Balogh, A., Robertson, D. M. & Diczfalusy, E. (1979). ElTect ofthe norethisterone minipill on
the plasma levels of biologically and immunologically active luteinizing hormone in
women. Acta endocrin., 92,428-436.
Benagiano, G. (1977). Long-acting systemic contraceptives. In Regulation ofHuman Fertility.
pp. 323-360 . Copenhagen: Scriptor.
Briggs, M. H. (1977). Combined oral contraccptives. In Regulation of Human Fenility.
pp. 253-282 . Copenhagen: Scriptor.
Diczfalusy, E., Frazer, I. S. & Webb, F. T. G. (1980). Endometrial Bleeding and Steroidal
Contracept ion. Bath: Pitman Press Ltd.
DILEMMASIN CONTRACE PTIVE DEV ELOPM ENT 473
Diczfalusy, E. & Landgren . B.-M. (1977). Hormonal changes in the men strual cycle. In
Regulation ofHu man Fertility, pp. 21-71.Co penhagen: Scripto r.
Fotherby, K. (1977). Low doses of gestagens as fertilit y regulating agents. In Regulati on 0/
Human Fertilit y. pp . 283-321. Copenhagen: Script or.
Landgren, B.-M ., Balogh, A., Shin , M. W., Lindberg, M. & Diczfalu sy, E. (l979b). Hormonal
effects of the 300 ~g no rethisterone (NET) minipill. 2. Daily gonadotro phin levels in 43
subjects duri ng apretreatment cycle and during the second month of NET administration.
Landgren, B.-M . & Diczfalusy, E. (1980). Hormonal effects of the 300 ug norethisterone (NET)
min ipilI. I. Dail y steroid levels in 43 subjects during a pretreatrnent cycle and during the
second month ofNET administration. Contraception. 21, 87-113.
Landgren , B.-M ., Johannisson , E., Masironi, B. & Diczfalu sy, E. (l9 79a). Pharmacokinetic and
pharmacod ynamic effects of sma ll doses of norethisterone released from vagina l rings
continuously during 90 days. Contraception, 19,253-271.
Landgren, B.-M ., Unden, A.- L. & Diczfalu sy, E. (1980). Hormonal profile of the cycle in 68
normally men struating women. Acta endocrin.,94, 89- 98,
Martinez-Manautou, J., Cortez, V., Giner, J., Azn ar , R., Casasola, J. & Rudel, H. W. (1966).
Low doses of progestogens as an approach to fertilit y control. Fertility Sterility, 17.49-57.
Moghi ssi, K. S. (1976). Microdose progestogens for contraception. In Regulation 0/ Human
Fe rtility, ed. Moghi ssi, K. S. & Evans, pp . 57-84. Detroit, Michigan: Wayn e Statc
Rinehart, W. (1975). Minipill - A limit ed alt ernative for certain women. Population Reports
World Heal th Organization Spec ial Programme of Resea rch , Development and Research
Training in Human Reproduction (1979). Intravaginal and intracervi cal devices for the
delivery offertility regulating agents, J. Steroid Biochem.. 11,461-467.
Postgradutue Institute 0/Medical Education and Research,
The controversies, challenges and problems that arise when carrying out c1inical
trials of plants with antifertility properties can be appreciated better if viewed
against, a) a background of the historical use of medicinal plants, b) the past
where plants have been traditionally utilized.
Plants have been used for therapeutic purposes since the dawn ofmankind. The Irrst
description ofthe different prescriptions used in Egyptian medicine can be traced to
the famous Ebers Papyrus believed to have been written about 1500 B.e.The earliest
list of127 plants used in the Ayurvedic system ofmedicine was described around the
year 1200 B.e. in the Atharva Veda which provided a detailed description of
Ayurveda, the anc ient Indian system of medicine. The first Chinese pharmacopoeia
entitled Sheng Nung Pents ao Ching appeared during the Chou dynasty in 1122 B.C.
and listed 365 types of plant medicines. These were divided into three categories:
tonics from plants which could be consumed continuously, plants with little or no
toxicity meant for treating different diseases and plants which were toxic and needed
processing before being used. The c1ay tablets of Assyriaand Babylonia which
described the medicinal use of250 herbs were created in 650 B.e., while the first list
of 400 medicinal plants and other substances used in the Greek system of medicine
was compiled by Hippocrates around 400 B.e. Many of the plants mentioned in
these lists are in widespread use today. Two ofthe plants Commifera mukul (gugglu)
and Piper longum (pipali) for example, in the Atharva Veda are still being prescribed
regularly by the practitioners ofthe indigenous systems ofmedicine in India .
