Document 176244

How To Do It
Organise a multicentre trial
Multicentre and single centre clinical trials share
methodological problems which are well known
(box). Multicentre trials do, however, have several
distinct advantages.They provide:
(o) larger sample size so that the result is more
precise, appropriate subgroup analysis is more
feasible, and there is a lower risk of an apparentIy
"negative" result when the treatrnent is, in truth,
(b) quicker results before peoplelose scientÍfic and
cornmercialinterest in the treatrnentand before it is
modjfied or the theoretical indications for it are
(c) wider disseminationof the results and, possibly,
more widesrread helief in their \'alidit\':
(d) standardiseddefinitions of diseaseand measurements of outcomeamongcentresand amongcountries
in intemationaltrials;
(e)a wider rangeof clinical and methodologicalskiIIs
to solveprotocol problems;
(f) usually a wider range of patients,facilitating the
generalisationof results, which can be broadlyapplied
to futUrepatients in othercentresand other countries;
(g)large negativetrials which are more likely to be
publishedthan small negativetrials. This is important
otherwisesmaIIpositive trials, which aremore likely to
besubmitted for publicationand probablymore likely
to be acceptedrather iban small negative trials, will
tend to dominatethe scientÍficliterature;
(h) less suspicion and rivalry among centres and
countries without necessarily suppressing healthy
(J)better nationaland intemational collaboration;
(k) facilitation of further multicentre trials of
potentially important treatrnents,provided that the
initial trial is not too demanding.
The difficulties of multicentre trials comparedwith
singlecentre trials mainly concemthe coordinationof
many people in severalcentres and even countries
(see box on next page). There are usually severa!
possible solutions, the best depending on circumstances,geography,number of centres,budget,and so
on. What follows is not meantto be anossifiedblueprint
but somesuggestions.Suggestions,moreover, which
have not beentestedin randomisedtrials but which, at
least,arebasedon someexperience.
Department of Clinical
Neurosciences, Westem
General Hospital,
Edinbürgh EH4 2XU
Charles Warlow,
professOT of medical neurolog:,'
Methodological issues common to both
single and muIticentre iríais
or non-randomised trealment
or open treatrnent allocalion and outcome
to treal or on-treatment analysis, or both
size and duration of follow up
entry and exclusion crileria
of data lO collect on randomised and
non-randomised but eligible patients
applicability of lrial results; what to do
about non-randomised but eligible patients
anaIysis and the Tole of an independent
data monitoring cornmittee
intensively to look for adverse effects of
intensively to monitor compliance
of data
.Sharing of original data with overview groups
looking at similar treatrnents (meta-analysis)
with sponsoring company, if any.
problems, visit centres,and ser up and supervise the
tría! office. This personwilI usua!Iy,but not always,be
a doctor, presumablywhoever wanted to ser up the
tria! in the first place,who is going to be in the samejob
long enough to see the trial through to the end.
Medica!Iyqualified principal investigators must t~. to
enter their own patients into the trial to maintain
credibility and to experienceand share the practical
problems with the other coIlaborators.
Writing tbe protocol
This is a job for one person, usually the principal
investigator, and not a cornmittee. Of course, that
person will need comments and advice from all the
centres,tbe trial statistician,and outside expens in the
field, andthis mayall require one or more collaborators'
meetings and often several versions of the protocol
before everyoneis satisfied. Becausethere is no rule
againstmodifying a protocol if unforeseenproblems
ariseduring the trial (provided suchmodifications are
A multicentre trial must havean identifiable leader sensibleand not data dependent)there is no reason
or principal investigator, who should be able to to delay writing it and getting staned while some
cornmand the respect of collaborators and have centresfinally make up their minds whether to ;oin in.
the time and energy to keep the whole enterprise Indeed, it mar be desirable to involve more centres
under control. He or she must not lose interest in once the trial is underway and some of the teething
the dull bit betweengetting staned and getting the problems soned out, although the more centres that
results. Running a trial by cornmitteeis disastrous.A areconcernedfrom the very stan the better. It doesnot
prestigiouschairpersonof asteeringcornmitteemay be always hold, however, that centres concerned in
a "political" advantageor evena necessity,but such a writing the protocol are more likely to súck to it than
personis unlikely to ron the trial on a dayto daybasis. centres ioining later and having to accept ir. In
Someone mus¡ get the funding, gather together international trials the protocol mar have to be
centres, run meetings, answer questions, solve translated into several languages, which can be
20 JA~1:ARY 1990
surprisinglvexpensive. Fonunately, if it is \\Titten in
English translation is now hardly necessary, at ¡eastnot
in Western Europe, which is a huge advantage to us
in Great Britain and a great credit to OUT medical
colleagues on the continent.
