Joournal of Acdic(al Ethics, I975, r,I68 -173

The inherent paradoxof clinical trials in psychiatry*

II Helmchen and B Aluller-Oerlinghausen** The Psychiatric Clinic of the Free University, Berlin

The authors sum uip the central issue of ethics in theconduict of controlled clinical trials in these twoparadoxes: 'first, it is unethical to use treatment thecfficacv of which has not beenz examined scientifically;second, i't is also uinethical to examine the efficacy oftreatment scientifically.' In this paper they set out tocldenonstrate how these antithetical statements apply incontrolled trials conducted in psychiatric patients. Insutch trials the problem of obtaining, informnedconsent may be acute, but in these patients giving'inforned' consent might contribute to a furtherexacerbation of the illness. Nevcrtheless the problemcannot be evaded, and scientific judgments must beapplied to treatment for it to be sound and inmprovedfor the further bcnefit of patients. These problems inthe case of psychiatric controlled trials are a partof the methodology, and in Germany a new druglaw has been drafted to attempt to clarify the issue.T'he authors briefljy discuss its application, and itsconsequences if such a law were enacted. Britishpsychiatrists have exactly the same problems to facebut so far no attempts have been mzade to establisha l!cgal framework.

The paradox in medical ethics

The central issues of ethics in medical treatmentcan be summed up by the following paradoxicalstatements: first, it is unethical to use treatment theefficacy of which has not been examined scien-tifically; second, it is also unethical to examine theefficacy of treatment scientifically.

It should be clearly understood that the ethicaljudgment regarding the use of a treatment does notrefer to the motivation of the doctor but ratherto the efficacy of the therapeutic procedure in thepatient. Thus, a passionate intention to help theobsessed patient gave rise to the cruel, mediaevalpractice of exorcism1, and 'good-heartedness',therapeutic engagement and humanitarian ideologyhave caused some doctors today 'to relieve thecustodial-repressively treated psychiatric patientfrom the totalitarian institutions'. We know,

*A more academic discussion of the dilemma outlined inthis paper is published in the PsychopharmacologicalBtlletin.*Professor H. Helmchen; Professor B. Muller-Oerling-

hausen, Psychiatrisch Klinik, der Freien Universitat,Berlin i9, Nussbaumallee 36.

however, that some of these well meaning thera-peutic measures have partly resulted in dependence,increasing misery and criminal exploitation ofpatients. From the ethical point of view it must beasked why these 'therapeutic' measures have notbeen thoroughly investigated as regards suchnegative and unlexpected consequences before theybecame widely used2 3.On the other hand, many presently valuable

treatments, such as analytical psychotherapy,malaria therapy and insulin treatment, wereinvented during the early decades of this centuryand were introduced and applied intensivelywithout being submitted to appropriate controlledtrials. Clinical evidence and possibly comparisonsbetween individuals were regarded as sufficient tosupport a new therapeutic method4.The ethical aspects of a new treatment have

always been judged according to the therapeuticresources available at that time. Thus, whenstrait jackets were substituted for chains at thebeginning of the last century, it was considered to behumanitarian progress. Similarly, the establishmentof state mental hospitals was widely praisedl.However, the use of strait jackets is no longerjustified from the ethical point of view and atpresent some people believe that tlle admission ofpsychiatric patients to our state institutions isobjectionable for ethical reasons. We, however,believe that the use of a new treatment can beconsidered as unethical only when its efficacy hasnot been tested according to scientific standards incomparison witlh all other practicable therapeuticmethods.

Ethical problems of 'controlled trials' inpsychiatric patientsThe statement that it is unethical to test theefficacy of a treatment in a scientific way is provoca-tive although Martini5 and his colleagues havealready pointed to the indissoluble nature ofhumanity and service toward mankind. Establishingthe efficacy of any treatment demands 'controlledtrials' according to contemporary standards. Thecontrolled trial is intended to eliminate unspecificinfluences by suitable controls. Known objectiveinfluences are excluded by using controls, unknownobjective influences by randomization, and sub-jective influences in the patient or the doctor by a

copyright. on S

eptember 13, 2020 by guest. P

rotected byhttp://jm

e.bmj.com

/J M

ed Ethics: first published as 10.1136/jm

e.1.4.168 on 1 Decem

ber 1975. Dow

nloaded from

Tizc inzherent paradox of clinical trials int f-sychiatry L69

blind technique6.In the following paragraphs we shall focus on the

practical consequences of three essentials in control-led trials when applied to psychiatric patients.

