Clinical research and trials in developing countries

STATISTICS IN MEDICINEStatist. Med. 2002; 21:2859–2867 (DOI: 10.1002/sim.1290)

Clinical research and trials in developing countries

Salim Yusuf∗

McMaster University; Hamilton; Ontario; Canada

SUMMARY

Over 80 per cent of the global disease burden occurs in developing countries. Yet the proportion ofresearch conducted in these countries is less than 10 per cent of the global research activity. This articleemphasizes the need to conduct research in developing countries on locally relevant questions, providesgeneral principles that may assist in establishing such studies, and describes some experiences in thecardiovascular area. Copyright ? 2002 John Wiley & Sons, Ltd.

KEY WORDS: clinical trials; clinical research; developing countries

INTRODUCTION

Over the past 50 years clinical trials and epidemiologic studies have contributed greatly to ouradvancement of knowledge in relation to the causes of diseases, their prevention and treatment.During the 1960s and 1970s, most epidemiologic studies and trials were conducted in singlecentres or among populations that were geographically segregated (for example, workers in afactory or company, inhabitants of a town or members of a speci�c profession). However, inthe 1980s onwards, trials and epidemiologic studies involved multiple centres or sites initiallywithin a country, and later in several countries. Two factors provided special impetus for theinternationalization of randomized trials. First, it was increasingly recognized that trials hadto be very much larger than those being conducted at that time and one practical way wasto involve a large number of centres in several countries. Second, with the simpli�cation ofstudy protocols, it became more practical to conduct multi-centre international trials. Withbetter communications (telephone, faxes, e-mail, electronic data transfer) the infrastructure toconduct such studies were increasingly developed. The �eld of cardiovascular trials played aleading role in their developments with the establishment of the ISIS (International Studies ofInfarct Survival) series of trials involving some dozens of countries and several hundreds ofhospitals utilizing ultra-simple protocols [1]. This approach was rapidly extended from shortterm trials to long term trials, not only in cardiology, but also in other disciplines.These initial approaches were still largely con�ned to North America and Western Europe

and it was only around the mid-1980s that trials in the cardiovascular �eld were expanded toinclude Eastern Europe or South America.

∗ Correspondence to: Salim Yusuf, Canadian Cardiovascular Collaboration Project O�ce, Hamilton General Hospital,237 Barton Street East, Hamilton, ON L8L 2X2, Canada.

Copyright ? 2002 John Wiley & Sons, Ltd.

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One of the �rst networks to conduct trials in South America was the EMERAS groupspearheaded by Dr Ernesto Paolasso and Dr Rafael Diaz from Argentina [2]. Similar e�ortsat conducting trials and epidemiologic studies have occurred in China [3] and to a lesserextent in India [4].

DEVELOPMENT OF TRIALS IN SOUTH AMERICA

In 1986, at a meeting in Buenos Aires I was approached by Dr Ernesto Paolasso about thepossibility of developing similar trials of thrombolytic therapy in Argentina. Over the sub-sequent 6 to 9 months, Dr Paolasso and his colleague Dr Diaz (neither of whom had anyresearch training, but made up for this with substantial enthusiasm, hard work and a will-ingness to learn) developed the EMERAS (Estudio Multicentrico Estreptoquinisa Republicasde Americ de Sur) protocol with help from me and colleagues from Oxford (Rory Collinsand Richard Peto). The study was modelled along the lines of the ISIS-2 study [5], whichwas ongoing and was supported by a modest grant from Behringwerke (a former subsidiaryof Hoechst, which through numerous mergers is now part of Aventis). A large number ofArgentinean investigators (116 hospitals), Brazilian centres (82 hospitals, under the leadershipof Dr Leopoldo Piegas), Uruguayan centres (9 hospitals), Venezuelan centres (11 hospitals),Chilean centres (15 hospitals) and Paraguayan centres (3 hospitals) collaborated to randomizeabout 4000 patients. The study was of su�ciently high quality (99 per cent complete data) towarrant publication in the Lancet [2]. The key elements for success were the commitment ofinvestigators to address an important question, inspiring and sel�ess leadership and a sense ofenthusiasm. Assistance from the Clinical Trials Service Unit at Oxford, coupled with a verysimple study (one page of data=patient) facilitated the successful completion of this study.Since the EMERAS study, the group has transformed itself into the ECLA (Estudios Cardi-

