expressed in a Confere nce held in Was hingto n in Januar y 1979. T he proceed ings of
th is Co nfere nce is mu st read ing for th ose int erested in thi s subjec t (Co nference
Proceeding, Pharmaceuticals for Developing Co untries . 1979: O ffice of Publ icat ion s,
Na tiona l Aca de my of Sciences. 2101 Co nstitution Avenue, N.W. Was hingto n. D.C.
20418). From th e United States exa mple cited above, the sea rch for efTective new
drugs and vacci nes is only par t ofthe efTort needed.
The development of dru gs specifica lly addressed to the needs of under-developed
co untries may be conside red fro m seve ra l aspects: I) the nature of pharmaceutical
resea rch ·and development (R& D) in ind ustria lized co untries, 2) the sta te of health
ca re delivery in less develop ed nat ion s, 3) current resear ch activity in tropical
diseases, and 4) co nstrai nts on th e tran sfer of ph armaceut ical R&D to the need y
Surveys reported in th e Was hingto n Co nference assess ed pharmaceuti cal R&D in
industrialized co untr ies (Sar ett , 1979: DiR add o & Ward ell , 19791. It is c1ea r th ese
efTo rts benefit all peopl e. lnd eed , most diseases occur in rich a nd poo r countries
alike. Thus, new drugs for high blood pressure, rheumatic disorders and infectious
major probl em s of less dev elop ed countries (Wescoe, 1979). The success of the
pharmaceutical industry in deliverin g efTective medication s for th ese disorders is a
matter ofrecord. There a re fou r gene ra l a pproa ches employed by th e pharmaceutical
industry in see king new drugs: I) random scree ning, 2) str uctura l modification of
co mpo unds with known activi ty , 3) extraction or modifi cati on of na tura l substa nces,
and 4) designing agents to int1 uence specific biological processes in pat ient s or
organisms (Va nc, 1978). T hese approaches are just as suitable for fmdi ng drugs for
tropi cal diseases as for any other. In th e field of tro pica l and/o r parasitic diseases, 35
drugs were approved for th ese ind icat ion s by th e U.S. FDA between 1940 and 1979
(Di Rad do & Wardell , 1979 ). T he Medica l Lett er (1 979) recentl y publ ished a list of39
drugs for pa rasitic infect ions . T hus effective, albei t irnperfect, dru gs for diseases in
wit h severe eco no m ic limitatio ns have a special intere st in these drugs. However ,
avai lable thera pe utic modalities are generall y under-u tilized in underdeveloped
popul at ion on health issues. Malnutr itio n. poor sanita tion and po pulation pressures
a lso co mplica te th e probl em s. lndeed , diarr hoea and respi ra tory infections in infa nts
are largely beyond th eir pu rview. T he valia nt efTo rts of th e World Health
Org ani zati on and the United Nations in aiding scientific development and health
ca re delivery is acknowl edged.
Table I U.S. pharmaceuti cal com panies engaged in tropical disease research .
As noted, effective drugs are available for most diseases endemic in poorer
countries and research continues. In the United States, fourteen companies have
Substantial activity against these diseases also exists in European countries (Vischer
& Oberholzer. 1979). Faecally-borne diseases are prominent in the countries under
discussion and seven U .S. companies are attacking cholera, nine typhoid, thirteen
infectious diarrhoea and fifteen intestinal parasites. Merck has active programmes
against helminthiasis, onchocerciasis, and trypanasomiasis. A separate list of eleven
drugs available from the Communicable Disease Center also exists (Johnson & Ellis,
In the field of imrnunology, the development of vaccines for leprosy and malaria
are in advanced stages and research is in progress in schistosorniasis, filariasis,
trypanasorniasis, and leishmaniasis (Goodman, 1978).
