Vose, C. W., Butler, J. K., Williams, B. M., Stafford , J. E. H., Shelton, J. R., Rose, D. A.,
Palmer, R. F., Breckenridge, A. M., Orme, M. L. 'E. & Serlin M. J. (1979). Bioavailability
and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate.
Walls, c., Vose, C. W., Horth, C. E. & Palmer, R. F. (1977). Radioimmunoassay of plasma
norethisterone after eth ynodiol diacetate administration. J. St eroid Biochem.. 8, 167-171.
Warren, R. 1. & Fotherby, K. (1973). Plasm a levels of ethynyloestradiol after administration of
eth ynyloestradiol or mestranol to hum an subjects. J. Endocrinol.. 59, 369-370.
Westph al, U. (1971 ). Steroid-protein interactions. In Monographs on Endocrinology, 4, Berlin:
Williams, M. c., Helton, E. D. & Gold zieher, J. W. (l975a). The urin ar y metabolites of
17a-ethynylestradiol 9a , 11 f-3H in wom en. Steroids, 25, 229-241.
Williams, K. I. H., Layne , D. S., Hobkirk, R., Nilsen , M. & Blahey, P. R. (1967). Metabolism of
doubly labelIed ethynylestradiol-3-methyl ether in women. Steroids, 9,275-287.
Williams, J. G., Longcope, C. & Williams, K. I. H. (l975b). Metabolism of 4-JH and
4- 14C-17 aethynylestradiol-3-methyl ether (mestranol) by women . Steroids, 25,343-354.
World Health Organization (1977). Special Programme of Research, Development and
Research Training in Human Reproduction. In Sixth Annual Report, pp . 67-69. Geneva:
World Health Organization (1979). Special Programme of Research, Development and
Research Training in Human Reproduction. In Eighth Annual Report, p. 88. Geneva:
Zuleski, F., Loh , A. & Di Carlo, F. J. (1978). Determination ofethinyl estradiol in human urine
by radiochemical GLC. J. pharm. Sei., 67, 1138-1141.
Drugs for Developing Countries
Department of Pharmacology and Therapeutics,
Drug evaluation is the procedure by which the true value of a drug is determined .
Th is evaluation begins with the testing of the drug for safety using experimental
an imals. In some cases, some pharmacological action useful in therapy may be
demonstrated and investigated dur ing this stage. The evaulation is then completed
from the total clinical experience with the drug. Every new drug thus passes through
investigations which make up clinical evaluation take place in a number of phases
which can be identified as: I) Initial studies in man ; 2) Formal therapeut ic trials; 3)
The objecti ve of drug evaluation in developing countries is the same as that in
developed countries - the provision of drugs with proven efficacy and safety. For the
satisfactory evaluation of drugs, certain princ iples and requ irements have, over the
years been formulated (World Health Organization, 1966, 1975).These principles are
scient ific and ethica l and it is in complying with them that problems arise. It will be
true to say that man y ofthe problems of drug evaluation in developing countries are
similar to those that developed countries have already solved, but the problems are
complicated in developing countries by peculiar socio-cultural and economic factors
which make it unwise to transfer solutions without adaptation from developed to
developing countries. In many instances, completely different approaches are
The production and tests for the safety of drugs require technology and equipment
that are outside the present resources of many developing countries. Most drugs
introduced for use in developing countries would therefore have been produced, and
submitted to pre-clinical testing for safety in developed countries. Although there are
guidelines setting out the minimum requirements for the pre-clinical assessment of
drugs, the view is widely held that the extent ofsuch pre-clinical tests depends on the
country of origin, the pharmaceutical company producing the drug, and the disease
for which the drug is being introduced. In effect, varying standards ofsafety for drugs
are sometimes employed by pharmaceutical companies in different countries, with
less stringent standards often applied to those sold . in developing countries.