THE DESIGN OF THE TRIALA rigidly designed trial is one of the requirementsof controlled trials according to contemporarystandards. It requires that the individual needs of apatient - such as the additional drug treatment ofinsomnia or anxiety - must be sacrificed in favourof the formalized design which excludes additionalmedication or reduction of dosage. The objectiveof such a trial is to prove that, for example, theantidepressant drug under investigation possessesfewer side effects or a faster onset of action than thereference drug. Thus, a conflict arises between theethical obligation to relieve the suffering of theindividual patient here and now t-3 the best of ourknowledge, and the scientific necessity for anunobjectionable experimental design. But it is alsoevident that a tlerapeutic trial which is inconclusivedue to a poor design or negligence in carrying out agood design is also unethical because (a) it burdensor at least troubles the patient needlessly; (b) it willcall for additional experiments unnecessarily andadd to the burden of other patients; (c) it preventsthe medical community from reaching a clearjudgment about the advantages and disadvantagesof a new drug as quickly as possible.The new C erman drug law (39, I. I) allows

the performance of a drug trial only if there isenouglh evidence for the assumption that thedrug to be tested restores the health of the patientor relieves his suffering. This formula secures thetherapeutic trial legallv; however, it does notresolve the ethical dilemma7. The ethical problemis not whether the patient can be wholly cured bythe new treatment, but rather whether - un-restrained by the drug trial design - the patientcould have been treated more efficiently.

THE NECESSITY FOR RANDOMIZATIONEthical problems can also result from the scientificdemand to randomize and to avoid selection. As anexampie, we may consider the investigation in theUnited Kingdom (supported by the MedicalResearch Council) which was performed with greatscientific care to determine whether it would bepossible to examine with unobjectionable method-ology the efficacy of several psychotherapeuticprocedures8. As it turned out, some investigatorsdid not keep to the rule of randomization in dealingwith patients who, according to the personalexperience of the investigators, could be helped onlyby analytical psychotherapy. These investigatorscame to the conclusion that because of ethicalconsiderations it was not feasible to prove theefficacy of psychotherapy in a controlled trialaccording to the methodological design they hadagreed upon previously (see also 9).

'Since ethical issues may have played a decisiveroie in determining the negative outcome of thestudy, the investigating team considered thisproblem in more detail. Not unexpectedly, itappeared that the issues are complex and operateat a number of different levels. Where uncertaintyabout the effectiveness of a certain treatment iswidely shared by all those concerned in its use, thenthere will be little difficulty in setting up properlycontrolled studies for its evaluation. But this is notthe case with psychotherapy. Some patients believethat thLis is the only form of treatment that will helpthem (and, in contrast to drug trials, the nature ofthe treatment they, in fact, receive cannot be con-cealed from them). Some general practitioners andgeneral psychiatrists believe that certain patienitsrequire psychotherapy, although this conclusioncannot at present be based on firm evidence. Thcinvestigating team itself must, of necessity, containmembers who are more troubled by ethical prob-lems than other members of the team, who see thestudy simply as an attempt to evaluate a treatmentthe effectiveness of which has n3t yet been establi-shed. So it seems that cooperative controlledstudies of psychotherapy are particularly vulnerableto limitations imposed by ethical considerations.These difficulties cannot easily be overc'me, sincewhere ethical issues are concerned, there can be noeasy compromise; once an ethical objection has beenraised, the limitations thereby imposed have to beaccepted, even by those who do not accept the forceof the objection. However, these problems are notconfined to psychotherapy trials'8.