There has been a resurgence in interest generally in the last few years in the use of
medicinal plants for therapeutic purposes and in particular in plants that could be
used for preventing implantation and inducing early abortion. The World Health
CLI NICAL EVALUATION OF A NTIFERTILITY PLA NT S 475
Organization (WHO) Special Programme for Research in Human Reproduction has
set up a Task Force on Antifertility Plants. The information available from 3000
plants has been computerized. Selection ofplants to be screened has been made by a
weighted system following which studies are being carried out at six centres around
the world (Soejarta, Bingel, Sla ytor & Farnsworth, 1978). At the Chinese Un iversity
of Hongkong an interdisciplinary project for carrying out research on plants used for
generations in China has been initiated. The South East Asia Region al Office of the
WHO at New Delhi has identified research on the traditional syste ms ofmedicine as
a priority area of research and has designated the Ayurvedic U niversity at Jamnagar
as a WHO Collaborating Centre for the Indigenous Systems of Med icine. The Indian
Council for Med ical Research has also established a Task Force for study of antifertility plants.
In the epic of the Ramayana which was written around 350 B.C. a vivid
description has been provided to us of the use of medicinal plants. When Ram's
brother Lakshman was lying prostrate and unconscious on the battlefield Susena
asked Hanuman to go to the mountain s, Asadhiparvat and bring the four medicinal
plants - mrtasanjivani, visalyakarni, suvarnakarni and sondhani - so that he could be
revived. Hanuman proceeded to the mountain but could not identify the plants and
after some thought decided to carry the entire mountain down to the battlefield
where , Lakshman regained con sciousness after being administered one ofthe plants.
Research workers, in the field of herbal and med icinal pharmacology, face
today a predicament not dissimil ar to Hanuman when he found hirnself on the
plants, ifhe is open to folk-lore suggestions regarding herb s possessing medicinal and
contraceptive properties and if he pays attention to unsol icited adv ice about use of
such plants from all quarters fmds hirnselfso deluged with information that he too ,
like Hanuman , is at a loss where he should begin . Th is predicam ent is illu strated by
the fact that in India alone in the last 75 year s, 35 official committees and many more
ad hoc committe es have gone into the question of how best th is rich heritage should
be utiliz ed for the maximal benefit of the people. The Central Co uncils for Research
in the Ayur vedic ('folk' medicine) and the Una ni (' modern' med icine) systems of
medi cin e have both compiled lists of plants used for contraceptive purposes in their
science and the number comes to abo ut 200 .
Research over the past 25 years has convinced a large bod y of scientists that the
cla ssical approach towards discovery of a new contraceptive from plants is fraught
with constraints and uncertainties. This may indeed be one of the major rea son s for
the disappointing results obtained so far. It is being feit more and more that instead of
carrying out extraction and fractionization of plant extracts and then screening such
fractions in animal models the approach should be to administer the plant or extract,
reputed to have antifertility properties, to the human in as similar a fashion as it is
reportedl y being used and thus assess its efficac y in man .
Some of the factors which may have been responsible for the disappointing
achievements so far and also for the general confusion pre vailing in the field , due to
co nflicting results obtained, are discussed below.
post in different areas while the plant Aegle marmelos is known as abiviagam,
iyalbudi, kuvilam, mavilangai, villuvassin and vilvan in different parts of the
Variation in the quality 01pharmacologically active substances
The quantity of the alkaloid which may be responsible for the pharmacological and
therapeutic effect varies and is influenced by several known and many unknown
factors . The same plant at the same place may yield different amounts of alkaloids in
different years - which would certainly affect the results of the screening of these
plants. Weil known examples of plants exhibiting this characteristic are P.
somniferum, Datura stramonium and lpomea violacea. Again, the same plant grown
at different places may possess different quantitites of alkaloids in thc same year.
Typical examples of plants of this type are Cinchona, Rauwolfia serpentina and
lpecacuanha. Biswas (1955) has shown, for example, that the root ofR . serpentina in
the same year yielded 1.6% of the alkaloid when collected from the Kumani forest,
1.4% when collected from the Kanchollorri forest, 0.8% when collected locally and
student in our country has had bad moments when reporting to his supervisor totally
different results each time he tries to confirm his earlier results with a new batch of
plants. Another factor influencing results is the variability of the alkaloid according
to the maturity of the plant. The hyoscine: hyoscyamine ratio for example, of the
plant D. stramonium is 80:20 when the plant has not matured but only 30:70 after
lncrease or decrease in activity after extraction andfractionization
It has been c1early shown that after demonstration of initial ant ifertility activity of a
plant extract, further extraction and chromatographic fractionation may increase the
activity of one of the fractions or may cause a decrease in the activity of all the
fractions. This is an important observation since attempts to isolate the active
principle in a plant that falls into the latter category would be futile.
Work carried out in this laboratory has provided us with examples of plants
exhibiting both types ofbehaviour. Fractionation ofthe active extracts ofthe plants
Daucus carota, Sapindus trifoliatus and Polygonium hydropiper increased the
activity of one of the fractions (Garg, Mathur & Chaudhury, 1978). For example,
while the alcoholic extract of P. hydropiper prevented implantation in 60% of
animals at a dose of 200 mg kg-1 the petroleum ether fraction of the same alcoholic
extract prevented implantation in 80% of animals at half the dose. Again while
500 mg kg-1 of the alcoholic extract of D. carota prevented implantation in 66% of
animals, 50 mg kg! of the chloroforrn-methanol fraction of the same alcoholic
extract prevented implantation in 80% ofthe animals.