Finding the centres
Having accepted that a multicentre rather than a
single centre trial is scientifically necessaryto solve a
particular treatment problem, friends and colleagues
from a fe\\"centres usually get together to discuss a
protocoloFrom there, other friends and colleaguesare
brought in from centre to centre and from country to
country unúl enoughcentres are found to saúsfythe
sample size requirements in a reasonableperiod of
time. After about three years recrwtment gets tedious
and may fall off, but follow up is usually less Úffie
consuming and may need to continue much longer,
depending on the treatment. Key people in a country
are often very successful in recruiúng their own
compatriots,far more so than an outsider. Advertising
in medicaljournalsand through specialistorganisations
Pharmaceutical companies may, through their
naúonal and internaúonal networks, approach
numerous potential collaborators simultaneously.
Howeverthe centresare found, they must be seriously
interested and reasonablycompetent in the field but
not necessarilyspecialists.In any eventspecialistsmay
already be involved in their own compeúng studies;
relaúve non-specialistsin district generalhospitals or
generalpracúcemay be extremely keento collaborate
-and make very effecúve collaborators. Usually they
have more patients than teaching hospitals; they may
haveno other wayto take pan in medical research,and
to be involved with specialists in the field who are
organising the trial is often educative. But whoever
the collaboratorsare, they are all equal when it comes
to recruiúng patients, and it is theír trial not the
principal invesúgators' whose role is organisaúonal
and catal~"tic:there should beno "star billing."
Randomísation must be centralised and is best done
by telephone or perhaps by a coroputer link to some
central point which may be the triaJ office or, if 24 hour
cover is required, a hospital ward or switch board. This
is the only way for the triaJ organisers to have an
irnmediate binding record of who has been randornised,
when. and froro which centre. Sealed envelopes or
locaJly held randoroisation lists are simply not good
Issues that may
difficulties in
multicentre trials
.Wriúng tbe protocol
.Finding the centres
.Patient registration
.FoUow up
.Trial coordinator
.Trial office
.Visiting tbe centres
.CoUaborators' meetings
.Quality control¡
Writing th.: papers.
Superfluous data must not be collccted and nor should
"add on" studies be permitted without adequate
human and financial resources. Indeed, all the
collaborators must have a very clear idea of the aim oi
the trial and concentrate on that. Nevertheless. it
may be possible for a few particularly interested
collaborators to collect more data than the others, but
this should be optional and certainly not to the
detriment of paúent recruitment or answering the
basic trial quesúon.
FoUow up
Follow up must :lIso be simple and require liule
more Iban what would be done in routine clinical
practice. ObviousJy, the outcome must be recorded
and measuredbut tbis may not require leng¡hy follow
up, and sometirnesit can be obtained from routinely
collected data (such as death certificates, cancer
registries)thus disposing with the need for follow up
at all. Some follow up might be more simply, and
even more accurately, obtained by telephoning the
patient rather Iban by contacting the patient's doctor.
Overelaboraterecording of and testing for compliance
should be avoided as should unnecessaryblood tests.
Too frequent and too detailed folIo\\" up may add very
litde to the statistical power and may kill recruitment
in a multicentre trial once trial patients and collaboratorsrealisewhat they have 1ft themselvesin for.
Wriuen forms should be no longer Iban one side of
A4 paper; if they are they probably will not be
completed fully or reliably. In any event trials should
not interfere with routine clinical practice.
Trial coordinator
This is the key person even if the tria! is not large
enough to merit a full ÚIne appointment. The job is
administrative, not medical. She, for it is seldom he,
stands at the centre of the tríal and must be commined,
energetic, sensible, well organised, have some
knowledge of computing, and be able to work flexible
hours. T o collect the data, organise them, and transmit
them to the statistician she must be meticulous
and even obsessiona!, but she must algo be good
with people so that she can ron the trial office and
maintain harmonious relationships with the distant
collaborators. She must be adroit at dealing with
the awkward (and some doctors can be remarkably
awkward) and flexible and energetic enough so rhat she
can hop on and off trains and planes and pUl up with a
certain amount of discomfort as she travels from centre
to centre extracting data from iorgetful coliaborarors,
encouraging them ro randomise more patients, and
generally nurruríng
while still
retaining a sense of humour.