Ethical considerations have led to the exclusionof suicidal patients from some trials with newantidepressant drugs, or at least from the placebo-washout period. In other cases, patients might nothave been admitted to a study because it wasassumed that the fixed dosage regime might beineffective or poorly tolerated'0. Such a proceduremay satisfy the treating physician but it can resultin a specific selection of patients, eg, those sufferingfrom only moderate or light depression, and thusmake it impossible to judge critically the efficacy ofthe new drug. Such an allegedly ethical selection ofpatients could also prevent the discovery of animproved treatment of the most severely ill andsuicidal depressive patients. This situation must beconsidered as unethical because the final evaluationof a new drug for its therapeutic usefulness mustcomprise a clear statement about the entire scopeof possible indications. By the same token, it seemsdoubtful whether a restriction of a drug trial onlyto 'therapy-resistant depressions' can be justified onethical grounds.

INFORMED CONSENTA very serious ethical and legal problem can arisewith regard to the use of 'informed consent' intherapeutic trials. This also can be illustrated by

copyright. on S

eptember 13, 2020 by guest. P

rotected byhttp://jm

e.bmj.com

/J M

ed Ethics: first published as 10.1136/jm

e.1.4.168 on 1 Decem

ber 1975. Dow

nloaded from

170 H Helmchen and B Miiller-Oerlinghausen

two paradoxical statements: first, it is unethical toperform a therapeutic trial without the informedconsent of the patient; second it is also unethical toperform a therapeutic trial with informed consent.The first statement seems to be self evident, but

it should nevertheless provoke some reflectionsabout the inconstancy of ethical standards. Forexample, there is no evidence to suggest that the 26hospitalized acute schizophrenics in whom Klaesiused 'sleep' therapy for the first time in 1920, orthe catatonic schizophrenic subjected by Cerlettiand Bini to the first treatment with electroshockin I938, had been informed about the experimentalquality of the new therapy or were even asked fortheir consent*. None of these early investigatorswould have considered informed consent to be anecessary prerequisite for his experiment; ratherthey judged their experiments as ethically justifiedby the expected therapeutic benefit for mankind.In our times, however, the demand of society forscientific progress competes more and more with themodem, liberal consciousness of the individual'sright to self determination"1. It also seems wellfounded that this right to self determination shouldbe explicitly defended in view of the immanentdangers resulting from the explosive increase inexperimental investigations in human subjects andalso because of the demand for more therapeutictrials which will be the inevitable consequence ofthe new German drug law 7, 12, 13.The second statement of the paradox raising

ethical objections against the informed consent ofthe patient may be less evident. This statement canbe clarified, however, by considering the specificmethodology as well as the therapeutic customs ofpsychiatry.The specific scientific methodology in psychiatry

derives from the fact that the effect of treatmentmight be related to the specific personality of thedoctor as well as to that of the patient. Thedifficulties in investigating these influences ofpersonality on the therapeutic effect arise from thecomplexity of the human individual and theobscure relationship between the biological milieuinterne and the social milieu externe. Therefore,when testing the efficacy of a new psychiatrictreatment, the therapist must be the object of thetrial as a specific therapeutic factor or his un-specific influence must be reliably controlled. Thesame applies to the influences resulting from thesubjectivity of the patient. Thus, it is evident thatthe blind technique plays an important role inscientific trials of new therapeutic procedures inpsychiatry. The fact that the double-blind techniquehas its own methodological limitations, and thatunder certain conditions its results are not superiorto those of an open trial14 15, does not invalidate therequirements for the use of the double-blindtechnique. It may be mentioned in this connexionthat the use of the video technique in an open trial

allows a blind evaluation with certain limitations'6.We cannot in this paper go into the ethical prob-lems of using the double-blind technique forprophylactic trials17' 18, 19. The crucial point isthat many investigations of new psychiatrictherapies cannot dispense with the blind technique.However, little is known about the influence of