The results obtained with the alcoholic extract of the seeds of Butea monosperma
however demonstrated a different type ofactivity. While 100 mg kg-I ofthe alcoholic
extract inhibited implantation in all animals, the petroleum ether, benzene,
chloroform, acetone and methanol fractions did not demonstrate activity comparable
to that of the total alcoholic extract. This loss of activity has been observed by
pharmacologists working with plants not only in the field ofcontraception but also in
the field ofhypoglycaemic and anticancer plants. It appears essential for the different
alkaloids in the plant to work togcther to exert a pharmacological effect. It is
interesting but not surprising that adding all the fractions together and then
administering the total extract to the animal does not restore the original activity.
CLINICAL EVALUATION OF ANTIFERTILITY PLANTS 477
Loss ofbiological activity oft he plant
The traditional steps followed in research on plants consist of, a) identification ofthe
plant, b) collection, c) transport of the sampies to the research centre, d) drying,
e) chemical extraction and f)screening for biological activity in experimental
animals. (Chaudhury & Vohra, 1970). This is a far cry from the actual use ofa plant.
For example, the fresh juice pressed from the roots of the plant Plumbago rosea is
mixed with some alcohol distilled from the madhuka plant and taken for four
consecutive nights to induce early abortion, as is done by large segments of our
aboriginal population in certain parts of India. However, the early abortifacient
activity present in a mixture of fresh P. rosea juice and madhuka alcohol would not
be detected in animal screeni ng after the plant has gone through all the stages listed
above. At any or at more than one of the se steps the act ivity could be lost or
destroyed and ifthe activity is due to a combined effect ofthe juice and the madhuka
alcohol then that normally would not even be tested.
As a result of experience the scientists working in thi s field have considered the
alternative approach mentioned earlier. Here the clin ical evaluation of plants for
efficac y would be assessed after administration ofthe substance(s) in the manner it is
usually used. This approach ma y rule out many problems normally encountered as
So me concepts in the indigenous systems of medicine
Since man y of the plants would be clinically evaluated for antifertility activity
because of their widespread use in the traditional systems of medicine, it would be
important, when planning such tr ials, to be a ware ofat least a few ofthe concepts that
underlie use ofplants as contraceptive agents.
Administration of more than one plant at a time
In the indigenous systerns of medicine several plants may be added together and
administered but only a few ofthese plants would exert an antifertility effect. Others
would be there to counteract the side effects ofthe effective plants wh ile a few more
plants would be added to counteract the side effects ofthe second group ofplants.
Use of substances as catalytic agents
Some substances are very commonly used in preparations of indigenous medicines
ginger , molasses, honey, ghee and extract ofthe madhuka plant. Arecent experiment
carried out on rat s has shown that when the plant Embelia ribes was administered to
implantation in 70% ofthe animals. (Kurnari, personal communication).
Plants may be toxic and contain pharmaeologieally aetive substanees
It is no longer accepted that plants are innocuous by nature and would not induce
toxicity . Certain of the plants reportedl y used for contraceptive purposes like Abru s
preeatorius and Rieinis eommunis contain ph ytotoxins, while a third such plant,
Semeearpus anaeardium is a potent histamine liberating agent. Again plants may
themselves contain pharmacologically active sub stances. Mu sa paradisioea contains
5-hydroxytr yptamine, P. rosea, used for contraceptive purposes widel y in tribai
populations in lnd ia, conta ins arachidon ic acid while Mu cuna prurienes contains
Importance ofthe c1inical trial for plant antifertility substances
The place of the c1inical trial in the quest for an antifertility agent of plant origin is
unique because this trial may dernonstrate, for the first time, the antifertility effect of
the plant. This is quite different from a c1inical tr ial with a synthetic compound that
has alread y demonstrated contraceptive efficac y in several species of animals.
Ordinarily, a compound is c1inicall y evaluated when its chemical con stituents are
known, its pharmacod ynamics and pharmacokinetics have been worked out,
methods for standardization and measurement ofthe drug in plasma established and
the acute and subacute to xicological studies completed. The position as regards a
plant that is to undergo c1inicaI evaluation is quite different. Even though it ma y have
been used for contraceptive purposes for hundreds of years its characteristics would
not have been worked out - and even if they have been worked out in animals, the
results may not be strictly relevant. Controversy begins when the c1inical investigator
has to decide whether to adopt the widel y accepted criteria and guidelines for c1inical
Controversies in the c1inical evaluation ofplant antifertility substances
There are many different aspects of research in th is area that could generate
cliscussion. In thi s present at ion attention has been focussed on the ethics of carrying
out c1inical evaluation offertility relating plants. The four topics relating to thi s are :
a) Should animal toxicology studies be carried out before c1inicall y evaluating plants
for antifertility act ivity? If so - to what extent?
b) Should c1inicaI evaluation of these plants be carried out prior to standardization
ofthe substances in the plants?