It must also be noted, however, that ofthe 35 U .S. drugs for parasitic diseases, only
three were developed since the present Investigational New Drug/New Drug
Application (IND/NDA) system went into effect and only three open INDs existed in
1979 for diseases in this category (DiRaddo & Wardell, 1979). Thus, there is a
problem transferring part of the $1.3 billion U.S. pharmaceutical R&D effort to the
benefit ofunderdeveloped countries (Table 2). Among the constraints on this process
Table 2 Constraints on the application ofU.s. pharmaccutical R&D to devclopingcountries.
I) Export provisions ofFood and Drug regulations
2) Monopoly, antitrust and restraint oftrade laws
Sanitation, nutrition , health education, population
2) Limited health care infrastructure
3) Shortageofresearch facilitiesand cadre
4) Lowgovernmental health priority
are export provisions of current Food and Drug Administration (FDA) regulations
which require INDs or NDAs for investigation or marketing, respectively, of U.S.-
manufactured drugs overseas even for diseases that don't exist in the United States.
Since the IND/NDA process now costs about $24 million and takes six to nine years
to complete (DiRaddo & Wardell, 1979), the disincentive is substantial; add to this
the lack oftrained individuals in less developed countries capable of carrying out the
c1inical research needed to obtain NDA approval. Other regulatory requirements
also limit the applicability ofthe IND/NDA system to the development ofdrugs for
underdeveloped countries. The FDA is sensitive to these issues and changes have
States could be exported under special license upon evidence that the importing
government was fully informed about the drug and assented to its importation. The
basic test would be the benefit-to-risk ratio for the importing country. The legislation
also provides for technical assistance to governments of developing countries to aid
the decision-making process (Kennedy, 1979). Western governments should also
DR UGS FO R DEVELOPING COUNTRIES: IN DUS TRIAL VIEW 547
Govern men t co nstrai nts a re not Iimited to the industria lized countries. Man y
emerging countries do no t adeq uately rec ogn ize t ha t th e pharmaceutical ind ustry is
p r ivat e ly fmanc ed . In vestment across nat ional boundaries is funded from domest ic
profu s, H ost co untries must , th erefo re , p ro vide a n oppo rtu n ity for a reasonable
return. T he be nefrts a re not o n ly need ed d rug p roducts b ut economic a nd technica l
The pharmaceutical ind ustry is de velo pin g novel ne w agents which coul d im prove
the trea tment of di seases specia l to underdevelo pe d coun tries. A ne wl y p roposed
o rga n isa tion , th e Drug a nd Vacci ne D e vel o pment Corporation, wo u ld a ltem pt to
coordinate th e efforts of ind ustry a nd academi a to wa rd s th is end . Rapid deli very to
th e peopl e, ho we ver, wi ll require im provemen t in health care del ivery syste ms in
host countries a nd rnodification ofgove rnmen ta l restrictions o n both sides.
Abrarns, W. B. (1 976). Th erapeuti cs and govern ment: 1776 and 1976. Clin. Pharmac. Ther.. 20,
Allen . V.. (1 970). Medi cine in the American Revolution. Oklahoma Stat e med. Ass. J.. 63,
DiRadd o. J. & Wardell, W. M. (1 979). Innovat ion and availability in the United Stat es ofdrugs
for tropical diseases. In Conf Proc.. Pharma ceuticals for Developin g Countries. pp .
187-1 91.Washington : Institut e ofMedicine.
Goodman, H. C. (1 978). Immunology a nd tropical diseases: Challenges and opportunities.
Ann. fm m unol. (Inst. Pasteur). 129, 267-274.
John son , R. H. & Ellis, R. J. (1974). Immunobiologic agents and drugs avai lable from the Cente r
for Disease Co ntro l, Ann. Intern. Med.. 81, 61-67.
Kennedy, D. (1 979). Food and Drug Administratio n and pharmaccuticals for develop ing
Mcfrermott, W. (1979). Histori cal perspecti ves. In Conf Proc.. Pharmaceuticalsfor Developing
Countries. pp . 9-27. Washingto n: Institute ofMedicine.