Patient registration
If large numbers are required and the budget is
limited patient registration must be simple, practical,
The trial office,organisedand supervisedby the trial
and quick. Collaborators should have to do little more
coordinator, has the task of collecting, checking,
than what is normally required in routine c\inical
and entering the data from the distant centres and
practice. Patients must be identified (name, sex, date
requestingmore informaríanif (hereareinconsistencies
of birth), data on a few important prognostic variables
or omissions.The office must supply (hecollaborators
collected, and possible prespecified subgroups
with all the necessarydocumentarían(entry and follow
identified. It is often feasible to collect a11or some of
these data on the telephone before treatment a11ocation up forms, freepost envelopes,sticky labels, etc), and
possibly even (he trial medication, dispatch regular
is made so obviating the need to complete, post, check,
newsletters and listings on missing data, listings of
code, and punch data entry forms. It also means
when patients are due for their next follo~' up, and
that me treatment a11ocationis not made unless and
answerquestions from (he many centres. The office
until the entrv data are recorded centrallv. Another
must be available, friendly, helpful, knowledgeable,
advantage is that data recorded bejore randomisation
reliable, and efficient, perhaps in more (han one
are unbiased with respect to any knowledge of
languagefor internacionaltrials; al(houghdoctorsmay
treatment a11ocation.Computer networks which do the
speakexcellentEnglish, the samedoesno! necessarily
samething are another possibility but more expensive.
20 jANUARY 1990
apply to their hospital telephonists. The collaborators
must seethe office as a "black box" into which data go
in and out of which informaúon comes. Any strife,
inefficiency, or chaos should remain hidden. Such an
office needs to be clase to the principal investigator
and, if possible, to the staúsúcian, although with the
avaiJability of modero high speed computer links this
mar not be so imponant now. The office requires
secretarial and clerical staff, a telephone and answering
machine independent of a busy hospital or university
switch board, a facsirnile machine (Fax), a photocopier,
several rnicrocomputers,printers, filing cabinets, and
adequate storage space. It must have enough resources
to do its job properly and take as much as possible
of the burden of the trial organisaúon from the
collaborators. The resources required will gradually
increase through the recruitment period after which
they will stabilise but probably not decline.
Visiting the centres
This is time consuming and expensive but must be
done, often regularly, for the following reasons: to
discuss any local problems arising from understanding
and implementing the protocol; encourage recruitment
to the trial and so]ve problems relating ro rhis; collect
outstanding data, although wíth advance warning
these usually appear in the trial office shortly before the
visit; discover neighbouring centres interested in
joining the tríal; reiriforce the role of each centre,
without which the tríal would faíl; and keep everyone
informed of what is goíng on in the trial as a whole. The
meeting must be arranged well in advance because it is
importanr to ger all the local collaborators around a
rabie. But the vísít need not last long, perhaps an hour
or so. Remember, the local collaborators are busy and
the trial is unlikely to be their majar preoccupation
or priority. Who does the visits depends on the
circumstances; the trial coordinaror is usually the best
person to collect data and the principal investigator
best at sorting out scientific and medical problems, but
a regional coordinator can be helpful if the centres are
widely dispersed. Whoever ít ís must not waste time;
often several centres can be visited in a day and
work can be done on trains. Trains with sleeping
compartments perrnit an early start to the day. A voíd
visíts during the surnmer when collaborators are on
holiday and the trains are full of additional passengers,
and avoid the depths of winter when snow and fog
dislocate transporto Don't carry too much wíth you but
take enough to read in case you gel delayed; take train
and 'plane timetables and be prepared to change your
plans; sort out how to get money quickly in foreign
countries; and make sure the trial office and your
farnily know your whereabouts.
etc. Funhermore, it may be scientificalIy attractive
(and indeed cornmercialIy attractive if registration
fees and sponsorshipare fonhcoming) to organise a
symposiumor educacionalmeeting alongside the trial
Quality control
In a single centre trial it is imponant that the trial
treatment is properly described, well delivered, and
any complications fairly assessed. This is even more
imponant in multicentre trials, when there are cenain
to be differences among centres, both real and due to
chanceo Even drug treatment may differ among centres
because of different storage conditions or possibly
circumstances of delivering it to the patients. But of
more concem is variation among centres in other
non-drug treatments being evaluated such as surgef)",
speech therapy, psychotherapy, etc. Obviously all the
centres must agree to standardise more or less such
treatments so that about the same amount is given
for about the same time and that it is reasonably
uniformo Such non-drug treatments, however, will
never be exactly the same in all centres and it is
counterproductive to insist that they are; as long as
they are roughly similar no problem.; \vill ari.;e and the
trial result will be applicable to other centres giving
roughly, but never exactly, the same treatment.
