Annals of Oncology Advance Access originally published online on March 5, 2008
Annals of Oncology 2008 19(5):831-833; doi:10.1093/annonc/mdn034
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editorials |
Developing innovative models for North–South cooperation in clinical research—experience from the INDOX Cancer Research Network
1 INDOX Cancer Research Network, & Department of Clinical Pharmacology, University of Oxford, Oxford, UK
2 Department of Medical Oncology & Delhi Cancer Registry Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Delhi, India
* (E-mail: raghib.ali{at}clinpharm.ox.ac.uk)
Cancer, long thought of as a disease of richer, industrialised and high-income nations, is now the second leading cause of death in many lower income countries. More than 50% of the world's cancer burden, in terms of both numbers of cases and deaths, occurs in developing countries and is rising [1]. More particularly, some 45% of >1 million new cases of breast cancer diagnosed each year and >55% of breast cancer-related deaths occur in low- and middle-income countries [2, 3]. By 2020 it is estimated that 70% of all cancer cases will be in these lower income countries—and approximately one-quarter of these will be in India, with its (still increasing) population of over a billion [1].
India is experiencing rapid demographic, socioeconomic and risk factor changes, particularly in urban areas, leading to an alarming rise in the incidence of chronic diseases such as diabetes, hypertension, heart disease and cancer. As the epidemiological transformation gathers pace, the incidence of cancer is expected to double in the next 10 years to 2 million cases a year [1]. Changes are also occurring in the relative incidence of different cancers with stomach cancer in men and cervical cancer in women decreasing (traditionally cancers of low-income countries) and some tobacco-related cancers and breast and endometrial cancers in women and prostate cancer in men increasing (traditionally more common cancers in high-income countries (Table 1).
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As the mortality and morbidity from cancer increases in India, there is an urgent need for clinical research into the treatment and prevention of those cancers [4]. As far back as 1993 in an Annals editorial, Tobias and Mittra [5] recognised that, ‘Perhaps the greatest handicap that developing nations face in their fight against cancer is the lack of an adequate research base'. Suitable training opportunities for principal investigators, junior doctors and research nurses have also been lacking.
Even as India has been attracting a large number of the number of clinical trials in the last decade, the vast majority of these have been designed outside of India by either Western academics or pharmaceutical companies with little or no input from Indian investigators. These trials have tended to focus on cancers of primary interest to developed nations using India simply as a place to recruit extra patients. As Masera and Biondi [6] called for: ‘Research in the South should be conducted by investigators from the South, on persons from the South, and for the good of the people of the South, with the main goal not being to solve the North's problems. Close interplay is needed between North and South in drawing up research methods and mobilising resources to conduct investigations.’ Unfortunately, the country also suffers from a shortage of properly trained specialists in cancer—there are <150 properly trained medical oncologists and <100 dedicated surgical oncologists. The situation regarding radiation oncologists is slightly better with 
1000 of them qualified but many public sector hospitals do not have modern radiotherapy equipment. In many of these hospitals, chemotherapy is still practised by radiation oncologists, as departments of medical oncology have not been created.
In order to tackle some of these problems, as reported in Annals in 2005, a new partnership was established between the Institute for Cancer Medicine, Oxford University, and six leading cancer centres in India, the INDOX (INDia–OXford) Cancer Research Network, with the assistance of an educational grant from GlaxoSmithKline (Figure 1) [7]. ‘So two years on, what has been achieved—have the network's aims been realised and what challenges remain?’
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The INDOX network's initial priorities were to improve the clinical research infrastructure at the Indian centres as well as the skills and expertise of researchers in India. Although all the Indian principle investigators were senior professors with extensive clinical trial experience, training of more junior staff as well as research nurses and trial pharmacists had been far more limited. Phase 1 trial experience was virtually non-existent as phase 1 trials with foreign molecules had not been allowed in India until 2005 and Indian pharmaceutical companies had previously concentrated solely on producing generic drugs.
Another aim of INDOX was to ensure that Indian clinicians were involved in clinical trial design from the outset, working with the sponsor to ensure that protocols were developed which are practically suited to be carried out on patients in India with appropriate eligibility criteria and in those cancers which are common in India.
progress to date
There were a number of practical problems we faced in the initial stages with one of the major challenges being able to recruit and retain high-quality clinical research staff to run the trials. Dedicated site coordinators were therefore appointed at all six centres and a comprehensive training program was established for all staff involved in clinical trials consisting of multidisciplinary seminars, workshops and courses held in both Oxford and India.
A fellowship scheme was also setup with a number of 1-year clinical research fellowships leading to a diploma in clinical trials and short-term visiting fellowships were awarded annually. The training and fellowship scheme has proved extremely popular and a total of 24 research staff including principal investigators, sub-investigators, site coordinators and research nurses from all six sites have now attended clinical trials training sessions in Oxford. The fellowship scheme has also been successful in reducing the staff attrition, which was one of the main problems sites were facing in building effective clinical trial units.
