Introduction

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Demand is increasing for research to be prioritised according to the importance of health issues,¹ and burden of disease measures have been proposed to aid this process.² There is concern that little medical research is done on diseases affecting people in developing countries.³ Sub-Saharan Africa is a developing area facing severe, pressing, and often unique health challenges.⁴ Its burden of disease per million people is estimated to be five times higher than that of established market economies.²

Effective interventions are needed to improve health, and efficacy is best assessed by randomised controlled trials. Randomised controlled trials in Africa have not been comprehensively assessed, and it is not known whether the trials cover the local health needs. We therefore constructed a comprehensive database of randomised controlled trials conducted in sub-Saharan Africa over the past 50 years. We then evaluated whether the amount of randomised evidence relates to the burden of different health problems and whether specific conditions are neglected.

	Methods

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Eligibility criteria
We considered all randomised controlled trials conducted in sub-Saharan Africa that investigated one or more health problems.² We excluded non-randomised and pseudorandomised controlled trials; trials enrolling non-local populations (such as tourists); and trials not in humans. Studies in northern Africa² and meeting abstracts, books, and other reports were also excluded.

Identification of trials
We searched sequentially Medline (to February 2000), the Cochrane Controlled Trials Register (issue 2, 2000), and the African Published Trials Register of the South African Cochrane Center. The African register has been developed and continuously updated over the past three years from seven diverse international and African databases plus hand searching of back years from 12 major African journals. Terms reflecting randomised controlled trials were conjugated with "Africa," "sub-Saharan Africa," and specific geographical names.

Database
From each article, we extracted the following information: author, journal, year of publication, unit of randomisation (individual or cluster), sample size, disease(s) targeted (and taxonomy in the Global Burden of Disease²), type of intervention (therapeutic or preventive), and country or countries of recruitment.

Analyses
Descriptive analyses include the geographical distribution of trials, number of new trials published, and estimates of the number of trials performed per million people in various countries (1990 population estimates).⁵ The main analysis evaluated the number of trials and the number of randomised participants for each category of health problem in the Global Burden of Disease taxonomy. ^{1 2 6 7} Burden of disease estimates add the number of lost years due to early death plus equivalents of "lost" years due to living with disability from various diseases. The sum is measured in disability adjusted life years (DALYs). For each major disease category we estimated the ratio of burden of disease per each trial and the ratio of burden of disease per participant. We used rank correlation analyses to evaluate whether the number of trials or participants correlated with the DALYs attributed to each health problem.

View larger version (17K): [in this window] [in a new window]   Fig 1.   Number of randomised controlled trials in sub-Saharan Africa published during 1965-99. Twelve trials were published during 1949-64 and eight in early 2000

View larger version (17K): [in this window] [in a new window]   Fig 2.   Correlation between burden of disease and number of randomised trials in sub-Saharan Africa for major disease categories defined in global burden of disease taxonomy. Data on skin diseases are not shown as the burden of disease was small and no exact data were given

	Results

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We screened 2803 references (Medline 875, Cochrane Clinical Trials Registry 940, South African Cochrane Center Registry 988) and fully scrutinised 1334 articles. Of the 1179 eligible randomised controlled trials, 93 studied two diseases (and were thus counted for both). A total of 795 trials (67%) focused on treatment rather than prevention. The median sample size was 90 (interquartile range 42-238). Only 535 trials had over 100 participants; 154 trials had over 500 participants; and 79 trials had over 1000.

Publication of randomised controlled trials increased over time (fig 1 ). Ninety two were published in 1999, more than in any previous year. Almost half of the trials had been done in South Africa (n=565). Four other countries accounted for another quarter (Nigeria=98, Kenya=89, Gambia=56, Tanzania=50). Only 19 countries had more than one trial per million population. South Africa accounted for over 90% of all trials on malignant, respiratory (31/33), digestive (69/76), musculoskeletal (27/27), and congenital (2/2) diseases and 75-90% of trials on diabetes (10/13), endocrine (9/10), cardiovascular (75/99), and genitourinary (29/34) diseases and injuries (26/31), but for only 14% of trials on infectious and parasitic diseases (74/150).

Overall, there was good correlation between burden of disease and randomised evidence (table 1) with modest differences depending on how randomised evidence was measured (table 2). However, good correlation does not ensure a proportional relation (fig 2). For the burden of disease per trial performed, the worst ratios were for congenital anomalies, injuries, respiratory infections, and conditions arising during the perinatal period. The best ratios were for oral conditions, diabetes mellitus, musculoskeletal diseases, maternal conditions, and digestive diseases (table 1).

Infectious and parasitic diseases
An analysis restricted to infectious and parasitic diseases showed good correlation between the estimated burden of disease and the amount of randomised evidence, with modest differences depending on how randomised evidence was measured (table 2). Despite the good correlation, differences in emphasis were discernible. Least attention had been given to diarrhoeal diseases (834 000 DALYs per trial), childhood cluster diseases (628 000/ trial), and HIV (571 000/trial). Results were similar when we considered DALYs per participant.

	Discussion

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Strengths and weaknesses
Although the number of trials or enrolled participants is a measure of research activity, it may not reflect the public health emphasis given to a disease. Firstly, trials can vary substantially in size and importance. Nevertheless, analyses limited to studies with over 100 or over 500 participants gave similar results. Secondly, other types of clinical research are also important. However, randomised controlled trials are the standard for therapeutic and preventive interventions, are easy to identify, and provide a measurable surrogate of the intensity of topical clinical research. Thirdly, for some conditions it is more difficult to run trials. For example, war is a major contributor of DALYs in this area. Randomised trials may be almost impossible to implement in war stricken areas, although it is questionable whether medical research is helpless against war and its consequences.⁸ Despite this difficulty, other unintentional injuries account for more DALYs than war and are amenable to preventive interventions.⁹ Finally, publication bias may influence if and where African trials are published. ^{10 11} Nevertheless, our search included local journals and it is therefore unlikely that we missed many published trials.

Randomised evidence in other continents
For many diseases relevant randomised controlled trials may have been done in other continents. Systematic screening of all trials worldwide would have been impracticable. In addition, extrapolation of results from other continents to Africa causes problems because interpretation of generalisability would be subjective and the trials would not take into account the important local challenges that often occur when implementing medical interventions in Africa.¹²

Almost a million randomised trials have been done worldwide,¹³ but most have been done in countries with an established market economy. Even if we assume that 150 000 trials have been done in such countries (a low estimate), the overall ratio of burden of disease per trial is about 400 times higher in Africa than in established market economies. Estimates are worse if we exclude South Africa, a country with a mixed economic profile.

Implications for policymakers and the future
Most African countries cannot afford to support medical research.¹⁴ In addition, the pharmaceutical industry may be reluctant to sponsor trials in the developing world because the prospects for profit are limited, even if effective treatments are developed.^15-17 Not for profit organisations may also have difficulty supporting such research on their own. They may have difficulty in setting priorities¹⁸ and often prefer to offer practical help rather than foster research.

Despite these limitations, the major health problems of the developing world cannot be set aside. Their consequences also affect the developed world.¹⁹ Success can often be obtained with limited funds. Many diseases in sub-Saharan Africa coexist in vulnerable patient groups, and treatment or prevention of one disease may have a major effect on another (for example, HIV and tuberculosis).²⁰ Seemingly expensive interventions can become affordable if there is strong political will and collaboration with the industry.

The pace of clinical research is accelerating in sub-Saharan Africa. The area needs more international support, but this should be provided without fostering just another form of colonisation.²¹ African researchers should have a meaningful say in setting research priorities,²² and outside support should help develop sustainable local research capacity.