ologicos Latino America) group and has involved ¿200 hospitals in several Latin Americancountries. ECLA has developed its own capabilities for data management and now have a ca-pable sta� to run studies with little assistance from other countries or investigators. ECLA hasparticipated in several international trials (ISIS-3 [6], ISIS-4 [7], other trials of thrombolytictherapies, trials of unstable angina, for example, OASIS [8], CURE [9] etc. and notably inHOPE which required the long term follow-up of patients for about 5 years) [10]. Participa-tion in these international trials has provided the group with an opportunity to collaborate withother leading groups worldwide, and understand and incorporate the principles of evidencebased medicine in their scienti�c dialogue.However, the most notable developments are the independent and original studies initiated

by members of this group or other investigators in South America. They include the ECLAunstable angina registry [11], ECLA studies of glucose insulin potassium in AMI [12] and twolarge case-control studies of risk factors for AMI (co-ordinated by Mario Ciruzzi in Argentina[13] and a second study co-ordinated by Leopoldo Piegas and Alvaro Avezum in Brasil) [14].

EPIDEMIOLOGIC STUDIES AND TRIALS IN CHINA

Chinese investigators (in collaboration with Western scientists) have been active in estab-lishing a number of epidemiologic studies examining the relationship of blood pressure to

Copyright ? 2002 John Wiley & Sons, Ltd. Statist. Med. 2002; 21:2859–2867

CLINICAL RESEARCH AND TRIALS IN DEVELOPING COUNTRIES 2861

cardiovascular diseases, notably strokes (many of these studies are represented in the East-ern BP Collaborative studies) [15]. Large randomized trials are also being conducted. Theseinclude trials of BP lowering with calcium blockers (alternate, allocation), post-stroke withdiuretics (PATS of 5600 patients) [16], acute MI (CCS-1 with Captopril of 14 000 patients[3], and the just initiated CCS-2 study evaluating beta blockers and clopidogrel), acute stroke(20 000 patients evaluating aspirin and=or heparin) [17]. Centres in China are also participatingin major international studies (for example, PROGRESS involving 6000 patients with cere-brovascular disease [18], and the CREATE study evaluating glucose-insulin-potassium [GIK]and=or low molecular weight heparin [LMWH]) [19]. In addition to these cardiovascular trials,large trials of cancer prevention have been completed.

EPIDEMIOLOGIC STUDIES AND RANDOMIZED TRIALS IN INDIA

Although India represents one-sixth of the world’s population, clinical research remains rela-tively underdeveloped. Several investigators have established single-centre trials or epidemio-logic studies in one region. Most of the latter studies have been cross-sectional or prevalencestudies and there are practically no long term cohort studies. In the last few years, some in-vestigators have established case-control studies evaluating risk factors for AMI [4], initiallya single centre such as the study by Pais et al. of 300 cases and 300 controls, which hasthen spawned a national study in �ve centres funded by the Indian Council for Medical Re-search. This study is expected to involve 1200 cases and 2400 controls. Several medium sizedpopulation-based studies examining the prevalence of risk factors in urban and rural popu-lations have been conducted [20]. A remarkably large cohort study involving about 100 000subjects evaluating the impact of tobacco use on a variety of causes of mortality is cur-rently under way in Bombay [21]. Large trials of supplementation of vitamin A in childrenin Madurai, Tamil Nadu, were conducted in conjunction with the U.S. National Eye Institute(demonstrating a 50 per cent reduction in mortality) [22]. A large multi-centre survey forS. pneumoniae was recently completed in South India by the Invasive Bacterial InfectionSurveillance Group [23] and indicated that this organism was responsible for a substantialproportion of hospital cases of meningitis, pneumonia, septicaemia and peritonitis. Some multi-centre studies have documented practice patterns for AMI and unstable angina. A network ofabout 100 hospitals are collaborating in evaluating GIK and LMWH in acute MI as part ofthe CREATE Study (10000 patients expected from India and a similar number from China).In both countries, the capacity to co-ordinate large studies and manage data either exists oris being developed.

