisers in the Pharmaceutical Industry, Tan. 22, 1964; see Lancet, Feb. 1, 1964, p. 263. 1.
McCance,
R. A. Proc. R. Soc. Med.
1951, 44,
189.
OF TRIALS
It is true that the quality of many so-called clinical trials is still below what can reasonably be expected; but any trial is easy to criticise, and some of the most severe critics seem to speak from a purely theoretical standpoint that makes one wonder whether they have had any practical experience themselves. By contrast, most people who have distinguished themselves in clinical trials are moderate and constructive in their opinions. Having been associated with numerous trials, we cannot recall any that have been entirely satisfactory. All have entailed some compromise short of the ideal. Perhaps the greatest difficulty in designing a trial is to decide the optimum conditions. If you wait until you can do it perfectly, you will probably never do it at all. We should not set our sights unrealistically high, but should seek continued improvement. When sights are lowered, it is almost always because of the doctor and his practical difficulties. On the part of a drug firm the commonest reason is the necessity for speed. This is something that is arguable, and few clinicians understand or sympathise with the reasons why a company may be in such a hurry. Conversely, the firm’s executives find it equally difficult to understand why the doctors take so long to reach any conclusion. Good judgment and better understanding are needed on both sides. FACILITIES
Practical difficulties should be identified and overcome by all possible means. Many will be insurmountable, but careful study would probably show ways of obviating some It
is, for example, a world-wide experience that the supply of case-material is in inverse proportion to the facilities for studying it. In this country
recurrent
problems.
2. Med. Trib. 1963, 4, 15. 3. Hill, A. B. Brit. med. J. 1963, i, 1043. 4. Brit. med. J. 1963, i, suppl. p. 238. 5. Hatry, P. Clin. Pharmacol. Therap. 1963, 4, 4. 6. Schreiner, G. E., Bogdonoff, M. D. Clin. Res. 1963, 7. Bowker, W. F. Canad. med. Ass. J. 1963, 88, 745.
11, 127.
1151
few of
our
big hospitals
seem to
be
willing and able
to
undertake trials, though it has been pointed out many times that the standard of care does not suffer but is
usually improved by the spirit of inquiry that is created. A small minority of hospitals has tried to encourage these activities and some have appointed a subcommittee to foster clinical research. Much could be learnt by inquiring what success they have achieved or why they have failed. Present methods of obtaining physical and financial help, at least in regional hospitals, seem to be much too cumbersome and discouraging.8 Specialist associations are in some ways well placed to carry out coordinated trials, which are difficult but increasingly necessary. An outstanding example of the constructive approach is the declaration by the British Tuberculosis Association’s subcommittee on clinical trials that it was " formed to try to provide a service for pharmaceutical firms in the organisation and conduct of clinical trials of their products. Drugs are still being marketed without adequate clinical assessment; and this is by no means always the fault of the manufacturers, who have to rely on the clinicians themselves to do the investigations."9 Certain specialties undoubtedly lend themselves better than others to such studies; but it would bear investigation why some associations are more successful, and what could be done to help activity of this type. It would be a pity if any of them shied away simply from lack of staff or because of a too-perfectionist approach.
experience of clinical trials. A possible system would be to appoint a new fellow annually. He would spend two-thirds of his time on trials and a third on departmental duties. In the following year he would become the (N.H.S.) departmental registrar, and give only one-third of his time to trials and twothirds to departmental duties. This arrangement would give continuity and put the fellow back on the conventional ladder with valuable experience behind him. A smaller number of fellows could be at senior-registrar level at a suitable area centre, preferably in an academic department. These would be longer-term appointments, and, apart from teaching, the holders could supervise and coordinate the work of junior fellows and possibly general practitioners.
