Surgical research, experimentation and innovation

C. M. Ward

Clinical surgical research is an inexact science open to criticism from all quarters: not just in the particular method of investigation but in potentially or actually violating fundamental principles ofautonomy by what may be interpreted as coercion and exploitation of patients in studies which appear to be more for the enhancement of the reputation and of the financial security of the surgical institute and its staff than for the benefit of the present and future sick. The research team may be accused of promoting an over paternal- istic stance which not only threatens the bond between surgeon and patient but which transgresses Codes of Ethics relating to research within the Helsinki Declaration such as paragraph 6 of Basic Principles.’

” Every biomedical research project involving human subjects should he preceded by careful assessment of predictable risk in comparison with foreseeable benefits for the subject or to others. Concern for the interest of the subject inust always prevail over the interest ofscience and society”.

It is therefore not surprising that by the time a new project has finally been approved by the research ethical committee and is underway. the added battery of tacit and expressed disapproval from nursing and medical colleagues. bioethicists, lawyers. patients and their relatives and the lay press. an element of paranoia is apparent in the behaviour of the surgeons leading the research. Should prior animal research have been necessary the surgeon may already have frank para- noid symptoms following abuse and aggression from the more fervent members of animal rights organis- ations.

However, if one accepts that the duty of a surgeon is to treat patients to the highest possible standard with a minimum of distress and morbidity within the resources available. it would also seem reasonable that if surgeons wish to improve further the standards and quality oftreatment by the use of research methods the same constraints should apply in that they should be prepared not only to accept constructive criticism if certain principles are breached, but also to correct any medico moral flaws in the pursuit of better patient care. They should also realise they are not working in an entirely hostile environment. There is a public interest in encouraging new and more widely available surgical technology and treatment providing that, in the sprint to the finishing tape. scientific methods are not abused. ethical principles are not trampled and the law, is not trespassed. What principles are at issue’!

Animal research

In spite of the Golence of certain advocates of animal rights one cannot fail to acknowledge that animals are capable of suffering and are due some form of moral respect in terms of protection from harm even in the face of the weak counter argument that humans, as a morally superior group, have no moral obligations to the animal community.’ Experimental animal surgery is only a means to the end and potential welfare of the human. The animal itself does not benefit: conversely it is likely that it will be harmed, as can be illustrated in experimental surgery of the cleft lip deformity in the monkey foetus. Initially, via a hysterotomy on a pregnant mother a cleft is artificially created in the foetus followed later by another hysterotomy to repair the induced cleft. Finally. after delivery. the baby monkey is likely to be killed for anatomical and histological analysis. The research is of no therapeutic value to monkeys in general, the monkey mother or foetus. so that even a utilitarian who would judge the merit or otherwise of this act of experimentation according to the consequences stemming from it, would be unable to identify any moral justification. Indeed. if the monkey proves to be the ideal model. other monkeys would then become more susceptible to experimentation and sacrifice. thereby reinforcing the utilitarian objection. In fact animal research has long been the subject of parliamentary concern through the Cruelty to Animals Act of 1886 and more recently. through the Animals (Scientific Procedure) Act 1986 which sets out strict conditions under which a project licence for animal experimentation can be granted.

Human research

Yet there is no statutory law to govern principles of research in humans: even the legislation within The Mental Health Act 1983 does not address the question of research in the mentally incapacitated. There are, however, two exceptions relating to specific research : firstly, statutory law providing for the development. licensing and monitoring of new drugs within the Medicines Act 1968 introduced in the wake of the Thalidomide tragedy. Secondly. the Human Ferti- lisation and Embryology Act 1990 sets the permissible limits on embryo research.

Without effective statutory controls for human research in general one turns to the common law to

provide ~hr boundaries which might constrain re- search. where one discovers that the courts are wary about inhibiting innovation through the tort of neg- ligcncr. I_. .I. Muhtill stated in relation to the carlq tlevrlopmcn~ <jt’ neM’ therapy that ” If the decision to cmtxrrk on the treatment ;II all was justitiablc and was taken M.ilh the informed consent of the patient the ~~oui-t should be particularly careful not to impute negligence simplv because something ha5 gone \\ rang”:’ (‘ommenling in Siduway Lord Diplock said that potential patients would not be well served by the Iailurr to adapt new techniques if the doctor ” runs the risk of beins held liable in negligence simply because Ix l~vci tried some more modern treatment and bq ~me un;l\ oidablc mischance it failed to heal but did ~mc harm to the patient -‘.’ In similar vein Lord President (‘Iv&. supporting the notion that innovation through deviation from normal practice should not be obstructed by fear of risk of an action of negligence in the c\‘ent cjf an untoward outcome stated that such ;I I estraint ‘I would be disastrous: for all inducement to progress ..lnd medical science would be destroyed “.I,

If through statutory and common law surgeons appear to ha\c such ;I free hand ho\48 can human rescarch I-W regulated’!