SPECIAL CHALLENGES OF CONDUCTING RANDOMIZED TRIALS ANDEPIDEMIOLOGIC STUDIES IN DEVELOPING COUNTRIES

The above experiences in three regions (not all generally considered to be ‘developed’ coun-tries) are only partially illustrative of the types of studies conducted in these countries. Thislist is by no means complete and there have been several studies in other developing countriesof vitamin supplementation, vaccines etc. The currently available experiences provide some


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guidelines to conducting trials in developing countries and overcoming some of the specialchallenges.

WHY ARE RANDOMIZED TRIALS NEEDED IN DEVELOPING COUNTRIES?

A super�cial point of view might suggest that one should primarily continue to conduct trialsin developed countries, since there is a strong tradition for research and the infrastructure andnetworks to conduct such studies exist. The results of such trials could then be extrapolatedto the developing countries. There are several reasons why such a view is not tenable:

(i) Over 80 per cent of the global burden of all diseases (for example, measured as disabilityadjusted life years (DALY) lost) occurs in developing countries [24].

(ii) The diseases that contribute the most to DALYs lost in several developing countries (forexample, infectious diseases or childhood diseases) di�er substantially compared to thedeveloped countries (for example, mostly chronic diseases in older individuals) [25].

(iii) Even when the same disease occurs in both developed and developing countries, di�er-ences in environmental factors (for example, di�erences in nutrition level, socio-economicstatus and access to care) creates special circumstances, so that results obtained in de-veloped countries are not necessarily applicable to developing countries.

(iv) There may be di�erences between individuals of di�erent ethnic backgrounds in theway drugs are metabolized or di�erences in the response to drugs (for example, ACE-inhibitors di�er in their hypotensive e�ects in African Americans and those of Europeandescent) or their side-e�ects may occasionally vary (for example, angioneurotic oedemais more common among African Americans) [26].

(v) Many treatments that are a�ordable in developed countries are beyond the reach of alarge number of individuals in developing countries. Hence there is a clear medical needto conduct trials of relevant preventive and treatment strategies targeting diseases thatare common in developing countries.

In addition to conducting trials to evaluate treatments, the individuals who are involved in trialsalso become familiar with the principles of clinical research methodologies. This stimulatescritical thinking and creates a group of clinicians who are more likely to practice evidence-based medicine. Such an approach will gradually gather momentum and will have an impacton a much broader group of physicians and health care workers than those directly involvedin the trials. Over a period of time, these approaches will be incorporated into the curriculumof both undergraduate and postgraduate medical education.

SPECIAL CHALLENGES IN CONDUCTING TRIALS IN DEVELOPING COUNTRIES

Asking an important and relevant question

A question may arise from any one of multiple sources. It may arise from a perceivedneed that could a�ect national policy (for example, a potentially important public healthrecommendation that has no clear proof), investigator interest, or from a funding agency (either



a government agency, charitable organization or a pharmaceutical company). The questionwould generally re�ect the interests of the parties proposing the study. Sometimes the motivesare altruistic, at other times purely commercial but often both. An extreme example occurswhen a pharmaceutical company tries to evaluate a treatment in a developing country, butthis would be considered to be unethical or impractical, in the context of the developedcountry. Alternatively, expensive or complex treatments that are likely to be e�ective, butare potentially una�ordable in developing countries, are evaluated in such countries in orderto save money for the sponsors of a study. In general, the motives and questions addressedusually re�ect multiple interests. The ideal question would be one that is locally relevant,applicable to a signi�cant proportion of individuals with the condition in the country and theresults would be accepted and applied rapidly, not only in the particular country where thetrial was done, but also in other similar countries.