Th e Medica l Lett er (1979). Dru gs for parasitic infectio ns. The Medical Letter. 21, 105-112.
Vane, J. R. (1978). Finding the resou rces to fight tro pical disease. Tran s. Roy. Soc. Trop. Med.
Oberholzer. R. (1 979). T he Euro pean Pharrnaceu tical Indu stry. In
Pharmaceuticals ior Developin g Countries. pp . 187-1 91.Was hingto n: Institute of Medici ne.
Wescoe, W. C. (1 979): Co nstrai nts on expanding the role of the U.S. Pharmaceutical Indu stry.
A. United States ind ustry perspectives. In Conf. Proc.. Pharmaceuticals fo r Developing
Countries. pp . 179-186. Washington : Institute ofMedici ne.
Ethics, Liability, Compensation
M. N. G. DU KES, The Netherlands
An yon e who sets out to review briefl y for an int ernation al audience the ethica l and
legal problems which arise in drug th erapy runs th e risk of lapsing into tru isms. Not
onl y is the field immense, but the laws, eth ics and traditions relat ing to medi cal
pract ice differ very widely in vario us parts of th e wo rld, and even ph ysiology and
toxicology exhibit variations; the th ings we un iversall y have in com mon a re rather
more lim ited than is some times thought.
In introducing th is topic, discussion will be pr imaril y abou t the doctor and his
pa tients, and then about those other parties wh ich may affect th is doctor-patient
relationship, including the pharmacist and the health a utho rities ; ot her papers will
have much more to say about th e drug industry.
One general point to be made at th is stage is th at when probl ems ar ise in med icinal
therap eutics and result in injury to the patient - ph ysical injury, mental injury,
fman cial inj ury or an y other type of injury - there may be repercussions on various
ethical and legal fronts (assumi ng, that is, that th e matt er ever goes beyond the
confmes ofthe con sulting room).
Firstly, the injury ma y involve qu estions ofprof essional discipline. The do ctor who
Ne xt, the problem may involv e qu estions of civil law. Inju ry to another party can
result in proceed ings for damages under the law oftort, which has often been invoked
in suits brought by customers against manufacturers, including manufacturers of
drugs - notabl y the oral contraceptives. Where there is a contractual relationship -
and a patient does have such a relationship with his doctor, his pharmacist and his
hospital , sometimes actuall y in the form of a written document - bre ach of contract
In addition the se problems ma y involve crim inal law, abortion and euthanasia,
for example, are in some legal systems criminal acts, and qu ite apart from thi s a
doctor ma y treat his patients so carelessly as to be guilty ofcriminal negligence.
Finally, of course, iatrogenic injury can arise in situations in which there is no
fault , no one to be blamed, no one to sue, no one to punish . All on e has is an injured
patient calling - and rightfully calling - for help. That help socie ty mu st try to give
The doctor and his therapeutic responsibilities
Five basic types of problem involving the prescription of drugs will be considered.
None of them is quite as straightforward as it may appear at first sight. Wherever
possible , examples from actual practice will be given.
I) Firstly a doctor may prescribe unnecessary and potentially harmful therapy.
Subsequent papers will go more deeply into the point that any drug is potentially
harmful; therefore the question as to what constitutes 'unnecessary' therapy will be
considered. Plainly, ifa patient goes to his doctor with a bad cold and a sore throat
with a range of drugs having potential adverse reactions and interactions. This is
more reprehensible in some circumstances than others. Doctors who continued to
prescribe hormonal pregnancy tests in Europe after in vitro diagnostic kits became
generally available in the mid-sixties were presumably either idle or had failed to
keep abreast ofthe literature; it is still not entirely clear whether hormonal pregnancy
tests are harmful, but they are certainly unnecessary.