(:ontrolling human research

In the guidelines for medical research involving human beings research ia described as “the systematic in\,estigalion to establish facts or principles in general- i?ahle kno\vledge”” with emphasis on differences of 1 he two rnajot~ classes of research as non therapeutic \\ here th#:re i< no intention to treat the subject of research (for example healthy volunteers invited to test ;I new drug) and therapeutic research which may benefit the individual participants.

The surgeon is more likely to be involved in clinical therapeutic rcsrarch which begins at the bottom run? of the ladder \\.ith the anecdotal case report providing litllc mot-c than serendipitous clinical impressions \vhich m;r>’ be fascinating material for members of plastic surgical travelling societies meeting in exotic places but \vhich hay little place in the context of proper e~,alua~~on. Next come case and case series \vithout controls. prone to selection bias and suspect ;ind false conclusions which can be as high as 50 “VO.’

Even \vith historical controls and data base analysis Incorrect conclusions can easily be made.H but they can be of interest Lo the plastic surgeon. such as in rare diseases where ;I large series cannot otherwise be accumulated. .41 the top of the ladder comes the prospective randomised control trial (RCT) which. \\ith careful design. is the most efficient means 01 ~~vercoming bias ;n the selection of patienta and is regarded ;IS the gold standard for proper e\xluation.” l3uum analvscs the hierarchy of clinical research from .I philosopl;ical viewpoint.“’ I’ viewing anecdotal reports ;IIKI uncontrolled case series as the weakest evidence which can only be inductive and which cannot be I;tken seriously compared to Ihe other extreme of the po\verful hypothctico-deductive methodolog of true

scientific empiricism. leading inI\) ihe pi~qx~‘ti\e randomised clinical trial which is percciicd b!, him to be the most sophisticated form of TurFical cpislcn- OlO_c).

The mcrrt: elegant the st!,le of rexarch. the preaIcr_ IS the rish and confusion to the palien through the ;~busc of consent. C’nnscnt is not an important issue in the analysis of caxc series unless the initial \urger!; has innovative whereas. given the randomixition ot patients to either ;1 standard form ot‘~urgcry c~~mp:~red to II new form of surgery believed but 1101 yet cx)nfirmcd to be of greater benefit. but which could yet prove to be damaging. consent is crucial. Furlhermorc. the ran- domised controlled trial promote3 ;I clash of etlkical imperati\,es in \vhich the utilitarian responsibilities of the surgeon a5 a clinical scientist scarchins for the increased \velfare of present and future patients JS ;I whole conflicts with his or her moral Jut) ;15 a doctor to respect the right of his or her patient ;,> bc able to choose the best kno\vn and Iea~~ harmt’ul aGl:tble trentment at that time and not to be trcatcd ;I\ ;I mc‘ans to an end in the form of a subject in :I research prniect. Not surprisingly the ethics and Iau rclatmg to RCTs is the subject of much healthy debate:” ” ho\\e\,er it is unhelpful to abandon RCTs. as has been suggested on the grounds of the perceived unaccrpt;ible lx-each ot

patient autonomy. and better. to heel\ \S;IV\ of‘ implc- menting efYecti1.e consent without compromising the design of the trial. Indeed Schafer concludes” that it is unethical to solicit patients for ;I Irial without letting them knob ho\\ Ihe treatment fill be helecled \+hile others, expressing reservations on the vlabilitj s)t‘ 3 trial if all the patients are so informed. helic\,c that as most of us at some time in our Ii,,,, u ill becsmc patients there is a moral sacriticc to be matlc in order to avoid returning to the dark age\ Lvhen ~rtxtment was determined by conceptual rationalism rather I ban scientific method.“’

In fact. most patients arc pleased to contribure to the well being of fellou patient> and. prc’l,lding that the) knoti what is involved. maq not be unwilling recruits to an RC‘T. In allowing the patient to determine ho\\. he or she should act. the surge(‘n IS obliged to outline the principles of ;I prospective randomised trial before describing the detail\ in which the patient would be voluntarily in\,ol,rcd. \I hilt emphasising that there is no compulsion to participate and that there i$ freedom to opt for an established time honoured treatment: also that. should the palient volunteer for the trial. he or she is free to lea\.e at any time to recei\,e the standard acceptable trcatmrnt. This theme is underlined in the Department of Health publication on the Role of Local Research Ethical Commitlees’ ‘ which are the hospital bodies respon- sible for sanctioning new research pro.iects and proto- cols. in spite of the fact thaw. in law. there i\ no requirement for a research committee or t:,>r planned research to be submitted to an LREC.