salary cost of 50 junior and 10 senior fellows would roughly equivalent to 1%of what the industry now spends on research, and less than 0-2% of what the State pays for its drugs. By any criterion it should prove a The
be
sound investment. Most of the fellows would doubtless return to other branches of medicine, but a few would find a permanent career in therapeutics. Such training would be a great asset to a medical adviser in the pharmaceutical industry, especially if he could retain some association with the area centre after his appointment. MEDICAL ADVISERS
STAFF
The success of these collective efforts ultimately depends on the enthusiasm of individuals. For too long clinical trials have been a spare-time hobby for the dedicated few. The rest of the profession and the public do not seem to realise what an enormous debt they owe these enthusiasts, even for evaluating the good drugs; and still less for eliminating the bad. We should try to find out why so small a proportion of doctors take an active interest in trials. It has been estimated as 5 % 10 but is probably considerably less even in hospitals. The gospel should be spread by more determined undergraduate and postgraduate education. In view of its obvious importance, the teaching of therapeutics is surprisingly patchy. The number of academic departments is lamentably small, and clinical pharmacology is hardly recognised as justifying departmental status, whereas there are at least twenty such departments in the United States.11 We should also do more to see that ancillary staff, including nurses, are taught at least to appreciate the reasoning behind clinical trials, so that the investigator can rely on them for the help he increasingly needs. They are likely to respond by becoming more useful members of the team, and by helping to correct the guineapig image of clinical research that is being projected by the popular press.
One way of overcoming the shortage of staff is the creation of research fellowships. Some drug firms and other agencies already sponsor fellows, but we should like to see a more ambitious scheme, preferably financed from a central fund and administered by independent trustees. Prof. Graham Wilson has said that a few more chairs in clinical pharmacology and therapeutics would ultimately produce more talent than many fellowships.12 We endorse the need for more chairs, but we also need 8. Lancet, 1963, i, 1039. 9. Tubercle, Lond. 1961, 42, 373. 10. Brit. med. J. 1963, i, 872. 11. Carr, E. A. Clin. Pharm. Therap. 12. Wilson, G. M. ibid. p. 255.
fellowships, because these serve a different purpose. Indeed, we believe that there should be fellowships at both registrar and senior-registrar levels. The majority would be at registrar level in large general hospitals. The fellow could be attached to clinicians with
1963, 4, 587.
In clinical trials the medical adviser is a key figure. Though he rarely does the clinical work himself, he may be concerned with: Conception and development of research project.
Laboratory work and documentation. Choice of investigator. Design of trial. Provision of materials in most appropriate form. Coordination of work in several centres. Analysis and interpretation of results. Writing for publication. Reporting to management.
Even if his role is usually more restricted than the full list would imply, his influence is important. In their report on the clinical testing of drugs, the New York Academy of Medicine recommended that the status of medical advisers should be raised, so that they may be better able to discharge their responsibilities. 13 Clearly, the higher their status, the greater their value is likely to be both to the industry and to the profession. This report recommended that a medical adviser should be a good clinician, have an adequate knowledge of pharmacology, be competent in trial procedures, and know suitable clinical investigators. It might well have added that the investigators must be able to trust him completely. Occasionally, it has been possible for a doctor or a technician to be seconded from a firm to work as a member of a clinical department during a trial. This admirable arrangement should be encouraged for several reasons: for example, it solves the problem of temporary help and makes collaboration much closer. Alternatively, it may be sufficient for specimens to be sent to the firm for analysis. The continual variation in requirements calls for a flexible
approach. However, apart from finance, perhaps the greatest contribution the industry could make would be to refine the laboratory screening of drugs, so that only probable winners are offered for clinical testing. Undoubtedly, 13. Bull. N.Y. Acad. Med.
1962, 38, 415.
1152
there is still scope in this direction-for example, in the development of methods for measuring micro or submicro amounts of drug in body-fluids, so that its disposition and fate in animals and man can be more accurately followed.14 AN INSTITUTE OF THERAPEUTICS
In 1959 the Hinchliffe Committee said: " The present arrangements for the organisation and interpretation of such (clinical) trials and for the publication of results are inadequate." 15 Five years later the situation is worse and is continuing to deteriorate. There are several ways in which it might be improved; but every cause needs a champion, and it is difficult to see how any of the changes could come about of their own accord. A positive effort is needed, but at present it is no-one’s job to make it. For some years one of us has canvassed the idea of an Institute of Therapeutics. Several of the functions originally proposed for it have since been taken over by other newly created organisations, but there still seems to be a need for a body to support therapeutics as a scientific
discipline. Foster
Such
an
institute could:
in and clinical therapeutics investigation. Support studies on methodology, including operational research. Advise individuals, institutions, and if necessary the Government, on training, on the best method of using available facilities, and on future trends. Raise money and allocate grants-e.g., for fellowships. Although at the moment it seems to’ lack a lead, the
undergraduate .and postgraduate training
drawn up. In particular, those who actually do the work should be asked what their problems are. To organise this research with sufficient authority, and to ensure that the results and recommendations carry enough weight to be put into effect, we recommend that a small committee of the highest standing should be created,
SUCCESSFUL REATTACHMENT OF A COMPLETELY SEVERED FOREARM A COMMENTARY
J. S. HORN M.B.
Lond., F.R.C.S.