c) Should c1inical evaluation for antifertility activity of plants be carried out in the
setting ofa hospital ofthe allopathic system ofmedicine (ASM)?
investigators var y. Some investigators feeI that plants must go through the rigorous
toxicity tests undergone by a synthetic cornpound, as the plant may be toxic. They
feel that it would be unethical to administer this to man without making certain that
the plant would not cause harm. Other investigators feel that it is totall y unnecessary
to carry out any toxicological studies with a plant that has been used by large
numbers of the population for hundreds of years and is also, at the ver y moment,
being administered to man by the practitioners of the ISM. National regulatory
agencies do not help the investigator, as the y deal , in countries where the ISM are in
use, onl y with drugs of the ASM . The Ind ian Council of Medical Research (1980)
states, 'the Council would suggest that for c1inical evaluation of plants being used in
the traditional systems of medicine the protocols for such c1inical research should be
approved by the ethical committee of an institute. There is no need for c1earance to
be obtained from the Drugs Controller of India for such trials of
products al ready in widespread use in the ISM today in the country'.
CLINICAL EVALUATION or ANTIFERTILITY PLANTS 479
There does appear to be an acceptance, to some degree , ofthe fact that widespread
use ofplant products for a prolonged period oftime does indicate to some extent that
the plants were not toxic as otherwise they would not still be in use. This type of
thinking is common in countries where plants are widely used for medicinal purposes
without preclinical toxicological studies. What is perhaps more surprising is the fact
that societies in the West with no tradition in the use of plants are also beginning to
accept this thinking. Three examples will be provided to support this . A herbai
product call Liv -52 (Himalaya Drug Company), consisting of eight plants, is widely
available in European countries. The product is supposed to 'protect the liver against
various hepatotoxins, corrects liver dysfunction and damage and promote appetite
and growth'. No toxicity studies have been carried out with the plants. Cystone
(Himalaya Drug Company) is another preparation, a mixture of plants, which is
supposed to dissolve kidney stones. Again, it is widely available and used in several
countries even though no toxicity studies have been carried out. Finally 80 million
dollars worth of ginseng is exported annually from Korea - a large proportion of
which fmds its way to the markets in the West. It is used in different ways - these have
not undergone any rigorous toxicity testing .
To try and evolve some rational guidelines for toxicological assessment of plants
that would ensure that the ethics of human clinical trials are not violated and yet not
stop attempts to evaluate plants, a modified toxicology schedule has been
developed. This includes the usual acute toxicology studies followed by a six week
subacute toxicity study where haematological tests, liver function and kidney
function is assessed at three dose levels before and at different intervals up to six
to two species but only by the route which would eventually be used. Plants
belonging to any ofthe categories below may be subjected to, a) complete toxicology,
b) modified limited toxicology as deseribed above, e) no toxieology. The eriteria
followed in the author's Iaboratory is given below .
Plants mentioned in the literature but not in use today
These plants would undergo complete toxieology since, in spite ofbeing mentioned
in the literature, they are not being used. This could imply either that the plants are
ineffective or toxie . The full range of toxicity studies need to be earried out before
Plants mentioned in the literature and in widespread use today
These plants would be subjected only to limited toxicology since it is believed that,
had the plant been toxic , it would not be still in widespread use. It is this category of
Plants not mentioned in literature but being used widely by practitioners oI/SM
It is feit that Iimited toxieologieal tests need to be earried out before clinieal trial.
Folk-lore tradition and use 01a plant in an isolated community
Since the plant has not been mentioned in the literature and is only being used in a
eommunity it would be important to earry out a full toxieology profile of the plant
Plants or plant extracts that have undergone pharmacological assessment in the
animal and demonstrated antifertility activity
There is general agreement that if a plant material has undergone an extraetion
proeedure then it should be eonsidered as a new produet and eomplete toxieologieal
studies need to be earried out before human trial.
These guidelines would appl y also for combinations ofplants which would then be
tested as a combination. It is felt by some investigators that a combination of carrot
seeds and jaggery, for example, mentioned in the literature throughout the ages and
still widely used for contraception, could be clinically evaluated without toxicity
studies in animals since it is already in widespread use. However, another group of
workers feel that a six week toxicity test would conform to ethical standards and yet
not hinder development of plant contraceptives.
Needfor more appropriate toxicological models
Newer more appropriate animal models need to be developed for toxicological
evaluation of different types of fertility regulating agents that are being developed
today. The toxicity studies required today are not totally relevant, for example, for
local use of prostaglandins as abortifacients, for contraceptive vaccines, implants,
tubal occluding agents or intranasally administered steroids, This is equally true for
plant antifertility agents. At the moment this department is planning a trial with two
plants. The first plant is ground to a powder and administered to postparturn
women for four consecutive nights to ensure irreversible sterility, The fresh juice of
the roots of the second plant is mixed with alcohol from the madhuka plant and,
when ingested, would induce early abortion. The animal toxicology studies required
for these plants are different from those classically followed.
for each plant to be clinically evaluated as needed. This has been very successfully
done by Landgren, Aedo, Hagenfeldt & Diczfalusy (1979) for the plant Montena
tom entosa used for early abortifacient activit y in Mexico, in the form of a tea.