Local factors a�ecting feasibility

1. Prior to commencing a study, it is crucial that the research team wins the support andtrust of the local community. In particular, local leaders, health o�cials, health workers(doctors, nurses, social workers) need to be involved early and often in developing thestudy protocol. Often, there may be more than one parallel ‘system’ (traditional andwestern) – and the support of both groups is needed. Such support is usually gained ifthe project is seen as helping solve a locally identi�able problem, it is self-sustaining(after the research team from the ‘city’ or from abroad has left) and is not perceived tobe exploitative.

2. Utilizing local personnel in the research project is critical to the success of the project.These individuals should be trained and provided with adequate time to meet these newresponsibilities.

3. Appropriate levels of funding are critical. However, overfunding is counterproductive inthe long term. It changes the culture and balance, so that future studies which may beadequately (but not overgenerously) funded of even important questions, may becomevery di�cult to conduct. Such ‘corruption of values’ is now already common in severalcountries, where the motivation for some investigators to participate in clinical researchstudies is primarily commercial gain, with less interest in the scienti�c or clinical valueof the study.

4. Patients may often be using concomitant over the counter medications or local herbalmedications and so extra care should be taken to document the use of these medications,in case unexpected adverse reactions occur.

5. Patients are often poor and they may need to be provided with all their medicines (in-cluding non-study medications) free, as an inducement to continue to participate in thestudy. Further, in a long term study involving multiple visits over a period of time,patients may have to be compensated for costs of transportation or missed wages. Alter-natively, health workers may have to visit the subject at his=her home or work place. Inlong term trials, patients may stop taking their medications once their symptoms improve.Therefore, special e�orts to enhance long term adherence and avoid patients being lostto follow-up are required.

6. Special challenges in data management may occur especially in studies conducted inrural or remote areas. Electricity can be unreliable, telephones may be inaccessible, and


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Table I. Performance in the HOPE trial by region. HOPE is a long term trial involvingan ACE-inhibitor and vitamin E with patients being followed up for 4.5 years.

North America Western Europe Latin American

Number of centres 156 76 35Number of patients 6506 1986 1049Clean CRF:initial 65% 64% 55%�nal 99.3% 99.1% 98.6%

Time to clean data (days) 52 40 72Adherence (2 years) 82% 82% 90%Lost to follow-up (5 years) 0% 0% 0.6%

CRF= case report form.

when they exist they can be quite undependable. Transportation of study personnel mayprove challenging when good roads do not exist, or monsoon �oods wash away roads.Collecting blood samples and keeping them cool poses special challenges in tropicalcountries, especially if electricity is unreliable. One approach that we are trying is theuse of portable liquid nitrogen containers (about the size of propane gas tanks) that keepsamples frozen at −196◦C for 2 weeks. Storing study materials dry and cool may attimes be problematic.

7. Safety of study personnel may be an issue under special circumstances, especially fromguerilla attacks, petty thefts or from indigenous diseases.

8. Bureaucratic problems that may delay materials at customs, multiple ethics committeeapprovals (for example, both in the developing country where the study is to be conductedand the collaborating ‘foreign’ country), multiple governmental bureaucracies etc., coulddelay the initiation of a project by a year or two.

9. The need to ensure accuracy and completeness of study data often needs to be empha-sized. Often investigators may not fully understand the importance of strictly adhering tothe protocol. This requires repeated explanations, local training, strong leadership in thecountry and a zero tolerance approach to minimizing sloppiness or fraud. (These issuesare similar to studies conducted in any country.)