fully or partially informing the patient on thevalidity of blind trials. 'Full information' includesnot only information of the expected effects andrisks of the drug to be tested, but also the fact thatthe patient will be subjected to an experimentwhich is based on randomization and the blindtechnique*. A serious problem can arise if thereference drug in a double-blind trial is a placebo,since many patients might refuse to consent to thetrial. In addition, those patients who do consent tothe trial represent a biased sample, and the resultsobtained from them will not be representative ofthe entire group of patients with the particularillness under investigation but only of thosepatients who will consent to a therapeutic trial. Aslong as the influence of the information remainsobscure and its scientific relevance doubtful, fullyinforming the patient may be of doubtful import-ance from an ethical point of view. Here, it is to benoted that ever since the first edition of Martini'smethodology2' in I947, it has been regarded as anecessary prerequisite of a controlled therapeutictrial that the patient be unaware of the experimentalcharacter of that therapy. The German Pharmaco-logical Association has supported this fundamentalpostulate when commenting on the first draft ofthe new German drug law22' 23, 24. The ethicalfoundation of experimental work will probably notbe improved if this scientific-ethical principle isrenounced. It seems to be much better under somecircumstances to burden the investigator with thefull responsibility that a clinical trial is un-objectionable from an ethical point of view25 thanto obtain the 'informed consent' of the patient. Ifhelp is needed in making this decision, it could befound in a peer committee whose members musthave sufficient inside knowledge of the psychiatricreality (see also reference 26). Quoting Ingelfinger27,'The subject's only real protection, the public aswell as the medical profession must recognize,depends on the conscience and compassion of theinvestigator and his peers'.The requirement of 'informed consent' in

general treatment could also lead to ethical prob-lems. For example, the psychiatrist would have todecide at the beginning of a course of analyticalpsychotherapy whether the patient should beinformed about the danger of his suicide during

*It is striking that the statements concerning 'ethics' indie latest Food and Drugs Administration 'guidelinesfor psychotropic drugs' do not even touch upon thisproblem 8.

copyright. on S

eptember 13, 2020 by guest. P

rotected byhttp://jm

e.bmj.com

/J M

ed Ethics: first published as 10.1136/jm

e.1.4.168 on 1 Decem

ber 1975. Dow

nloaded from

The inherent paradox of clinical trials in psychiatry 171

treatment or of exacerbation of his illness; at thebeginning of treatment using behaviour therapyabout the risks of a shift of symptoms; at thebeginning of a course of treatment with anti-depressive drugs about the probability of a drug-induced agranulocytosis. The physician might preferto consider that not informing the patient wasethically justified since such information mightbring damage to him rather than benefit. With-holding information seems to be not only ethicallyjustified but even necessary if, for example, thehopeless feelings of a depressed patient would bereinforced by the information that antidepressiveactivity can be observed only in approximately 6oper cent of treated patients, or if the retardeddepressive patient is unable to decide whether ornot he will consent to the trial, in spite of all theinformation given to him.

In many cases the real question might be whetherthe patient is able to give informed consent at all. Apatient who suffers from delusions of guilt andbelieves that he should be punished and is notworthy of receiving a new drug treatment cannotin fact give his 'informed consent'. According tothe law, the guardian of the patient should be askedfor permission in such a case. However, it appears tobe unethical to install a guardian only in order toperform a drug trial because the social consequencesof guardianship may be more injurious to thepatient than the very small risk of injury caused bythe drug trial. Keeping strictly to the law can thuslead to unethical behaviour. This suggests that theresearcher should not be completely relieved of thenecessity to make his own ethical decisions in thissituation2O0 27

Legal rules or improved ethical standards?Several individual aims are in conflict: i) theindividual's right to self determination must beprotected despite the demand of society forscientific progress, and 2) the necessity to performcontrolled trials goes against the obligation to treatthe individual patient in an optimal way. Theseproblems cannot be solved by making one ideasuperior to another but only by reaching the bestcompromise between the individual aims, all of themhaving their special ethical justification. Suchcompromises will not be facilitated by preciselegal rules, for the more detailed the rules thatexist, the greater become the following risks.

I) The conditions under which scientific trialsmust be performed could become so different fromthe reality of treatment that the results of suchtrials will lack validity. To quote Lasagna, 'Certainlymost drugs would not be applied under the condi-tions of a double-blind trial, including informedconsent, hospitalization, avoiding additional medi-cation, prescription by experts, etc'29.