Appropriate and adequate toxicity studies were carried out following development of
the toxicology profile after wh ich the plant was clinically evaluated.
Standardization procedures have not been established for most of the plants
in the search for antifertility plants. The criteria that has been established for
synthetic compounds, however, cannot be transposed for plants used for fertility
regulation for generations and still being uscd. The approach proposed is that
standardization procedures for the plant would be established after the plant has , in
early clinical trials, demonstrated effective fertility regulating activity. It would be
essential, however, before initiating the trial, to ensure that adequate plant material
from the same source, collected at the same time has been procured and stored under
uniform conditions and that this material is enough for the complete trial. Ifthe plant
demonstrates effective and significant antifertility activity then, at that time,
procedures would be established for markers that could be used for standardization of
the plant. Thereafter the plant would be used only after proper standardization
procedures vouch for the plant material that would be used.
Clinical trial ofplants in a 'modern ' hospitalsetting
A patient or a subject seeking advice on family planning or a woman requiring
abortion comes to a hospital or clinic of the ASM. How justifiable or ethical is it to
ask that person to take part in a clinical trial aimed at assessing the contraceptive
property of a herbai medicine? There can really be no one answer to this question.
The ethics of carrying out such trials would be determined by the attitudes of the
patients, doctors and society to the ISM , by the presence, or otherwise, ofthis system
in the country and by the confidence ofthe public and the Government in the seien-
CLINICAL EVA LUATION OF ANTIFERT ILITY PLA NTS 481
tists who would carry out th e tr ial. Na tura lly, the ethica l committ ee of the in stitute
author's institute clinical eva lua tio n of anti ferti lity plants would be ca rried out in a
sepa rate wa rd provided for these tr ial s. T he use oftrad itional med icine for over 2000
years in Ind ia , the incorpora tion ofthis system in the nat ional health poli cy. no twith -
standing, it ha s been a slow tra nsit ion towards acceptance of plant cl inical trials.
Preclin ical tox icology wo u ld need to be ca rried out, th e results of whi ch would be
considered by th e institute ethic s co mmittee. The same com mi ttee wo uld al so assess
the protocol for th e clinical tr ial and recommend whethe r the trial should be carri ed
out. The tri al at th e Karolinska Institute (La ndgren et al.. 197 9) demonstrates th at it
where there ma y be no tradition in the use of plants for medi cinal purposes.
Clinical trial 01'plants in an 'indigenous medicine ' hospital setting
It has often been suggested that in countries and hosp ital s where the ISM are being
used one approach to assess the antifertility properties of pl ants would be for
scientists and researchers to ob serve the use of such plants by pr actitioners of the
ISM. Res earchers, by careful and critica l observation, could come to a conclusion, at
lea st, as to whether a plant deser ves a further trial. A further step forward ha s been
the suggestion that the indigeno us practitioners adopt a protocol developed by
clinical investigators and administer the plant according to the protocol. The
ind igenous pr actitioner could make his obse rva tions wh ile th e researcher makes his.
The final step would be for th e indige no us practitioner and th e researcher to jointly
de velop a protocol and eva lua te th e plant in the setti ngs of an ay urv ed ic or un an i
ho sp ital or fa mily pl anning cl inic .
There is so me experien ce in th e use of this approach in a tri al where th e plan t
Mesua ferrea was used to treat menorrhagia . This was co nd uct ed at an ayurvedic
research centre joi nt ly by gynaecologists belon ging to both th e ASM and (SM
(Me harji, Shet ye, Munshi, Vaid ya, Antas kar, Koppi kar & Devi, 19 78). The
collaboration was be neficial a ltho ugh mutua l co nfidence , rapport and em pathy is
needed for suc h wor k. D ifTer ences in th e thi nking of the two types of in vestigat ors,
difficulties in agree me nt on pa rameters th at need to be defm ed , lack of agreeme nt
regard ing defmition s and terms, relu ctan ce on th e part ofthe ind igeno us practition er
to sa mpies being dra wn from his subjects, ina bi lit y of the cli nica l investigator to
int er ven e in th e trial ifreq ui red are some of the obsta cles th at have to be overco me . If
however th is ca n be ac hie ved, th en such direct observa tio ns on human s by a tra ined
inve stigato r co uld repl ace some of th e ex perime ntal animal toxicology required
tod ay witho ut any lowerin g of ethical standards.
In the pa st the world ofplants has provided us with drugs suc h as bell adona , dig italis,
th e cinchona alkaloids, reserpine, carbenoxolone and vincristine . It is possible that
with a shift in the approach fro m experimental screeni ng to clinic al evaluation,
plants may pr ovide us with so me une xpe cted surprises in th e field of co ntraception.
Biswas, K. (1955). Cultivation of Rauwolfia in West Bengal. Proceedings ofthe symposium on
Rau wolfia, October, 1955. C.S.I.R.