Monitoring uniformity of treatment is difficult but at
least it helps to monitor any irnmediate complications,
such as postoperative morbidity, and to have regular
meetings of the collaborators. If a centre is perfonning
badly (inadequate treatment, excessive complications,
not enough patients to ensure competence, etc) then it
should stop randornising patients, but not, of course,
stop following up those already randornised. Clinically
sensible cointerventions, such as drug regimens
adrninistered during a trial of a surgical procedure, do
not have to be exactly the same in each centre because
randornisation (stratified by centre if necessaf)') will
ensure that they are used in the same proponion of
"treated" and "control" patients across the trial
Mulúcentre trials are expensive but they need
not be prorubiúvelyso provided that collaborators are
reasonableand do not attempt to re-equip their entire
departmentand undertake major non-trial projects at
the expenseof a sponsoringpharmaceuúcalcompany.
lndeed, from the point of view of unit cost per
paúent randomised or per patient year of follow up
multicentre trials should be cheaperthan single centre
trials as they gajo from economies of scale. But, of
course, the trial office and collaborators' meetings
must be properly funded and the collaborators
Collaborators' meetings
themselvesreimbursed for any extra work (wruch is
Collaborators' meetings are needed to write, very linle in a well designed trial) over and above
and if necessary,rewrite the protocol; to discuss rouúne clinical practice. There are various ways of
diseasedefinÍtions, measurememsof outcome, and doing trus: a lump sum per patient randomised; a sum
documemation; to discuss any imerim results; per completedata form received by the trial office;-a
to encouragetreatmem; to plan new trials; and to formula basedon the number of patients randomised
encourage a group identity and common purpose. to support a researchnurse, etc. Whatever is done the
They are, however, time consuming to attend, collaboratorsshould be paid only for extra work done
extremelytime consumingto organise.and expensive. and not work that they saythey will do. In many rrials.
however, it is difficult to obtain proper funding; trus
They should therefore be frequem enough to fulfil
their purposebut not so frequem asto be prohibitively applies particularly to treatments from which no
profits are to be made-for example, non-patented
expensive. It mar be sensible-or evenessemial-to
organiseregionalor national collaborators'meetingsif drugs, surger:-',physiotherapy-so that it is totall:
thereare alarge number of widelydispersedcentres. It inappropriate for trial funding to be left entirel~'to the
mar alsobe possibleto link trial meetingsto othersthat pharmaceutical industry. Although a sponsoring
collaboratorsare likely to be going to an~"Way.
suchas compan~'must nor be concernedin either data analysis
national specialist societies. imernational meetings. or publicarion. it canbe extremely helpful in collecting
VOLl"."iE 300
20 JA~LARY 1990
baseline (but 7101outcome) data, maintaining trial
discipline, and encouraging recruitment through
its own networks of medical representatives and
researchers. Whatever the cost of a trial, it should
be compared \\.ith the casI of the disease being
treated and, perhaps. against the casI of non-medical
endeavours such as 10\\. altitude military aircraft
training or unemployment benefit. By any such
comparisons multicentre trials are usuallv extremelv
inexpensive and may lead to the rejection ~f expensiv~
but inetTective treatments-for
example, extracranial
to intracranial bypass surgef). for the prevention of
not al\\.ays to the introduction of more
expensive health careo
Writing the papers
Like the protocol, tbis is a job for the principal
invesugator, not a committee. Naturally, it will be
necessaryto have many discussions with the tríal
statistician and trial coordinator and commentsand
advicefrom all the collaboratorsasnumerousdrafts are
produced. It is crucial, however, that in the end aJIthe
results are published under the name of all the
collaborators;without them there would have beenno
trial at all, and they did the work. Although current1y
unfashionablein somequarters, the whole philosophy
underlying multicentre trials is that group effort takes
precedenceover individual effort; only by acting as a
group can the individuals get answersto therapeutic
questions which affect their own individual pauents.
Of course,any centrecan publish its own results but
there must be no "star billing" for author:; ",'hen the
results ofthe whole trial are presented.
Betore starting a multicentre trial the foIlowing
questions must be answered affirmatively: Is the
therapeutic question really important, preferablyeven
a burning issue?Are you sure there is no better way of
answering ir? Can you gel enough centres together?