The ethical and legal situation is however much less c1ear when the doctor is
actually under pressure to prescribe unnecessary therapy. An elderly gentleman with
psychosomatic complaints may emphatically demand an old-fashioned injection of
liver extract, which is an excellent placebo, and he may make the doctor's life a
Such practices sometimes constitute a national bad habit. Ladies with ach ing legs
in Germany expect to be treated with expensive extracts of horse chestnut; these
products, of most dubious value , are virtually unknown elsewhere, but the German
doctor who refuses to prescribe them might weil be widely thought to have failed in
his professional duty; such preparations have sometimes caused adverse reactions,
yet it is understandable that under the circumstances they are still widely prescribed.
For that matter, the whole question of the patient's right is now in astate of flux
throughout Europe. The old adage that the patient hirnself knows best what is good
for hirn is enjoying arevival, coupled to the new adage that the doctor does not. Just
as there are now associations of patients injured by Drug X, so too there are now
societies ofpatients c1aiming to benefit from Drug Y and contesting its disappearance
from the market. In the Netherlands there is the remarkably interesting case of
Vasolastine (Enzypharm) an old parenteral drug which was c1aimed to be ofvalue for
an extraordinarily wide range of serious disorders. The drug received a negative
assessment from the Committee for the Evaluation of Medicines, and the
Committee's decision was upheld on appeal by the Privy CounciI. Nevertheless the
Secretary of State for Health, making use of an exception allowed for in the 1958
Medicines Act but not previously employed, announced the intention ofallowing the
drug to remain on the market. Should any instance of injury be attributed to this
remedy , some fascinating legal problems will arise as to where the responsibility lies.
This case is cited at length because patient pressures on physicians to prescribe
non-orthodox remedies seem very likely to increase further. Since some
non-orthodox remedies do cause injury, whatever their proponents may say, a need
may weil arise for a disclaimer procedure by which the physician can provide and
even inject the drug in question whilst accepting no responsibility for the
2) A second problem arises when a doctor prescribes grossly inappropriate drugs.
He will obviously be at fault ifthis is a consequence of aninexcusable diagnostic or
therapeutic error. The physician who prescribes aspirin to relieve gastric pain or a
drastic purgative for sudden constipation possibly due to acute intestinal obstruction
ETHICAL AND LEGAL PROBLEMS IN THERAPEUTICS 553
may have a lot to answer for. But the problems are rarely as c1ear-cut as this . Let us
take a more subtle case. It is fairly certain today that c1ioquinol is ofIittle or no use in
chronic intestinal disorders and that it can in the long run cause serious neuropathies
and blindness, but when in the earl y 1970s a young child in Holland was rendered
virtually blind by this treatment the physician who had prescribed it was acquitted on
the charges brought against hirn; the Disciplinary Council considered that, despite
briefwarnings which had appeared in two journals in the doctor's possession , he had
not acted unreasonably; the case against c1 ioquinol was still as it were, in statu
nascendi. Even had that not been the case, this decision would raise the question as to
what the minimum required reading is for a general practitioJier if he is to keep
abreast of adverse reactions, contra-indications and the like. In some such instances
the manufacturer may out of sheer self-interest warn physicians emphatically about a
new adverse development. Some of the most delicate cases however relate precisely
to issues on which the manufacturer hirnself was at the time the prescription was
issued still contesting the allegations brought agains t his product; this was the
situation with both c1ioquinol in 1972 and triazolam in 1979 in the Netherlands. lt is
difficult to know what drug literature the physician should read , and even when the
suspicion arises that a ph ysician has done too little to keep his knowledge ofdrugs up
have known and in fact did know .