Chaudhury, R. R. & Vohra, S. B. (1970). Indigenous antifertility plants. In Advances in
Researchin Indian Medicine. Varanasi: Banaras Hindu University.
Garg, S. K., Mathur, V. S. & Chaudhury, R. R. (1978). Screening oflndian plants for antifertility
act ivity.lnd. J. exp. Bioi.. 16,1077.
Garg, S. K., Vohra, S. B. & Chaudhury, R. R. (1969). Investigations on Butea monosperma
(Lam) Kuntze.Ind. J. med. Res..57,1946.
Indian Council ofMedical Research (1980). Policy statement on ethical considerations involved
in researchon human subjects. New Delhi .
Landgren, B. M., Aedo , A. R., Hagenfeldt, K. & Diczfalusy, E. (1979). Clinical effects of orally
administered extracts of Montana tomentosa in early human pregnancy. Am. J. Obst.
Meharji , P. K., Shetye, T. A., Munshi, S. R., Vaidya ,R. A., Antaskar, D. A., Koppikar, S. &
Devi, P. K. (1978). Screening of Mesua Ferrea(Nagkesar) for estrogenic and progestational
activity in human and experimental models. Ind. J. exp. Bioi.. 16,932-933 .
Soejarto, D. D., Bingel, A. S., Slaytor, M. & Farnsworth, N. R. (1978). Fertility regulating agcnts
from plants. Bull. WHO, 56,343 .
Special Programme 0/ Research, Development
and Research Trainin g in Human Reproduction,
The World Health Organization Programme
Family planning is a relati vely new area ofhealth care all over the world . lts newness
and complexity have given rise to man y questions, some of which requ ire research ,
for instance on birth control technology, on motivation and psycho social factors, and
on service deli very. The Member States ofthe World Health Organization requested
the setti ng up , in 1972, of a 'Special Programme of Research, Development and
Research Training in Human Reproduction ' to address itselfto these questions . It is
essentiallya collaborative programme, directed primarily to the needs of developing
countries, and involving scientists from over 70 countries both developed and
developing (World Health Organization, 1979).
In thi s pap er, we will focus on two specific are as of activity in the Programme:
research on the safety and efTectiveness of current contraceptive methods and the
development of new birth control technology, and , within these two areas, on the
multicent re clin ical testing ofcurrent and new drugs.
Over 100 million women, or , if one includes China, over 150 million women in the
world are at pre sent employing contraceptive drugs or devices. These large figures
hide the fact that, in the developing world , excluding China, onl y 15% of married
women of reproducti ve age are at pre sent using famil y planning methods. We are
therefore tal king of a very large bod y of actual and potential con sumers, which
should command, by their very numbers, the attention of clinical pharmacologists.
But they merit attention for other reasons. Family planning methods, as distinct from
all other agents used to eure an illnes s, will be used mainly by healthy men or
women , over long periods oftime, and with little or no medical supervision. Unlike
other therap eutic agents, the y are intended to interfere with normal bod y processes.
Moreover, these being reproductive processes, the theoretical possibility exists of an
These requ irements have not , howe ver , extended to the testing of these drugs in
countries, given differences in basic health status, geneti c constitution, diet,
484 A. KESSLER & C. C. STANDLEY
reproduetive patterns and aecess to health eare. Moreover, some problems are
specific to developing countries, for instanee the effeets of eontraceptive drugs in the
presence ofehronic malnutrition or endemie parasitic diseases.
For these reasons, the WHO Programme has established a multinational network of
eentres in developed and developing eountries to assess the safety, effeetiveness and
ae eeptability of eurrent methods of fertility regulation and those developed by the
Programme or by other ageneies and industry. Through the network the aim is to
eonduet clinical and epidemiologieal studies under standardized eonditions using a
single protoeol. These 30 or more eentres have been seleeted to permit reeruitment of
Table 1 Main topics ofWHO multicentre international c1inicaltrials on birth control methods
I. Oral contraceptives- comparison 01different preparations
oestrogen-progestogen combin ations
'paper pill' v tablet combination
progestogen only vcombined preparations
Effects on lactation of progestogen only and a combination containing 30 ~g ethinyl
Effectson women with schistosomiasis
Effectson blood coagulation and lipoproteins
Phase III comparative studies of Lippes loop, copper devices and a progesterone releasing
device inserted post-partum, post-abortum and interval
Effect ofnon-steroidal anti-inflammatory agents on menstrual blood loss in lUD users
Phase 11 trial oflevonorgestrel releasing device
Phase II comparative trials of depot-medroxyprogesterone acetate (DMPA) and
norethisterone-oenanthate (NET-OEN)
Return ofovulation following DMPA and NET-OEN administration
Metabolism ofDMPA and NET-OEN in obese and thin women
Phase 11 trials ofmonthly injectables
Phase 11 trials oftubal occlusion with methyl-cyano-acrylate
Phase I trial ofvaginal rings releasing 10 levonorgestrel day"
Phase 11 trial ofvaginal rings releasing 20 uglevonorgestrel day"
6. Prostaglandinsfor term ination ofpregnancy
Phase 11 and 1Il trials of different PG analogues by vaginal suppositories or intramuscular
INT ERNATI ONA L T RIALS AND TRIBU LAT IONS 485
subjects over a relatively short period of time so that tr ials, whether they be Phase I,
Phase 11 or Phase 111 , can be expeditiously completed. For trials ofcurrent methods of
fertilit y regulation, a majority of develop ing country cent res are included; for studies
of new meth ods, the Programme involves equal nurnbers of centres from developing
and industri alized countries to obtain comparati ve da ta from the earl iest s tage of
drug development and to guard against any possible accusation of using subjects
from developing countries as experimental material.