Fortunately, most pharmaceutical companies appear to adhere strictly to the general
principles governing the pre-c1inical testing of drugs , detailed compilation ofthe pre -
c1inical data and their review by an independent drug regulatory agency being
absolutely necessary before administration of the drug to man. It is obvious that
where a drug is to be used in the country of origin and in other developed countries,
developing countries, who do not have drug regulatory agencies or whose drug
regulatory bodies do not have the appropriate technical experts to review the
submissions, have nothing to fear as to the adequacy of the pre-c1inical animal
studies. The problem arises when a drug has been developed specifically for diseases
found only in developing countries, for example such tropical diseases as filariasis,
bilharziasis, leishmaniasis and trypanosomiasis. Since such drugs would not be used
in developed countries and licence is therefore not required to administer them to
man there, the companies may not feel inclined to submit the drugs to the same
variety of animal tests and for the same duration that they would
otherwise have done. They may argue that considerations of the risk-benefit ratio
with regard to the population for which the drug is intended do not justify such
countries do not fall into this category. But the problem is real, and what is more, the
developing countries believe that it exists. Many developing countries have therefore
taken steps to protect their populations from the risks that could result from such
practice. A few developing countries have demanded that pre-c1inical testing of drugs
be performed locally in their own countries, but there are several problems, including
shortage of human and material resources, that make this an unrealistic solution in
most cases . A different solution adopted by other developing countries is for them to
undertake a comprehensive review and assessment ofthe data on pre-c1inical studies
supplied by the manufacturers. This is a more realistic solution, but, for a number of
developing countries, it is not easy because their drug regulatory agencies are not
backed by the technical expertise necessary for assessing such complex data. The
result is a long delay in giving permission for c1inical evaluation ofthe drug whilst the
views of expert advisers are being sought on the adequacy of the pre-c1inical data.
This contributes to the delay in introducing new drugs in developing countries. In an
atternpt to avoid this delay, some developing countries allow the c1inical evaluation
of a drug to commence even when they are still not sure of the adequacy of the preclinical data.
should be a central body which will, on behalf of developing countries evaluate the
pre-clinical data compiled by pharmaceutical companies and issue certificates of
c1earance. This ensures uniformity of standards in pre-clinical testing and relieves
developing countries ofthe need to evaluate the pre-clinical data by themselves. The
central body uniquely placed to fulfil this role is the World Health Organization.
In the context of developing countries, the term drug should apply not only to
therapeutic substances but also to prophylactic substances including vaccines. Many
of the so-called tropical diseases are diseases of underdevelopment and their control
DRUG EVALUATION IN DEVELOPING COU NTRIES 523
rests as much with prophylactic vaccination as with drug treatment. The c1inical
evaluation ofvaccines and other prophylactic substances is therefore as important in
developing countries as the evaluation oftherapeutic substances.
Drugs used in developing countries fall into two broad groups: I) drugs used in
diseases found mainly in developing countries, for example, helrninthiasis,
leishmaniasis, trypanosomiasis and other communicable tropical diseases and 2)
drugs used for diseases of world-wide distribution. Thus cancer, cardiovascular
diseases, mental disorders and metabolic diseases affect developing countries (as they
do developed) and exert an enormous toll in terms of human suffering and costs to
their economy. For both groups ofdrugs, the principle that drugs for use in any given
population should be assessed for efficacy and safety in the particular population
applies. For the second group, since the drugs, which are usually produced in the
more developed countries would have been extensively tried in the country of
origin and other developed countries for efficacy and safety, only limited c1inical
evaluation is required in developing countries. Such limited evaluation is necessary ,
I) to answer the scientific question as to whether differences in race, geographical
location, c1imate and nutrition have any effect on the already known responses to the
drug and 2) to satisfy statutory requirements laid down by each country's drug
regulatory agency, prior to the introduction of a new drug for general use. With the
first group of drugs, it is often necessary to carry out detailed c1inical evaluation -
Besides the problem oftesting new drugs in man , there is also a need to re-evaluate
many established or commonly used remedies . Many of the presently weil
established tropical disease drugs have never had adequate pharmacokinetic testing
(for example, tests for enzyme induction, protein binding, interaction with other
drugs) and judgements oftheir safety and efficacy rest as much on intuitive reasoning
as on acceptable scientific evidence .
One ofthe major justifications for testing a new drug in man or for testing an old drug
for a new indication is the specific medical need it is hoped the drug will meet. For
most of the endemic trop ical diseases, the need for this study is easily justified.
However for the more cosmopolitan diseases and the so calied diseases ofaffiuence, it
is difficult to justify the commitment ofwhat may turn out to be a sizable fraction of
the medical manpower resources of a developing country to the execut ion of a
c1inical trial of sufficient quality and size as to command international acceptance.
Thus, for exarnple, in the now famous Madras studies (Menon, 1969) to evaluate
different treatment schedules in pulmonary tuberculosis, the central, state and local
governments in India co-operated maximally whereas , it would be almost impossible
countries are now affiicted with these maladies. Evaluations ofdrugs for such diseases
in developing countries are usually limited in size and number and therefore lack the
kind of authority that the Madras studies have.