Comparison of quality indicators in trials conducted in multiple countries

Trials conducted in multiple countries provide us with the opportunity to assess the qualityof performance between countries. Tables I and II summarize the data from two studies thatwe have been involved in. The data suggest that for all quality indicators, di�erent regionsperform similarly. Adherence rates were the highest in Latin America. Although initial datafrom Latin America were less clean on �rst arrival (likely due to language issues, as all theforms were in English), ultimately data quality was identical to other regions. However, inthree trials that we were involved with, the rates of lost to follow-up were slightly higherin Latin America, compared to other regions. By contrast, in an ongoing study involvingChina, Japan, Australia and New Zealand as well as Western Europe, all indicators of quality(BP lowering, per cent on study medication and completed visits) were signi�cantly better inChina compared to other countries (Table III) (B. Neal and Stephen MacMahon, personalcommunication).



Table II. Performance in the OASIS-2 by region. OASIS is a trial of a novel antithrombotic (hirudin)given for 3 days in unstable angina.

North Western Central LatinAmerica Europe Europe America

Number of centres 66 177 55 62Number of patients 2063 4353 2040 1685Average number of patients recruited 115 218 120 112per monthClean CRF:initial 60% 58% 59% 51%�nal 99% 99% 99% 98%

Adherence to infusion 85% 89% 89% 91%Lost to follow-up (6 months) 0.6% 0.6% 0.2% 1.6%

CRF= case report form.

Table III. Comparison of China versus other countries in the PROGRESS Study [18].PROGRESS is a study involving blood pressure lowering after stroke (data were provided by

B. Neal and S. MacMahon).

Number randomized BP di�erence between Per cent o� study Per cent of patientsactive and control medications with no dataSystemic=Diastolic in last 12 months∗

Overall 6105 −9:7= − 4:2 14% 6%China 1520 −14:7= − 5:8 3% 1%

Other countries include Australia, France and Belgium, Italy, Japan, Sweden and U.K.∗Note that these �gures are derived from a report during the conduct of the study and this indicator wouldbe expected to improve by the end of the study.

SUMMARY AND CONCLUSIONS

With the increasing proportion of global disease burden occurring in developing countries, it isimperative that large, well designed epidemiologic studies and randomized trials are conductedin these countries. These studies are likely to be successful if they address locally relevantand important questions, recognize the special cultural and organizational challenges, keepthe studies very simple, share appropriate credit with local investigators and be committedto developing both the intellectual and infrastructure capacity in the local country to sustainsuch e�orts (perhaps independently) long term. Conduct of such studies can be scienti�callyand emotionally rewarding and will signi�cantly improve the health of a broad cross-sectionof humanity.

ACKNOWLEDGEMENTS

I thank Professor Chitr Sitthi-Amorn from Bangkok, Thailand, Professor Prem Pais from Bangalore,India, Dr Rafael Diaz and Dr Ernesto Paolasso from Rosario, Argentina and Dr Shamir Mehta fromHamilton, Canada, for helpful comments.


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REFERENCES

1. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Statistics in Medicine1984; 3:409–420.

2. EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur) Collaborative Group.Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet 1993;342:767–772.

3. Chinese Cardiac Study, Oral captopril versus placebo among 13,634 patients with suspected acute myocardialinfarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995; 345:686–687.

4. Pais P, Pogue J, Gerstein H, Zachariah E, Savitha D, Jayprakash S, Nayak PR, Yusuf S. Risk factors for acutemyocardial infarction in Indians: a case-control study. Lancet 1996; 348:358–363.

5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenousstreptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.Lancet 1988; 1:349–360.

6. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison ofstreptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among41,299 cases of suspected acute myocardial infarction. Lancet 1992; 339:753–770.

7. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group: ISIS-4. A randomised factorial trialassessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients withsuspected acute myocardial infarction. Lancet 1995; 345:669–685.

8. Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. E�ects of recombinantHirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, andrevascularization procedures in patients with acute myocardial ischaemia without ST elevation: a randomisedtrial. Lancet 1999; 353:429–438.