3) A third issue, which overlaps with the previous one, is that of careless and
inaccurate presc ribing, and there are so many errors to be made here that it is
impossible to list them all. The c1assic case ofthe indecipherable prescription is one ,
confusion between micrograms and milligrams another. Confusion between drug
and patients would in the author's personal view be much better served if physicians
were tra ined to prescribe drugs by generic names only, specifying the name of a
reputable company whose product the physician wishes to see dispensed. For the
very few fixed comb inations the existence ofwhich is justified an analogous solution
can be adopted; co-trimoxazole is a first example of a generic name endowed on a
4) Th erapeutic errors mayaiso be of a negative type . The doctor may fa il to pre -
scribe essential treatment . Again , however, changing therapeutic concepts obscure
the issue. In the Netherland s it is considered vital to treat the patient who has had a
myocardial infarct with ant icoagulants for a very long period. That view is not shared
in every country, nor should it be, since such universal treatment is only defensible if
one has the facilities for intensive monitoring ofpatients on anticoagulants which can
be ma intained in a country as densely populated as the Netherlands. Therapeutic
concepts in any case change. In post-infarct cases, drugs such as sulphinpyrazone,
aspirin or dipyridamole may in due course come to be regarded as essential. Often the
merits of alternative forms oftherapy are so disputed that the only ph ysician who can
be c1earlysaid to have failed in his dut y is the one who has not looked after his patient
5) The fifth and final point to be made about doctors relates to the physic ian who
gives his patient m isleading or inadequate information about the treatment which he
is receiving. Once again , the concept as to what is misleading or inadequate will
depend entirely on the circumstances of the case, the norms which the community
maintains, and the state of pharmacotherapcutic knowledge . Is it irresponsible to
withold from a suicide-prone patient the fact that he has cancer and is receiving a
cytostatic drug? Is it, in the present state of knowledge, proper and necessary to warn
every patient who receives a tranquillizer that he may drive his car past a red traffic
light? In every one ofthese matters, and with respect to all the others which have been
raised, a disciplinary board or a court ofjustice will often be faced with borderline
medico-Iegal issues, with the expert witnesses mak ing life difficult for the lawyers and
sometimes for each other as weil. This whole concept that the physician - or some
other party - should provide the patient with appropriate information on a drug
when it is prescribed involves some glorious fictions, In theory the patient should be
given information, in terms adapted to his understanding, on how to use the drug,
when to stop using it, its severe or frequent adverse reactions, its interactions and
suchlike. In the actual circumstances in which drugs are prescribed and dispensed
this hardly ever happens. The patient is given some very summary advice or none
whatsoever. When he receives the drug it may have no package insert at all, one
which is in efTect an optimistic advertising brochure, or one which in miniscule
letters lists two hundred possible adverse efTects. Over-information of this type is as
inappropriate as under-information; some drug control agencies are prone to demand
this sort of absurdity, but so are the legal departments of certain drug companies.
Unhappily and unrealistically, the courts have also tended to favour the idea that a
maximum of information be provided; it is fair enough to have a document of this
type available for reference, but it is hard to see that it absolves the doctor from the
responsibilit y for giving the patient the few facts which he is likely to need, and
ensuring that he comprehends them .
Parties other than the physician
So much for the doctor. The question of entirely unforeseeable injury resulting from
therapeutic acts has not been discussed because this whole concept ofstrict liability
which clearly involves the physician as much as it does the drug manufacturer or
responsibilities and they may be held accountable for their failure to exercise them
notice, however, an increasing move among pharmacists to assurne other types of
responsibility for drug therapy as weil. Clinical pharmacists are beginning to advise
doctors on drugs, prescribing and adverse reactions. Retail pharmacists seem
increasingly anxious to assurne responsibility for giving the patient information
about the medicines he receives. These are splendid trends - the scientific potential of
the pharmacist is often under-used - but ifthese trends develop to the point where a
shift of responsibility occurs, irrespective of whether or not it is defmed in law, a
court or disciplinary board will have to take this into account. Anyone who is taking
upon hirnselfpart ofthe therapeutic responsibility ordinarily borne by the physician
must be prepared to face the consequences ifthe patient sufTers injury .
One party to the therapeutic act whose responsibilities in the event of injury or
misadventure have . never been very weil defined , is the drug regulatory agencies
which in almost every country toda y are responsible for the approval ofnew drugs to
extent the information which shall be available on these drugs in package inserts,
data sheets and advertisements. The doctor (or his patient) thus in efTect rely on these
ETHI CAL AND LEGAL PROBLEMS IN THERAPEUTI CS 555
agencies to assess matters on which he cannot possibly form an independent judgement hirnself.