About 25,000 women from Brazil , Canada , Ch ile, China, Colornbia, Cuba,
Egypt , Norway, Hungar y, India, Mexico, Nigeria, Pak istan , Philippines, Republic of
Kor ea, Singapore, Sweden , Th ailand, Tunisia, USSR, United Kingdom , United
Stat es of Am erica, Vietna m, Yugoslavia, and Zambia a re presentl y pa rticipat ing in
A larger number of women is involved in multicen tre epidemiologica l studies, on
topi cs such as the possible association of hormonal contraceptives and neoplasia,
intra-uterine devices and pelvic inflammatory disease, injectable contracept ives and
subsequent fert ility, and in field tria ls of methods new to a programme, for instance
Fundamentally, the organ izat ion and management of internationa l collaborative
trials differ littl e from those of comparable multicentre studies in one country. They
include the usual stages of writing the study protocol , select ing the participating
centres, standardizing terminology and procedures, laying the admi nistrati ve
groundwork for the study, recruiting and follo wing up subjects, monitoring,
terminat ing a study, processing data and analysing it, and report-writing . The
tribulation s ma y, however , be compounded by the multinational nat ure of the
Select ion of centres for a study will be more complicated than in anational study.
The approval of several drug regulatory authorities will be needed. Some study
requirements will eliminate a number of centres, for instance the stipulation that
abortion be available for cases of failure of a new contraceptive in a Ph ase 11 study.
The relu ctance of men in certa in cultures to masturbate for semen sampies will
eliminate some centres from particip at ing in tr ials ofbirth control methods for men .
Sim ilarl y, pharmacokinetic studies of contraceptiv e drugs for wome n are impossible
in cultures where repeated blood sampling is unacceptable. Appropriate laboratory
experti se and facilities mu st be availabl e, for instance for Phase land 11 studies, and
the Programme has usually had , in developing countries, to bu ild these up . Th is has
been a majo r effort , involving much staff time and man y millions of dollars, but
eminently worthwhile. It has provided developing countries with loca l facilit ies
Much more attention mu st be given, in a multinational study, to making sure that
all investigators understand the protocol, and that there are no hidden pitfall s in
terminology, such as different meanings atta ched to the same term. When forms are
tran slated into the local language , it is necessar y to ha ve them back-translated by an
independent translator to ensure correctness of the initial translation . We thus
discover that the Chinese for 'orgasm' is 'rocket to the moon', and that , in Malay,
there is no word for 'orgasm'. Ob taining agreement on cli nical procedures to be used
among investigators from different countries, whose medical educat ion has stemmed
fro m as diverse traditions as those of the UK, USA, USSR or France, can also
Th e Pro gramme requires the scientific and ethical clearance of all protocols by the
486 A. KESSLER & C. C. STANDLEY
partieipating institutions. This has demanded, in some eountries, a eonsiderable
etTortto eonvey the eoneepts ofthe Helsinki and Tokyo declarations, and has led the
Programme to help establish loeal ethies eommittees in a number ofinstitutions.
The logistieal problems ofproviding the eollaborating eentres with drugs, reagents
and forms are inevitably magnified by distanee and sometirnes by eustoms clearanee
difficulties . WHO has statT in nearly all developing eountries and a privileged
diplomatie status; this helps to overeome the eustoms problems.
Muneh's Third Law, whieh states that estimates of patients eligible for study in a
volunteering for clinieal trials . In some settings it may be neeessary to give a fmaneial
or material ineentive, partieularly for Phase I, pharmaeokinetie or metabolie studies.
This poses problems for the eentral reviewing body , whieh has to deeide whether or
not sueh incentives are ethical. It should be noted that men all the world over are very
reluctant to partieipate in trials of male fertility regulating agents and that, in their
case, the divisor in Munch's Law should be 20 rather than 10.
Geographie distanee is the major problem in monitoring multinational studies .
a single referenee laboratory, in the WHO multinational studies most analyses are
earried out loeally, but common reagents are provided to all centres, they use a
standard manual, and are mon itored through a tight quality control seherne.
trial to be fore-closed is built in to all studies. WHO 's intergovernmental status
avoids the problems eneountered in some multinational studies run by private
organizations , where loeal authorities have forbidden the sending of data or sampies
out of the eountry. There is inereasing reluetanee in developing eountries to have
data exported to developed eountry seientists, but this does not apply to WHO .