Are you likely to gel the resources?Have you gol the
time?Do you reaIly want to do ir? If so, thengo ahead,
but first visit one or two successfulmulticentre trial
organisationswhich will give you far more idea of the
problemsand pleasuresiban I havebeenableto within
the contextofthis article. Remember,only fools faíl to
learo from others' mistakes.And once you gel started,
always keep thinking about how the tríal can be done
more efficiently and effectively, lessexpensively,more
quickIy with a greater recruitment cateand with less
extra work being done by the coIlaborators. At the
same time remember that esprit-de-corps is what
countsmore thananything else: look afterir.
1 thank other devoteesof multicentre trials with whom 1
haveworked and who commentedon the manuscript (Livia
Candelise,David Chadwick, Rory Collins, BarbaraFarrell,
Jan van Gijn, Adrian Grant, Peter Sandercock,and Brenda
Smith), and also Richard Peto, who persuadedme and other
c1inicians,that really large sample sizesare crucial to make
any senseof treatrnents which have modest yet clinically
imponant benefits. But it is 1 who take the blame for alI the
opinionsexpressedin the anicle.
Fibromuscular dysplasia of renal arteries: a neglected cause of
acote loin pain
Simon Stinchcombe, Adrian R Manhire, Michael C Bishop, Roger H S Gregson
An arteriallesioD sbould i
be suspected in patients i
witb acute loÍD pain if
there is no evidence of
ureteric ot-struc!;o" O"
Department of Radiology,
Queen's Medical Centre,
Simon J Stinchcombe,BM,
senior registrar
Roger H S Gregson,FRCR,
Departmeots of Radiology
aod Urology, City
Hospital, Nottingham NGS
Adríao R Manhire, FRCR,
MichaelC Bíshop, FRCS,
Corres¡:x>ndence10: Dr
Sr ,\led] 1~,300
Fibromuscular dysplasia of the renal arteries is usually
associated with hypertension, but occasionally it may
presem with acute loin pain due to occlusion of the
renal arteries or embolisation of small peripheral
vessels. The preseming symptoms may then be
inuIslmguIsnaDie lrum a":Ull: ..:a!..:uiuusubstru..:uun ur
acute pyelonephriús. Early diagnosis of arterial occlusion is essemial to prevem permanem damage to the
urine gavenegativeresults. On intravenousurography
the right kidney was thought to be non-functioning.
On ultrasonographythe size of the kidney was nonnal
with no dilatation of the pelvicalicealsystem.Ureteric
obstruction due to a radiolucent calculus was diagnu~eJ,anJ he \\.a~lrealeJ cun~er\"al1\"e¡y.
The next day he developed a temperatureof 38°C,
and despite 24 hour treatment with intravenous antibiotics he did not improve. A right retrograde pyelokidney.
We report on three young previously fit patients who
gram was nonnal, but a -Tc diethylenetriaminepresemed with acute loin pain, in whom renal infarcúon
penta-acetate(-Tc DTPA) renogram showed that
occurred in relation to fibromuscular dysplasia of the there was no perfusion of the right kidney. Renal
renal arteries. We also discuss how paúems with loin
angiographyshowed that the right renal artery was
pain should be investigated so that arterial occlusion
completelyoccludedby thrombus 3 cm from its origin;
can be diagnosed early.
there \\'assomeirregularity of the wall of the left main
renal artery, and two stenoseswere seenin one of the
segmentalvessels.The findings \\.ereconsistentwith a
diagnosisof fibromuscular dysplasia.Despite the five
A 33 year old man was admitted with a four hour day interval after the onset of symptomswe anempted
bistory of acute right testicularpaÍn. Testicular torsion to revascularisethe kidney with intra-arterial strepwas diagnosedinitially, but an exploratory operation tokinase 5000units/hour. The thrombus in the right
disclosedno abnormality. Two daysafter admissionhe main renal artery was dissolved, disclosing a 75%
wasstill in pain, wbich had movedto the right loin, and stricture, which wastreated \\"ith balloonangíoplasty.
he developed frank haematuria. lnvestigations dis- Unfortunately pericathéter thrombus fonned, which
closedaraisedwhitecell count (20.7x 10./1)but normal embolised distally, and peripheral perfusion to the
plasmaureaandelectolyteconcentrations.¡\1.icroscopic kidnev could not be restored. The patient was given
examinationof the urine showedincreasednumbersof long íenn anticoagulant treatment and discharged.
red and wbite cells and granular casts.Culture of bis Detailed investigation subsequentlyfailed to disclose
20 jANUARY 1990