OF THE INSTITUTE OF ORTHOPÆDICS AND CHI SHUI TAN
HOSPITAL,
TRAUMATOLOGY,
PEKING
SALVAGE of incomplete traumatic amputations has been reported,occasionally 12 but, so far as I know, no cases in which a completely amputated extremity was reattached, survived in its entirety, and regained good function. A full account of the following case appeared in the Chinese Medical Journal.3 CASE-REPORT
On Jan. 2, 1963, a male factory worker, aged 27, caught his right hand in a machine and sustained a clean traumatic amputation just proximal to the wrist (fig. 1). He was immediately sent to the nearest hospital-the Shanghai Sixth Municipal
pharmaceutical industry has offered financial help to improve trial facilities,Io and there is no reason why money should not be raised elsewhere. Others facing the same problems are thinking along similar lines. In Canada a Foundation has been created " to stimulate the improvement of drug evaluation procedures". It will be concerned primarily with granting funds for training and research.16 17 Still more recently the United States National Academy of Sciences has appointed a drug research board to " foster the orderly progress of therapeutic research in the development and evaluation of drugs". The board will act in an advisory capacity and will attempt to reconcile the needs of investigators, industry, and the Government.18
Fig. I-Stump and amputated hand on arrival of patient at hospital.
is the usual type of 400-bed general hospital be found in most of the large cities of China, possessing no
Hospital. This to
No-one can feel complacent about the present quality or scale of clinical trials. They are an increasingly serious bottleneck in the development and effective use of drugs, but no real attempt has yet been made to tackle the
out-of-the-ordinary equipment or facilities. The amputated extremity was wrapped up in clean cloth and was also sent to the hospital. On arrival, the patient’s blood-pressure was 130/80 mm. Hg. The patient was not in a state of shock, and, although no tourniquet had been used, there was no active bleeding from the stump. Dr. Ch’en Chung-wei and Dr. Ch’ien Yun-ching operated on him and were responsible for his subsequent
problem.
treatment.
CONCLUSIONS
Better use could be made of resources already available. The following questions deserve study: How to match facilities and case material. How to overcome practical difficulties. The value and limitations of specialist associations and hospital research committees. Methods of providing physical and financial support. Why so few doctors undertake drug research; what motivates those who do.
We probably need additional resources: more academic departments, a fellowship scheme, and an Institute of Therapeutics. To allocate priorities in terms of men, materials, and money, a programme of operational research should be Brodie, B. B. in Absorption and Distribution of Drugs (edited by T. B. Binns). Edinburgh, 1964. 15. Ministry of Health. Cost of Prescribing. H.M. Stationery Office, 1959. 16. Canad. med. Ass. J. 1963, 88, 1299. 17. Murphy, C. W. ibid. 1963, 89, 1298. 18. Med. Trib. 1963, 4, 6. 14.
Operation Treatment of the amputated extremity.-The amputated extremity was thoroughly washed with sterile soap and saline solution, and the exposed soft tissues were carefully excised until only healthy-looking tissue remained. A slice of bone 0-5 cm. thick was sawn off from the severed ends of the radius and ulna. Large quantities of 10% heparin in physiological saline were instilled into the cut end of the radial artery, and the blood-vessels of the hand were irrigated until the fluid returning from the severed veins was clear.4-7 Treatment of the proximal stump.-Under brachial-plexus 1. Salesses, Moussu, Aupecle (Rapport de M. R. Soupault) Mém. Acad. Chir. 1962, 88, 32. 2. Kleinert, H. E., Kasdan, M. L., Romero, J. L. J. Bone Jt Surg. 1963, 45A, 788. 3. Ch’en, C. W., Ch’ien, Y. C., Pao, Y. S. Chin. med. J. 1963, 82, 632. 4. Breidenbach, L., Lord, J. W. Amer. J. Surg. 1948, 76, 578. 5. Ferguson, I. A., Sr., Byrd, W. M., McAfee, D. K. Ann. Surg. 1961, 6. 7.
153, 980. Seidenberg, B., Hurwitt, E. S., Carton, C. A. Surg. Gynec. Obstet. 1958, 106, 743. Shaw, R. S. J. Bone Jt Surg. 1959, 41A, 665.