9. Yusuf S, Mehta S for The CURE Study Investigators. The Clopidogrel in Unstable angina to prevent RecurrentEvents (CURE) trial program — rationale, design and baseline characteristics, including a meta-analysis of thee�ects of thienopyridines in vascular disease. European Heart Journal 2000; 21:2033–2041.

10. The HOPE Study Investigators. E�ects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascularevents in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. New EnglandJournal of Medicine 2000; 342(3):145–153.

11. Bazzino O, Diaz R, Tajer C, Paviotti C, Mele E, Trivi M, Piombo A, Prado AH, Paolasso E for The ECLACollaborative Group. Clinical predictors of in-hospital prognosis in unstable angina: ECLA 3. American HeartJournal 1999; 137:322–331.

12. Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G Metabolicmodulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) CollaborativeGroup. Circulation 1998; 98(21):2227–2234.

13. Ciruzzi M, Schargrodsky H, Rozlosnik J, Pramparo P, Delmonte H, Rudich V, Piskorz D, Negri E, Soifer S,La Vecchia C. Frequency of family history of acute myocardial infarction in patients with acute myocardialinfarction. Argentine FRICAS (Factores de Riesgo Coronario en America del Sur) Investigators. AmericanJournal of Cardiology 1997; 80(2):122–127.

14. Piegas L, Avezum A, Rossi J, Pereira J for The AFIRMAR Investigators. Risk factor for acute myocardialinfarction in the Brazilian population. AFIRMAR Study: A national, multicentric case-conrol study. ACC OralPresentation, Orlando, 2001.

15. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, andstroke in eastern Asia. Lancet 1998; 352:1801–1807.

16. PATS Collaborating Group. Post-stroke antihypertensive treatment study. A preliminary result. Chinese MedicalJournal (Engl) 1995; 108(9):710–717.

17. CAST (Chinese Acute Stroke Trial) Collaborative Group. Randomised placebo-controlled trial of early aspirinuse in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349:1641–1649.

18. Chalmers J, Neal B, MacMahon S. PROGRESS (Perindopril Protection Against Recurrent Stroke Study):regional characteristics of the study population at baseline. PROGRESS Management Committee. Journal ofHypertension Supplement 2000; 18(1):S13–S19.

19. CREATE Protocol. The Create Study. Clinical trial of reviparin and metabolic modulation in acute myocardialinfarction treatment evaluation. An international collaborative initiative of the Canadian CardiovascularCollaboration, the Indian Cardiovascular Collaboration and the Chinese Cardiac Society.

20. Reddy KS, Shah P, Prabhakaran D, Shah B, Prabhakaran AK, Shrivastava U, Joshi M, Puri SK, Bahl VK,Wasir HS. Coronary heart disease risk factors in an industrial population of North India. Canadian Journal ofCardiology 1997; 13(suppl B):0002.

21. Gupta PC. Socio-demographic characteristics of tobacco use among 99 598 individuals in Bombay, India usinghand held computers. Tobacco Control 1996; 5(2):114–120.



22. Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, Babu G. Reducedmortality among children in Southern India receiving a small weekly dose of vitamin A. New England Journalof Medicine 1990; 323(14):929–935.

23. IBIS Study Group (Coordinator Kurien Thomas). Prospective multicentre hospital surveillance of Streptococcuspneumoniae disease in India. Lancet 1999; 353:1216–1221.

24. Murray CJ, Lopez AD. Regional patterns of disability-free life expectancy and disability-adjusted life expectancy:Global Burden of Disease Study. Lancet 1997; 349:1347–1352.

25. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study.Lancet 1997; 349(9061):1269–1276.

26. Opie LH, Frishman WH, Thadani U. Angiotensin-converting enzyme inhibitors and conventional vasodilators.In Drugs for the Heart. 4th edn, Opie LH (ed.). WB Saunder: Philadelphia 1994:105–143.


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Clinical research and trials in developing countries