The first and most important prerequisite for a c1inical trial is the availability of a
preparation that has undergone adequate preliminary tests in experimental animals
and that has been approved for administration to human subjects by a reputable
safety organisation. Even after such apreparation has become available, there remain
problems posed by peculiar circumstances prevailing in the tropics where most ofthe
developing countries are situated. Thus, special tests have to be carried out and data
provided on the stability and storage characteristics under ditTerent conditions of
temperature and humidity. A vaccine for fteld testing will have to be stable in hot
humid environments since these are what are to be expected in many developing
countries. Even drugs to be tested in a relatively modern hospital setting would also
need to be stable in adverse conditions of temperature and humidity since it is not
special preparations for the developing countries; such special preparations have to
be tested for bioavailability and other pharmacokinetic properties, to ensure that
these properties have not been altered in the modification process to suit the special
elimatic conditions ofthe developing countries.
One ofthe most important responsibilities in the planning stage is the elear defmition
of the objectives of the trial. The statTstructure (medical, technical, nursing and
social welfare) and laboratory support would then be set at a level adequate to attain
all objectives. For example, for initial studies in man, a elinicallaboratory equipped
to measure a wide range ofphysiological and biochemical variables is essential. Such
laboratories are only found in a few teaching hospitals in developing countries and
they are so often overloaded with routine laboratory services that they are reluctant
to take on additional activities essential for the initial administration of a drug to
humans. This problem has made initial studies of new drugs in man uncommon in
The successful conduct of a elinical trial also depends on the type of team leader.
Ideally this should be a elinician skilled in the design and practice of scientific elinical
investigation in man and in the principles of elinical pharmacology. Although
experienced elinicians now abound in thousands in some developing countries, it is
only a few who have the commitment to scientiftc drug evaluation necessary for a
weil conducted and correctly evaluated elinical trial. One therefore still fmds in
developing countries, drug trials conducted by elinicians without the necessary
training and experience with the result that the studies are frequently of doubtful
For the proper design and evaluation of a elinical trial, elose collaboration with
statisticians, who already possess extensive experience in the design and conduct of
biomedical investigations is necessary from the earliest stages. Biostatisticians ofthe
right experience and training, are in short supply in many developing countries and a
review of many of the trials reported from these count ries often reveals shortcomings
which could have been corrected if the advice of a biostatistician were available
during the planning ofthe trial.
Most c1inicaltrials are conducted in hospitaloutpatients or inpatients. Very often the
elinical trial team has to compete with other units in the health care delivery system
for hospital space and facilities for which almost invariably, there is a greater demand
than supply . The health authorities may weil decide that provision ofstandard health
service is of such consuming priority to them that they cannot accommodate the
elaims of elinical trial investigators. The situation is even worse where a prolonged
stay in hospital is needed for a patient who is otherwise weil, for the observation of
the etTects of a drug, as may be the case in testing the efficacy of a new antimalariaI
drug. Unless a study is of an overwhelming national importance, the health
authorities are usually not prepared to participate in it and co-operate in its
DR UG EVALUATION IN DEVELOPING COU NTRIES 525
execution. Studies requiring the commitment of hospital beds or outpatient staff and
facilities to any substantial extent for several months are therefore difficult to sustain.
Field trials also have their own peculiar problems.
Ifthe goals ofthe World Health Organization are realised, there should be vaccines
against malaria and possibly other tropical parasitic diseases available for large-scale
use before the end ofthis decade. The vaccines will have to be submitted to field trials
before being released for general use. Ideally, for such field studies, an accurate
census of the population selected for the study should be available. Population
mobility should be known, accurate records ofbirths and deaths should be available.
There should be information on the identity and seasonal occurrence of all the
communicable diseases endemie in the area as weil as the transmission pattern ofthe
infection under study . Access of the population to drugs other than those to be
administered by the field team must be negligible. These data , which are so essential ,
are sadly lacking in many developing countries and this poses a problem to anyone
embarking on the large-scale field trial of a drug in such countries.
Selection of patients entails accurate diagnosis and accurate assessment of the
severity ofthe disease under study. This is not often easy in developing countries, due
to interference with the course ofthe disease by previous treatment which cannot be
evaluated. The widespread presence of co-existing diseases, especially parasitic, also
poses its own problems. Hence if protocols are too rigid in excluding co-existing
many instances is to group patients' ages in decades. Even then, this may only be
approximate. In a number of developing countries local customs or religious
practices forbid free movement of women in public places including hospitals.
Although women would come to hospital for treatment they probably would not be
available for the type of repeated public exposure that participation in clinical trials
would entail. Matehing of patients for severity of iIlness, age and sex, although
desirable, cannot therefore be rigidly pursued without seriously compromising the
number of patients available for study. The solution to the problem is to design the
study to allow for multifactorial analysis ofthe data.