All centres now have dedicated clinical trial units and are equipped to conduct trials to international Good Clinical Practice (GCP) standards with India-specific Standard Operating Procedures (SOPs) being implemented across all sites. To date, a total of eight trials in all phases have been conducted through the INDOX network and >100 patients have been recruited. Two INDOX sites also participated in our first phase 1 trial, which was one of the first to be approved by the Indian regulatory authorities using molecules developed outside India.
Our experience with the regulatory authorities has been mixed—in general the Drugs Controller General, India, has been very supportive of our efforts, but due to staff shortages and reorganisation, approvals have sometimes been slow. There, however, have been some positive regulatory developments during the last 6 months and a new system has now been put in place whereby new trial applications are being processed more efficiently.
ethical concerns
Much has been written about the ethical problems arising as a result of the rapidly increasing number of clinical trials being conducted in India with inadequate regulatory oversight [8, 9]. Our primary concern has always been to ensure that trials are conducted according to the highest ethical standards and all trials are approved by local ethics committees. However, we recognise that some ethical problems remain, particularly considering that a substantial proportion of the population are illiterate and ill-informed about medical research and it is therefore difficult to ensure that those who agree to take part in trials are both fully informed of and understand the risks and benefits of doing so. In the public sector, there also still tends to be a somewhat paternalistic doctor–patient relationship, leading to possible exploitation. Widespread poverty means that the usual standard of care is unaffordable to many, leading to possible inducement. These problems are, of course, not exclusive to India, but to address some of these issues further, we are planning to undertake India's first national and the largest ever survey of clinical trial participants to assess their motivation for taking part in the trials and how informed their consent really is.
We are also aware of the need that trials be relevant to the population in India and that there is a realistic prospect of these therapies being available to not just a small minority of patients in India once trials are completed.
future plans
To tackle India's increasing cancer burden it is of course necessary not only to undertake clinical trials using drugs developed in the West (which may be beyond the means of a large proportion of the population) but also to investigate whether alternative cheaper therapies are effective in treating different cancers. There continues to be widespread use of traditional Ayurvedic medicine among the Indian masses and we plan to undertake randomised controlled trials of some of these therapies to assess their true effectiveness in clinical practice.
Unfortunately, there are no national or statewide screening programmes for common cancers such as head and neck, cervix and breast. We therefore recognise the need to address prevention and are beginning to conduct epidemiological research into the causes of cancer in India. There is a need to investigate the importance of various risk factors and opportunities for prevention in those cancers, which are more prevalent in India (e.g. head and neck, cervix and gall bladder) as well as those, which are beginning to increase with changing lifestyles (e.g. breast and colorectal).
We also wish to expand the network to 12 sites and would like to include cancer centres in the east of India and rural areas which are densely populated and where clinical research has been neglected. There are also plans to work with sponsors to support investigator-initiated trials and so make greater use of the huge intellectual capital within the network.
conclusions
Over the past 2 years, INDOX has established itself as one of India's leading oncology networks as reflected by the enthusiasm of other centres in India to join us. It is a true partnership and a good example of how collaboration between Indian and Western academic institutions and the pharmaceutical industry can benefit all parties involved. Of course, much remains to be done—cancer in India is a huge and increasing problem—but we have made a start and with continued support from both the private and public sector there is huge opportunity to improve the lives of millions of people. We believe that similar models of North–South cooperation could be successful in helping to tackle cancer in other developing countries.
References
1. Stewart BW, Kleihues P. World cancer report (2003) Lyon, France: International Agency for Research on Cancer & World Health Organization.
2. Curado MP, Edwards B, Shin HR, et al. Cancer incidence in five continents, Volume IX (2007) Lyon, France: International Agency for Research on Cancer. (IARC Scientific Publications No. 160).
3. Porter P. "Westernising" women's risks? Breast cancer in lower-income countries. N Engl J Med (2008) 358(3):213–216.
4. Strengthening clinical research in India. Lancet (2007) 369:1233.[CrossRef][Web of Science][Medline]
5. Tobias JS, Mittra I. Improving cancer care worldwide. Ann Oncol (1993) 4:283–287.
6. Masera G, Biondi A. Research in low-income countries. Ann Oncol (1999) 10:137–138.
7. Raina V. Doing cancer trials in India: opportunities and pitfalls. Ann Oncol (2005) 16:1567–1568.
8. Srinivasan S, Loff B. Medical research in India. Lancet (2006) 367:1962–1964.[CrossRef][Web of Science][Medline]
9. Nundy S, Gulhati M. A new colonialism? Conducting clinical trials in India. N Engl J Med (2005) 352:1633–1636.
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