2) Legal rules for every detail of a clinical trialmight finally be ignored or shirked in an un-controlled way. This could lead to poorly planneddrug trials and make it very difficult to judge thescientific value of the experimental results.

3) Clinical trials might be regarded by cliniciansor investigators as too troublesome and even anti-therapeutic, or economic considerations mightcause pharmaceutical companies to refuse tosupport or stimulate such trials. Thus, there is adanger that disproportionate demands of govern-mental institutions might raise the costs of develop-ing a new product so excessively that industrywould be forced to concentrate their scientificefforts on only a few and popular lines of pharma-cological treatments and to cut off or considerablyreduce fundamental scientific research on com-pletely new drugs3O' 1, 31. In this respect the 'druglag', ie, the divergence between the developmentand introduction of new and effective drugsbetween the USA and other countries, eg, GreatBritain, should be considered as a warning symptom.To quote Wardell (1974), '. . . contrary to generalbelief, the early stages of new drug investigationare extremely safe... Rather than continuallyraising the animnl and human premarketinghurdles, society might benefit more from ascertain-ing intensifying postmarketing surveillance. Thelatter approach appears to be a major difference inpractice between the current drug regulatorysystem in the United States and Britain'31.

4) It could be foreseen that detailed legal ruleswith all their bureaucratic and administrativeconsequences would shift responsibility for the drugtrials from the treating and investigating physicianto the government or the pharmaceutical companies.Cavers (I972) pointed out that 'questions ofprofessional ethics fall under the broader rubric ofprofessional responsibility, and the effort toestablish effective governmental controls over newdrugs may in time produce a major shift in theresponsibility for carrying out drug investigation'32.The responsibility should remain with the investiga-tor not only to maintain his competence but also inorder to develop and to strengthen his ethicalconsciousness. Professionals in the medical fieldshould make every effort to introduce their ownethical standards, as they arise from modernmedical technology, into the shaping of new legalcontrols in therapeutics33' 34.

It might be considered unethical to demand'informed consent' from a psychiatric patient, andto obey rigidly precise rules in therapeutics mightresult in unethical behaviour. While this may betrue, the ethical demands for protecting the rightsof the individual as well as of society must also becarefully complied with. In this regard a medicaleducation which tries to make the physician sensi-tive and able to decide upon ethical questions iscalled for35 36. As a general conclusion we would

copyright. on S

eptember 13, 2020 by guest. P

rotected byhttp://jm

e.bmj.com

/J M

ed Ethics: first published as 10.1136/jm

e.1.4.168 on 1 Decem

ber 1975. Dow

nloaded from

A 72 H IlelinckCic cu B MiflIcr-Ocrlin,,iausmn

suggest that medical education and postgraduatetraining should develop a cloctor's competence toperceive where and when and to wvhat extent hisprofessional or scienrtific activities imply ethicalproblems and to find solutions which demonstratehis qualifications and competence37. Such qualifica-tion may sometimes also be expressed by the factthat the investigator would demand the advice ofexperienced colleagues. It seems necessary to,guarantee tlo the public the ethical competence ofphysicians. The eveintual em-nbodiment in law of theincreasing public concern over immoral and illegalbehaviour of physicians involved in medicalresearch can be bcst counteracted by establishingrigid professional control although it does notappear to be very helpful or practicable to transferdecisions about every psychiatric treatment to apeer committee38. However, in all cases where'informedl consent' cannot be demanded from threpatient, a group of competent persons should beinformed of the design of the planned trial. 'Com-petent persons' ioes not necessarily mean onlymembers of the medical profession, but alsDilncludes nurses, psychologists, or clergymen -- but,only those of them wiho have experience in treatingor helping psychiatric patients.

Novel and urgent ethical questions alwavs arisewhen the quality or quantity of new scientificdiscoveries has reached a certain limit. If, in thissituation, the ability to perceive ethical problemsand to decide on them in a competent way does notkeep up with scientific progress, then a moratoriumwill be needed in order tnat scientific progress doesnot get out of our ethical control39. Similar conceptsare beintg discussed at present in other scientificdisciplines, eg, in tle 'I;Id of human genetics40.