To what extent, then are these agencies responsible at law for an y injury which
patients ma y sutTer as a consequence of their dec isions, for example, where such an
agenc y licences a dangerous drug without providing for proper safeguards or
warnings? The point has not very often been the subject of legal debate, but there is
an interesting ruling on it in the well-known case of SMO N Patients v the Stat e, that
is, the c1ioquinol case in Japan. Both the State ofJapan and the various companies
selling the drug were defendents in thi s case. The court ruled inter alia that:
'.. . in view of the nature of administrative supervisory authority and in all other
therefore should bear one -th ird ofthe total cost ofthe compensat ion that the court
determines the defendents should pay . . .'
This principles, ifit is followed elsewhere, will be complicated enough at the national
level. It will be even more complicated if one is dealing with mutual recogn ition of
decisions between states (such as has been debated in the European Economic
Community) or with an international agency which has been accorded regulatory
authority to licence drugs in the member states , such as that which has been operative
in Benelux since 1978. From the strictly legal po int of view one is still dealing here
with right s granted by Minicipal (that is, national) Law in accordance with a duty
imposed upon the State concerned by a Treaty which it has rati fied, but this degree of
delegation to an international agenc y in matters directl y atTecting the individual is
However, to return to the national agencies. As has been said, the doctor and the
patient depend on the judgement of the se agencies. Th e manufacturer relies on such
an agency to confe r on his drug an independent blessing , and the agency in turn relie s
on the manufacturer's research department to provide hirn with the facts on the bas is
ofwhich it can do so. And who do es the research departm ent rely on? On the doctor,
naturall y, who performed the c1inical trials.
The doctor is the keystone in the whole process, inevi tably so, and he has been
discussed primarily for that reason. Hut even a.keystone is onl y one of the stones
wh ich make up an arch , and eac h of the others is essent ial as well; if the arch comes
tumbling down on the pati ent s' head - if the therapy cau ses injury - society's first
task will be to redress that injury, wherever possible; having done that one can sit
down and try to apportion the biarne, if blame there be.
The important th ing, in the coming years, will surely be to keep a degree ofbalance
and a sen se of moderation in these issues. It is proper and necessary that society
rush. The former reflects what I once termed the 'love-hate relationship which
exists between the public and its drugs - sub stances which are hailed one moment as
the solution to every problem and castigated the next as the cause of every ilI' .
(Dukes, 1980). The gold rush is the wild rush which developed in the U nited States
more than two decades aga to extract vast sums in compensation from ph ysicians and
drug companies for ever y th inkable and unthinkable adverse etTect of drug treatment.
But if moderation is to be ac hieved in that respect, then moderat ion must be learned
in oth er things as weIl. Negligence and human error apart, society as a whole must be
held responsible for much of the trouble which drugs cau se. Patients over-demand
them, ph ysician s over-prescribe them , pharmaceutical compa nies over-advertise
them. If something could be done about that, it will not onl y be possible to talk mo re
dispassionately about compensation for injury; there will also be rat her less injury to
Dukes, M. N. G. (1980). The Van der Kroef syndrome. Introductory Essay in Side Effects 01
Drugs Annual, ed. Dukes, M. N. G. Amsterdam and Oxford: Excerpta Medica.
Departm ent ofHealth & Social Security,
It is proposed to con sider product liability with particular reference to the European
Few issues of th is nature during the last few years have received such a mixed
recept ion as product liabil ity. Although tho se representing consum er interests have
been an xious to promote its early introduction, industry have found the prospect
unp alatable. Wh ile the Law Cornmission, the Scott ish Law Cornmission, the
Strasbourg Con vent ion (Council of Europe, 1977) and the Pearson Report have all
recommended its introduction, tho se representing the med ical and pharmaceutical
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