The use of other drugs concurrently with the drug under trial also poses its own
problem. In many developing countries the hospital is a place of last resort , the
patient having sought and received treatment from local traditional healers before
coming to hospital. If such a patient is included in a clinical trial, it is difficult to
restrain hirn from continuing with any medication he may weil be receiving from the
traditional healer. Fortunately most of this medication will be pharmacologicaly
inert but some are active and may affect the response to the drug under study. Also,
since drugs are generally available in the population in the black market and even in
licensed pharmacies without prescription, patients may continue to take other potent
drugs without reference to the clinical trial investigator.
The drop-out-rate amongst patients taking part in clinical trials in developing
countries appears to be higher than in developed countries. In arecent survey of
short-terrn clinical trials reported in three Journals in West and East Africa the
average drop-out rate was 30-40% (unpublished, personal study). Many reasons can
be identified for this amongst which are poor motivation, transportation costs,
unavailability ofhome help and unwillingness to be away from work too frequently .
The high drop-out would have to be borne in mind in deciding the numbers to be
admitted to a trial so that the minimum number compatible with statistical analysis
of results would complete it. This problem also indicates a need to involve medical
social workers in each major trial. They undertake regular visits to patients' hornes
and trace defaulters. If measurements to be made are not too specialised, the medical
social worker with a nursing background may take the measurements and supervise
drug administration. The horne visits mayaiso provide insights into habits of patients
which are not elicited in hospital. Hence , a patient who has one meal a day would not
be used in a trial in which drugs will be adm inistered three times daily after food.
Another way to reduce drop-out rate is to provide fmanc ial assistance towards cost of
travelling to and from hospital but this only improves the situation to a small extent
since cost oftransportation is onl y one ofseveral causes ofdefault.
Irregularity in the suppl y of drugs mayaiso constitute a rnajor handicap, if, as is
usuall y the case, importation of drugs is involved. There may be dela y in the issuing
ofimport licences or in the clearing ofthe drugs from congested ports .
The problems of ethics and law in human experimentation are alwa ys present in
clinical drug evaluation and they are no less important in developing countries than
in the technologically advanced and developed countries.
That consent for participation in clinical trials should be voluntarily given by a
patient after the objective, nature and possible risks of the study would have been
explained to hirn is und isputable. Investigators know how difficult it is to explain the
nature of an experiment to otherwise educated and intelligent but not medicall y or
scientifically qualified persons. The y can therefore imagine how much more difficult
it is to expIain the same thing to illiterate peasants in some remote village in Africa or
Asia. The result is that one often has to embark on a human study not being sure
whether, in spite ofhis etTorts, the nature ofthe stud y and the risks involved are fully
appreciated by the subjects. Asking patients to indicate accept ance to participate in a
idea ofsigning of documents is so widely regarded as an act ofself incrimination that
its suggestion is bound to scare away a good number of those who would otherwise
Even after the problem of recruiting informed voIunteers has been surmounted, there
is still the problem of whether active treatment should be witheld from any group of
patients in placebo-controlled trial s. Where the trial is on a drug used for a disease
found mainly in developing countries and knowledge on it has not gone beyond the
stage of initial administration to man , then it is easy to uphold the principle of
placebo-controlled evaluation of the new remedy . In other instances, there is
probablya lot of data already accumulated from studie s in developed countries and
justification for the trial in developing countries is probably to determine whether
there are racial difference s in response or whether a ditTerent dose range might be
required. Man y would conclude that in these instances a drug of known efficacy
should not be withheld from patients, arguing that the type of information required
could as easily be obtained from an open trial as from a placebo-controlled one. This
is not all. In man y developing countries - at least those in Africa - patients are strong
in their belief that hospitals exist to treat patients to the best of their abilit y. An y
suggestion of an experiment in which an ill person may possibly not receive the
known treatment is largely unacceptable. Even without saying it, man y people
DR UG EVALUATION IN DEVELOPING COU NT RIES 527
believe that the teaching hospitals, where most ofthe c1inical trials are conducted, are
centres where patients are used for experiments wh ich are not necessarily in the best
interest ofpatients. An invita tion to a pat ient to participate in a tr ial in which he ma l'
serve as a placebo-control ma l' therefore confrrrn his wor st fears and weaken his
co nfide nce in the doctor and the institution . U nfortuna tely, rather than giving an
outright refusal , many patients will accept to participate only to cease attendance in
The immediate objective of drug monitoring is to identify at the earliest possible
moment the liability ofa drug to produce undesirable effects which were not detected
during its c1inical trials (World Health Organization, 1970). The currently used
methods for the detection of adverse effects of drugs are observational and of an
epidemiological nature (Wendel , 1969). They cornprise, I) a voluntary reporting
system by doctors in general or hospital practice and 2) an intensive monitoring
system like the Boston Collaborative Drug Surveillance Programme (1974). The
voluntary system requires a high degree of commitment from pra ctitioners, and the
intensive monitoring system, a high-level technology with statistical and computer
an area ofminimal acti vit y in developing countries.