References

Jetter, D (I970). Dcr Humanitatsgedanke in derPsychiatrie. Das Zirztliche G;it:1rJ,ch nr 12, 5-15Tropon, KCln.

'Brill, H (I974). Die psychiatrischc Versorgung in denUSA. Bisheriges Ergebnis eines Experimei-tes.Vortrag auf dem Kongre der DGPN.

Wing, J K (I975). Die Evaluatioln gemeindenaherpsychiatrischer Dienste, Archit' far Psvchiatric 1!)1dNervc-enl Krawkhcitei, 220, 245--254.

'Helmchen, H (1973). Insulinbehandlung, Schlafoe-handlung, Psychochirurgie, Elektroschock. inMuller, C (Hrsgb.) Lexikon der Psychiatrie.Springer, Berlin - Heidelberg.

'Martini, P, Oberhoffer, G und Welte, E (I968).Methodenlehre der therapeutisch-klinischen For-schung. 4. Auflage. Springer, Heidelberg - NewYork.

tUberla, K (I972). Nachweis der Unbedenklichkeit(Unschadlichkeit) und der therapeutischen Wirk-samkeit. Der Standpunkt des Statistikers. Therapie-wvoche, 22, 2046-2052.

Ent%vurf eines Gesctzes zur Neuordnung des Arznei-

mittelrechts. Die Pharima4'entische Inidustric, 36,i-6o (1974).

'Candy, J, Balfour, F H G, Cawley, R H, Hildebrand,H P, Malan, D H, Marks, I M, anid Wilson, J (1972).A feasibility study for a controlled trial of formalpsychotherapy. Psvchological Afedicine, 2, 345 362.

"Hoffmann, S 0, und Gebhardt, R (I973). M\1oglicl1-keiten der Kontrolle psychotherapeutischerErgebnisse. Praxis der Pslychotherapie, 18, 241 252.

'"Lauritsen, B J, and Madsen, H (1974). A multinational,double-blind trial with a new antidepressantmaprotiline (Ludiomil) and amitriptyline. Acrapsychiatrica PcandinaVica. 50, I92-201.

In Der Becck, N\, und Wuttke, H (I969). Grundlagenund Grenzcn der airztlichen Aufklarungspflicht.Net venarZ!, 40, 587 -5 88.

''Freund, P A (Ed.) (1972). Experimentation withhumani subjects. G AlleIn and Unwin, London.

'Hasskarl, H, and Kleinsorge, H (1974). Arzneimittel-priifung, Arzneimittelrecht. G Fischer, Stuttgart.

',Helmchen, H (I969). Praktische Probleme Lerklinischen Doppelblindprufung von Antidepressiva.Arzneimnittel Forschung 'Drugq Research), I9881 882.

5Schou, M (974). Heutiger Stand der Lithium-Rezidivprophylaxe bei endogenen affektiven Erk-rankungen. Nervenarzt 45, 397- 4I8.

1Renfordt, E (1974). Audiovisuelle Methoden in derPsychiatrie. Nerveniarzt, 45, 505 509.

7Baastrup, P C, Poulsen, J C, Schou, M, and Thomsen, K(I970). Prophylactic lithium: double blind dis-continuation in manic-depressive and recurrenL-depressive disorders. Lanicet, 2, 326 333.

'FDA guidelines for psyrchotropic drugs (draft - Junr1974). Psychopharinacological Balletint, I (, 70.

''Hehichen, H. and Miiller-Oerlinghausen, B (I974'i.Ldingsschnittprofile der Wirkungen von Psycho-pharmaka aus kilnisch-methodologischer Sicht.Arznein-Forsch, 24, 976 --980.

`Ayd, F J (Jr), and Blackwell, B (I971. The scientificand ethical problems of psychotropic drug researc'in prison volunteers: a consensus communicationi.Psychopharmacological Bulletinl, 7, 35- 38.

It Martini, P (I947). Methodenlehre der therapeutisch-klinischen Forschung. Springer, Berlin G6ttingen.

