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and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate.

Contra ception.19,119-127.

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.

Weintraub , H. S., Abrams, L. S., Patri ck, J. W. & McGuire, J. L. (1978). Disposition ofnorgestimate in the presen ce and absence of eth inyl estradiol after oral administration to humans.

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17a-ethynylestradiol 9a , 11 f-3H in wom en. Steroids, 25, 229-241.

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Drugs for Developing Countries

Chairmen:

F. SJÖQVIST, Sweden

L. SALAKO, Nigeria

PROBLEMS OF DRUG

EVALUATION IN

DEVELOPING COUNTRIES

L.A.SALAKO

Department of Pharmacology and Therapeutics,

University ofIbadan,

Ibadan,

Nige ria

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

two major stages of investigation before becoming generally available on prescription . These two stages are: I) Pre-clinical evaluation; 2) Clinical evaluation. The

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)

Post-marketing surveillance.

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

necessary for their solution.

Pre-clinical evaluation

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

522 L.A.SALAKO

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

extensive animal tests. Admittedly, the major multinational pharmaceutical companies which have been associated with the development of drugs for developing

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.

There are two other possible approaches to this problem: firstly, all pharmaceutical companies should be bound to comply to a minimum standard of prec1inical drug testing irrespective of where the drug is to be used, and secondly, there

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.

C1inical evaluation

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 -

from the initial studies in healthy volunteers to the large-scale controlled, multicent re or field trials - in developing countries.

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 .

Justification

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

to obtain such co-operation for the c1inical trial of drugs for obesity or atherosclerosis, even though a substantial proportion of the population of developing

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.

Prerequ isite

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

524 L.A.SALAKO

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

always possible to ensure continuity in the supply of electricity necessary for maintaining drugs at particular temperatures. It is therefore often necessary to make

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.

Planning ofthe trial

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

developing countries.

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

validity.

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.

Siting of'the 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.

Conduct ofthe trial

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

diseases, adequate numbers for conducting a trial may never be obtained. Age specifications are not always easy to achieve with precision and the best that can be done in

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

526 L. A. SALA KO

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 .

Ethical issues

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.

Consent

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

trial by signing a statement to that etTect may be a good thing but is hardIy worthwhile when deaIing with pat ients who can neither read nor write. What is more , the

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

have volunteered.

Controlled trials

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

hospital altogether.

Post-marketing surveillance

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

backing. The effects detected by both methods are submitted to anational drug control agency whose responsibility it is to decide on whether there is any causal

relationship between the reported effect and the drug. The problems posed by insufficient commitment and moti vation on the part of doctors, lack of high level technology and ineffective drug regulatory agencies make post-markering drug surveilla nce

an area ofminimal acti vit y in developing countries.

Conclusions

The problems of drug evaluat ion in developing countries ha ve been discussed using

the intern ationally accepted principles of drug evaluation as a basis for the discu ssion.The problems are scientific and ethical and their magnitude va ries from

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

part in a study and the kind ofstudy the y can take part in. Consideration ofthe problem s and their possible solutions would lead to the following conclusions. It would

not be in the interest of developing countries to commit scarce human and economic

resources to the performance ofscienti ücally inadequate drug evaluations ofdoubtful

validity. There is a lot ofadvantage to be gained from co-operation between developing countries and between developing and developed countries and the pharmaceutical industries under the co-ordinating umbrella of a gIobai organization like the

World Health Organization.

Acknowledgements

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

to use some ofhis data.

528 L.A.SALAKO

References

Boston Collaborative Drug Surveillance Programme (1974). Reserpine and breast cancer.

Lancet. 2,669-671.

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,

58-62 .

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:

W.H.O.

World Healt h Organization (1975). Gu idelines for evaluation of drugs for use in man. Technical

Repon Serial Number 563. Geneva : W.H.O.

THE WORLD HEALTH ORGANIZATION

ESSENTIAL DRUG CONCEPT -

THREE YEARS AFTERWARDS

P. K. M. LUNDE

Division ofClinical Pharmacology and Toxicology,

The Central Laboratory, Ullev älHospital,

University ofOslo, Norway

Background

'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.

The tremendous increase in the number ofpharmaceutical products had led to a nonrational use of drugs, with the resulting waste of resources. In some countries up to

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

(Yudkin, 1978).

Despite the widely varying attitudes to drugs in our international society, many

developing countries feit unanimously that as the drug control measures in many

530 P. K. M. LUNDE

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

WHO, 1975) the Director-General tentatively outlined a strategy for the establishment of lists of essential drugs as considering the local health needs and situation.