The problems of drug evaluat ion in developing countries ha ve been discussed using
country to country depending upon their level of development and other social,
economic and cultural factors. The scientific problems arise from shortage ofskilied
man-power and lack of ph ysical facilities and these limit the qu ality and quantity of
organized studies. Ethical problems also limit the number of subjects that can take
not be in the interest of developing countries to commit scarce human and economic
resources to the performance ofscienti ücally inadequate drug evaluations ofdoubtful
I am grateful to my colleagues. Dr, J. O. Ku ye and Dr . A. F. Aderounmu for their
comments on the draft manuscr ipt. I also th ank Prof. J. B. Familusi for allowing me
Boston Collaborative Drug Surveillance Programme (1974). Reserpine and breast cancer.
Menon , N. K. (1969). Madras stud y of supe rvised once weekly chemotherapy in the treatment of
pulmonary tuberculosis: c1inical aspects. Supplement: The chemotherapy of tuberculosi s
in developing countries. Tubercle, 49, 76-78.
Wendel , H. A. (1969). Adverse drug effects and the controlled c1inical trial. Pharmac. clin.. 2,
World Health Organization (1966). Principles for pre-clinical testing of drug safety. Technical
Report Serial Number 34/. Gene va: W.H.O.
World Healt h Organization (1970). W.H.O. pilot research project for international drug
monitoring. OjJicial Record World Health Organization Nu mber /84. Annex 8. Geneva:
World Healt h Organization (1975). Gu idelines for evaluation of drugs for use in man. Technical
Repon Serial Number 563. Geneva : W.H.O.
Division ofClinical Pharmacology and Toxicology,
The Central Laboratory, Ullev älHospital,
'While drugs alone are not sufficient to provide adequate health care, they do play an
important role in protecting, maintaining and restoring the health of people' (WHO
Expert Committee, 1977). Thus, ideally speaking the basic human needs such as fresh
air , clean water, adequate food, heating and clothing, appropriate hygiene, sex and
love should be satisfied before priorities are given to drugs . In practice we are aiming
at establishing a reasonable balance by fulfilling - to the best of our ability - these
basic prerequisites, as weil as by providing appropriate drugs, as part of a total
programme for promoting health and combating disease.
During the last 10-15 years growing concern has been paid by health authorities
and various groups of health professionals to the fact that drugs are not used to their
full potential, neither in terms of efficacy nor ofsafety and economy (Sjöqvist, 1975).
The wide geographical variations in overall drug therapy profiles (for review see
Lunde, 1976; Lunde et al., 1979) also add to the complex question - what is
really rational and optimal drug therapy? In this context, a drug economy should be
considered which includes the identification of real patients, the basic question of
whether to treat or not, the choice between drugs and other alternatives, dosage
adjustment and evaluation of efTect. In today's medicine, drugs may even tend to
become an inadequate substitute for an inappropriate (or failing) health programme.
40-50% of the total health care budget is spent on drugs as compared to 8-10% in
others. orten a discrepancy develops between the real needs and the demands, as
claimed by the drug industry, many professionals and finally the public. Besides a
sometimes unlimited flow in many countries of drugs of an inferior quality, a rnajor
fraction of the populations may still be in urgent need of the most important drugs .
Limited funds, insufficient procurement and accessability as weil as shortage of
trained health personnel at all levels are obvious reasons for these deficiencies
Despite the widely varying attitudes to drugs in our international society, many
developing countries feit unanimously that as the drug control measures in many
developed countries were improved or became more restrictive, increasing pressure
from drug marketing interests was put on them. As a result of considerable political
pressure from various member states within the World Health Organisation (WHO),
not only reflecting several governments' increasing worries for the rising expenditure
on pharmaceutical products, but also referring to experiences already gained in some
countries on the selection ofbasic or 'essential' drugs, WHO was urged to take action.
In a report to the 28th World Health Assembly (WHA) in May 1975 (Official Record
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