-2.2Arbeitsgemeinschaft planrnaf3iger Professorcn firPharmakologie und Toxikologie. Schreiben vomI8.2.1974 an den Bundesminister fur Jugend,Familie und Gesundheit.

2'Deutsche Pharmakologische Gesellschaft. Schreibenvom 5.2.74 an das Bundesministerium fur Jugend,Familie und Gesundheit.

2 4Maxwell, C (I973). Clinical research for all. CambridgeMedical Publications, Cambridge.

'Brill, H (I974). Bundesverband zur AMG-Novelle.Stellungnahme der Pharmazeutischen Industriezum Regierungsentwurf (Stand I7.7.74) einesGesetzes zur Neuordnung des Arzneimittelrechts. --

Zweites Arzneimittelgesetz. Die Pharmia2eutische.Industrie, 36, 627--632.

2',Richardson, J (I970). Richtlinien fur Forschung-suntersuchungen am Menschen. Schweizerische

copyright. on S

eptember 13, 2020 by guest. P

rotected byhttp://jm

e.bmj.com

/J M

ed Ethics: first published as 10.1136/jm

e.1.4.168 on 1 Decem

ber 1975. Dow

nloaded from

The inherent paradox of clinical trials in psvchiatry 173

Akademie der Medizinischen Wissenschaften,Basel.

27Ingelfinger, F J (1972). Informed (but uneducated)consent. New England J7ournal of Medicine. 287,466. In Cooper, I S, Riklan, M, and Snider, R S(Eds): The cerebellum, epilepsy, and behaviour.Plenum Press, New York - London.

28Smith, H C (I974). Some ethical considerations ofcerebellar stimulation as an innovative therapy inhumans. In Cooper, I S, Riklan, M, and Snider, R S(Eds): The cerebellum, epilepsy, and behaviour.Plenum Press, New York - London.

29Lasagna, L (I973). Die Beweisfiihrung in der pharma-kologischen Forschung. Triangel II, 145-152.

30Heimann, H (I975). Administrative und juristischeProbleme der Psychopharmakologie. Arzneim-ittel Forschung (Drug Research) (In press).

3'Wardell, W M (1974). Therapeutic implications of thedrug lag. Clinical Pharmacological Therapy, IS,73-96.

32Cavers, D F (I972). The legal control of the clinicalinvestigation of drugs: some political, economic andsocial questions. In Freund, P A (Ed.): Experi-mentation with human subjects. G Allen and Unwin,London pp 225-246.

33Rieke, L V (I973). Some major guides for laws. InWilliams, R H (Ed): To live and to die: When,why and how? Springer, Heidelberg - New York.

34Wolstenholme, G E W, and O'Connor, M (Eds.):Ethics in medical pro-r-ss. CIBA FoundationSymposium. J A Churchill Ltd. London I966.

35Richardson, J (1972). Morale in clinical medicine.British J'ournal of Psychiatry, I20, 593-599.

36Veatch, R M, and Gaylin, W (I972). Teaching medicalethics: An experimental program. J7ouirnal ofMedical Education, 47, 779-785.

37Helmchen, H, and Miiller-Oerlinghausen, B (I973).Psychopharmakologie und psychiatrische Facharzt-weiterbildung. Nervenarzt, 44, 204-206.

38Halleck, S L (1974). Legal and ethical aspects ofbehaviour control. American J7ournal of Psychiatry,131, 381-385.

39Swazey, J P and Fox, R C (1972). The clinical mora-torium: a case study of mitral valve surgery. InFreund, P A (Ed): Experimentation with humansubjects. G Allen and Unwin, London, pp 315-357.

40Baltimore, D, Berg, P, Boyer, H W, Cohen, S N,Davis, R W, Hogness, D S, Nathans, D, Roblin, R,Watson, J D, Weissman, S, and Zinder N D (I974).NAS ban on plasmid engineering. Nature (Lond.)250, 175.

copyright. on S

eptember 13, 2020 by guest. P

rotected byhttp://jm

e.bmj.com

/J M

ed Ethics: first published as 10.1136/jm

e.1.4.168 on 1 Decem

ber 1975. Dow

nloaded from