Although there is no case law relating 10 informed consent and RCTs it is speculated” that an\ \urgc‘ons who choose to ignore the standards of conscnt set by Sidaway could in the context of an RC‘T run the ri4k of being sued either in negligence or in batter>. I.ord Scarman admits to the value of clinical trials but

points out that: “As the law stands at the moment any doctor who allows his patient to go into randomised trial without telling him runs a very real risk if things go wrong and the patient sutrers illjury or damage”.‘;

Research in plastic surgery

Plastic surgeons are unlikely to be in\,olved in the special classes of research which might involve the mentally incapacitated. acutely ill. or unconscious patients. They arc more likely to lead clinical research in competent adults or in children where outcome cannot be honestly judged until early adult life; and there cannot be a cleft lip and palate surgeon who fails to realise the potent impact of p&to-alveolar surgery on subsequent facial growth which C~IIIIO~ be assessed accurately until after the pubertal growth spurt. In this context the responsibilities of surgeons who introduce new techniques for the correction of major craniofacial anomalies in infancy are awesome.

Guidance on the ethics and law of research in children is to be found in several publications”’ Is where the messages and themes are sunmarised by the Medical Research Council. ‘There is a strong case fat allowing children to be included in medical research providing certain safeguards are observed. We fully recommend that children should only be included in research if:

i)

ii)

iii)

iv)

vj

The relevant knowledge would not be gained by the research in adults. Is approved by the local research ethical corn-- niittee. Either those included have given consent OI consent has been given on their behalf by ;I parent or guardian and those included do not object or appear to object in either word or action. In the case of therapeutic research. the benefits likely to accrue to a child participating outweigh the possible harm. Thecase of non-therapeutic research p;trticipating places ;I child at no more than negligible harm. ‘I!’

However plastic surgeons are not renowned for dedication to meticulously planned and monitored research uhether it be based on animal work or the more sophisticated style of human research in the form of RCTs. Research is more likelv to be ;I chore undertaken to add ;I glitter to cur&ula Iitae and to applications to higher posts culminating in the pin- nacle of one’s career as an accredited consultant plastic surgeon in the British National Health Service or whute\.er system of health care applies in other countries. There are. of course. notable exceptions in plastic surgery who have not only made major contri- butions to the specialty in the course of their training but continue to lead the way in research. The rest of us. having achieved our goal. now settle down to earn a living and indulge in what we all wanted to do in the first place innovate.

The ideas may come from attendance at ;I conference bvhen. on return. one simply tries out in practice what ha\ been relayed from the lectern. or alternatively. one might use an operation which is the derivative or

variant of some already described procedure. Seldom is there any entirely new idea. The innovati\,e and unprecedented surgical manoeuvre that strikes like :I thunderbolt as one is lying in the bath while mentally rehearsing the following’s day operating list or nego- tiating an escape route from the latest surgeon induced disaster must be very rare. But whether the next operation is inspired by others or through the Eureka phenomenon it \vill be, as far as that surgeon and patient are concerned. innovative surgery which is the esecution of ;L previously untried and untested pro- cedure in the hopeful expectation that it Lvill help [he patient concerned, while also being a\+xre that it ma) endanger. It is. therefore, ;I crude form of euper- imentation for which there is no professional body to whom the surgeon must declare intention. providing the consent is implemented as completely as possible.

To illustrate the uay in which LI patient may be put at risk one can look for ;I moment outside plastic surgery to the epidemic of ‘* laparoscopic fever”‘” in which general surgeons armed with ;I mm toy to do an old operation eagerly attempt to remo\‘e pall bladders through narrow tubes. Certain surgeons who ma> previously have had difficulty in performing ;I sat cholecystectomy through an Incision from the xlphi sternum to the pubis are now capable of creating even greater havoc at the porta hepatis. Departmental audit will identify the incompetent laparoscopic cholrcy- stcctomist hut should such a surgeon choose to ignore the outcome no State hospital bnd!. is empo\vered to divert him/her frown this new technology. even in the event of fatality which has been described follo\\?ng accidental bowel injury.“’ In those count% with huge experience of laparoscopic cholecystectomy it has been suggested that with such good overall results reported so far it would not be ethical to test the technicluc in an RCT”” yet the incidence of coninlon bile duct ii?iury after laparoscopic cholecystectonly is reported to be as high as 7 ‘!‘u compared to 0.1 to 0.5 ‘)/,, for open cholecystectotmy.“” In the light of this inforniation the counter argument is put that: ‘. While not wantinp to undermine the likely potential of Iaparoscopic chole- cystectoniy we believe that it is dangerous if not unethical to accept any new treatment as significantI!, better than a pre-existing one that gives excellent results without putting it to the ultimate test: that IS. ;I random&d controlled trial”.“”

The haphazard and cavalier fashion in which net< surgical techniques are allowed to be introduced, the failure of adequate monitoring and the impotence of the consumer and peers to prevent ;i surgeon fi-om continuing to USC a demonstrably useless or harmful procedure compares unfavourably with the rigorous control demanded in the introduction of ;1 new drug which might be construed by the pharmaceutical industry to be over burdensome and bureaucratic but which is intended to protect the interests and \veifare of patients.