No matter how carefully instruetions are given for the filling-in of the pre-eoded
forrns, difficulties are bound to arise. For instanee, ingrained habits in the way the
figures land 7 are written are difficult to overeome, as is the use of dots or eommas
for separating the deeimals. The WHO data-proeessing statThave beeome skilled in
interpreting sueh centre idiosynerasies and have even overeome the problem of our
Hungarian eentre sending its eomments in Latin .
In analysing data from multinational studies , the ternptation may be to aseribe
ditTerenees in findings between cent res to ethnie variations when in faet other faetors
may be at work. For instanee, the mean age of the clinie population, or its mean
parity, may ditTer systematieally between eentres: in China, the lowest age ofwomen
will be 25 years, and the mean parity one , eompared with 16 years and mean parity
three or four in some other developing countries. There are, however , genuine ethnie
ditTerenees: mean weights may vary eonsiderably even among developing country
women : in one WHO study , the mean weight ofthe women in Alexandria was 67 kg,
as eompared to 41 kg in Manila. In areas with mixed populations, the ethnie
composition of the sampie may turn out to be surprising: in a Los Angeles eentre,
60% of the subjeets were reeent Mexiean immigrants; in some English eities, a
significant proportion of volunteers may be Pakistani or Jamaican; and there are
established multi-ethnic eommunities, sueh as in Singapore and Bangkok.
Authorship may pose a problem in large multieentre studies. Some journals baulk
at aeeepting a list of20 or more eo-authors, eaeh with a ditTerent institution, eity and
country. The principle of multiple co-authorship has beeome aeeepted by physies
journals and we ean only hope that this example will be followed by all medieal
INTERNATIONAL TRIALS AND TRIBULATIONS
Taken all in all, the tribulations mentioned above are minor compared to the very
positive results that have come out ofthese studies. It is not possible here to give even
an overview ofthem. All that can be done is to mention a few examples.
Rapid progress has been made, by using the multinational approach, in the
clinical evaluation of a prostagiandin vaginal suppository for termination offirst and
second trimester pregnancies. Data on 55 ,000 woman months of experience from
comparative studies ofthe standard (Lippes loop) and copper-releasing IUDs showed
the lauer to be preferable for national family planning programmes. Quantitative
measurement of blood loss associated with the Lippes loop and copper- and
progesterone-releasing IUDs have shown that the hormone-releasing types caused
the least menstrual blood loss , a matter of great importance for women from
developing countries where malnutrition is common. An lUD developed by the
Programme which releases 2 levonorgestrel day-I and with an expected life-span of
more than ten years is now at Phase II testing. The WHO tr ials with vaginal rings
have already been described by Professor Diczfalusy in the first paper ofthis section.
In the area of oral contraceptives, the hypothesis that 'natural' oestrogens might be
associated in combination pills with fewer side efTectsthan ethinyl oestradiol was not
The value of international trials can also be illustrated by a more detailed example
from a study ofthe use-efTectiveness oftwo injectable contraceptives, norethisterone
oenanthate (NET-OEN) and depot medroxyprogesterone acetate (DM PA) wh ich had
to be terminated prematurely because the pregnancy rate with NET-OEN exceeded
the previously specified allowable ma ximum. One of the papers (World Health
Organization, 1977) in which these results were published states: 'Thirteen out ofthe
24 pregnancies among NET-OEN users (54%) occurred in two centres, Bangkok and
Chandigarh, which only provided 19% of the total woman years of experience. It is
important, therefore, to ensure that the high pregnancy rates in Bangkok and
Chandigarh were not due to specific factors . .. . There were no pregnancies with
DMPA in Bangkok and Chandigarh, therefore false positive pregnancy tests cannot
account for the number of pregnancies observed with NET-OEN in these centres. A
careful an aly sis of relevant subject characteristics suc h as age, parity, body weight
and open birth interval failed to demonstrate an y systematic difTerences between
these two centres and the other six centres wh ich recorded lower pregnancy rates on
NET-OEN. Fu rthermore, there were no general factors common to both Bangkok
and Chandigarh, but wh ich difTerentiated these two centres from the others. For
instance, the women in Chandigarh and Bombay are ethnically more similar to one
another than to the women in Bangkok, but no excess ofpregnancies was observed in
Bombay. Thus ethnic factors cannot account for the atypically high pregnancy rates.
Similarly, Chandigarh serves a partly rural area whereas Bangkok ha s largely an
urban population. Therefore socio-economic factors are unlikely to be responsible
for this difTerence . Finally, it is noteworthy that the high number of pregnancies
Thus, since no systematic factors which might influence the risk of pregnancy
phenomenon is a common occurrence in large-scale trials. Indeed, this experience
illustrates one of the major ad vantages of multi-centre trials since if the study had
been undertaken in only one or two centres, chance efTects could have led to spur ious
results. Furthermore, the contrasts between centres allow one to undertake multiple
488 A. KESSLER & C. C. STANDLEY
comparisons of a variety of relevant factors so as to systematically rule out the
The da ta from this study showing that the NET-OEN pregnancies tended to occur
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