Before a newly developed drug can be tested on patients there must be ~1 special clinical trial certificate: before it can be marketed a product licence is required. No medicine can be manufactured. imported BI marketed ivithout a licence from the Health Minister who relies predominantlv on the Cnmmittce on the

it

ii )

III)

il,)

1)

ii)

\ ii)

Y-l

3. W~lshcr v Essex Area Health Authority. All F..R. XOI at X12.

lY86.

1. S&wr/ v Bethlrm Roy11 Hospitul Governors and Maudslq

Ho&al. I. All E.R. 633 at 657. 19X5.

5. Hunter v Hanley. SC.200. lY55.

6. Royal College of Physicians of London. Guidelinea in the

practice of ethics committees in medical research involving human subject\ 2nd rd. 1990.

7. Vcnnin$ CR. The vahdity of anecdotal reports of‘ xqxcted

adverse reactions--the problem of fitlbe alamb BMJ 1982:

31: ‘49%5’ ._.

X. Sachs H. Chalmcr~ TC. Smith H. Randomiaed verbus historical

controls for clinical triala. Am J Med 1982; 22: 2??+IO.

Y. Srlrrat GM. Farndon J. Farrow. SC. Dryer N. The challenge of

evaluating surgical procedures. Ann R Coil Surg Engl 1991:

73: 80 3.

IO Baum M. The ethics ofclinical rescarch. In: Byrne P. ed. Ethics

and law in healthcal-e and research. Chichester: John Wiley &

Sonr. 19YO: I 1. I I. Kenned) I. The [a\\ and ethics of Informed cowem and

randomlsrd controlled trials. In Treat me right. ezsays in

medical I;IM and ethics. Oxford: Clarendon Press. 1991 : 213 2-l.

12. Schdl’er RA. Ethics of the randomisrd controlled trial. N En~l

J Med 19X2: 307: 717-2-I.

13. Baum M. Zilkha K;. Houghton J. Ethics of clinical research:

Icaon for the future. BMJ 1989: 129: 251 7.

14. Department of Health. Considerations of research propoxtlh in

local research ethics committees. 19Yl : I I-i.

15. Scarman R. Conhent. communiwtion and responsibility.

J R Sot Med 1986: 7Y: 6Y7 700.

j 6. Britihh Paedintrx Association. Working party of ethics on

raearch in children: widelines to aid ethical committees

considering work In~olvinechildren. BMJ 1990; 280: 229 3 I. I7. I\i~cholaon R. editor Medical research with children: cthica. lav,

British Journal of Plasiic Surgery

IX.

19.

20.

21.

17.

‘3.

11.

15.

16.

17.

and practice. Report ot an Institute ()I’ Medical Ethics

Lvorking p<irt). Oxford: Oxford Ilniversity Press. IVXO.

World Health Organisatlon. Proposcd internatwmtl guidellna

for biomcdwal research mvolying human subjects. Gene\ a,

World Health Organisation. 1982.

Medical Research Council Series. The ethical conduct 01’

research 111 children. London: Medical Research Council.

1991.

Banter JN, O‘Dwyr PJ. Lapwwopic or mini laparotomy 111

cholecystcctomy. BMJ 19Y31. 314: 559 60.

Wolfe BM. Gsrdincr B. Frey CF. Luparoscopic cholc- cysteclomy. JAMA I99 I 355: I573~1.

Neugcbauer E. Troidle H. Spangenberger W. Deitrich A.

L&ring R. Conventional versus lapal-oxopic chc)le-

cysteciomy and the randomiwd trial. Br J Stirs 1YY I : 7X: 150 3.

C;imeron JC. Gadacr TR. Laparoscopic cholecystcctom!. .Ann

Surg lY9l: 213: I-2.

Brazier M. Drug induced inlurieb. In: Medicine, patwnts and the law. Harmondsworth : Penguin Book<. I YY1: I61 YO.

Lcadingarticle. Qualms about Innovative wrgry. Lancer IYXi.

IJY.

Shinebourne EA. Ethica of Inno\ atike cardw ~urgeq. Br Hart J 19X4: 52: 527 601.

Jennett B. Health technoloe),Hbses\ment. BMJ IYY2; 305: 67 s

The Author

Mr C. M. Ward. BSc, MA, FRCS. Comultant Plastic Surg)n, The

Charins Cross Hospital. Fulham Palace Road. London W6 XRF.

Requests for reprints to the author.

Papc~- received I-1 June IYY?.

Accepted Ii September lYY3. alter I-rviaion