Clinical Trials in Low Resource Settings

1. Clinical Trials in Low Resource Settings Ian Magrath www.inctr.org

2. Outline Questions Propositions Addressing the Problems: Role of Clinical Trials Problems faced in developing countries Infrastructure: knowledge transfer Who pays?: sponsorships Conclusions INCTR Strategies

3. Propositions -1 Interventions that are evidence-based are important everywhere; Where resources are limited, wasted time, money and expertise, or actual harm to people, have particularly significant socioeconomic implications

4. Propositions - 2 In spite of existing obstacles, the conduct of Phase II-IV clinical trials in developing countries is essential, and would improve standards of care whilst creating a foundation of data on which continuing improvements in the outcome of health interventions can occur – i.e., sustainability

5. Propositions - 3 Drug development is not the highest priority in low resource settings, and phase I clinical trials initiated by international pharmaceutical companies should address the additional ethical issues that are created (benefit to study population)

6. Propositions - 4 Evidence collected in high income countries is directed towards their own problems in the context of their populations, environments and available resources. Not all of this can be assumed to be generalizable and there will be inevitable gaps

7. Questions - 1 What are the advantages and disadvantages of clinical research versus the use of clinical guidelines in improving care (early detection and treatment) in developing countries?

8. Questions - 2 How can clinical research be promoted and the necessary infrastructure built in countries with limited resources?

9. The Problem: a Vicious Cycle Many Patients With Advanced Disease and Many Potential Patients High Mortality Rate Limited Resources POOR ACCESS Unmet need for terminal care LOW CAPACITY

10. Quantitative Limitations • Limited numbers of cancer specialists (but some centers of excellence): number of patients overwhelming • Few specialized facilities: limitations in drugs and equipment (availability, cost and maintenance) • Public and academic salaries low : many seek some or full-time private practice, often out of necessity • Bright students go or sent for training overseas: many are permanently lost

11. Qualitative Limitations • Cancer often not considered by primary health personnel, or fatalistic attitude inhibits referral • Training often of poor quality and ceases after medical school (little or no continuing education) • Medicine often eminence-based, not evidence-based • Minimal discipline in implementation of interventions since limited supervision and accountability; no incentive to follow up or record outcome • Nursing, pharmacy, blood banks etc. often inadequate and non-medical staff generally ineffectively utilized (no specialist nurses, for example)

12. Factors Limiting Access • Poverty and ignorance delay seeking help • Primary (and secondary) care suboptimal: lack of focus and knowledge about cancer leads to misdiagnosis and misinformation • Few centers: average journey long (cost) • Result : late diagnosis; advanced disease

13. Limitations in Resources for Cancer Therapy • In Dec 2004, there were approximately 2500 radiotherapy centers and 3700 machines for cancer therapy (enough for 1.85 million patients per year compared to 3 million who need it. Maldistribution: >20 countries have none. (DIRAC) • In 2000 the USA accounted for 60% of anti-cancer drug sales, Europe, 19% and Japan, 16%. The rest of the world, 5%. (IMS)

14. Leakage of Talent to the USA 30% of Mexicans with PhD’s are in the USA All India Institute of Medical Science: 56% of medical graduates emigrated from 1956-80, 49% in the 1990s The 1million Indians in the USA account for 0.1% of India's population but the equivalent of 10% of India's total income

15. South Africa 933 Nigeria 466 West Indies 352 Zimbabwe 311 Ghana 272 Pakistan 205 Zambia 162 Mauritius 102 Kenya 99 Botswana 91 Nepal 73 Swaziland 69 Malawi 52 Sri Lanka 47 Lesotho 43 Sierra Leone 24 Nurses who joined the UK register from countries from which recruitment is banned (2004-5) Source: Annual Report, 2005, Nursing and Midwifery Council, UK Initial Registrants: 33,257; Overseas (non-EU): 11,477 India: 3,690; Philippines: 2,521; Nigeria: 466; Total 3301

16. The Solution: Build Capacity Education Screening Prevention Lower Mortality Rate Fewer Patients with More Limited Disease and Fewer Potential Patients Less Limited Resources Less need and greater capacity for terminal care GREATER CAPACITY IMPROVED ACCESS

17. Capacity Building • Improve quality of existing human, and to the extent possible, material resources • This will require training, at least of the national and regional leaders in “scientific medicine” • Expand by training more graduates in health related disciplines and creating centers for specialist training • Lessen loss to academic medicine by improving professional and economic circumstances – outside assistance essential

18. Why do Clinical Trials in Low Resource Settings? • An ability to conduct research is essential to the development of a high quality, sustainable, health system • Scientifically trained physicians are more able to learn from existing sources of information – the literature, web-based information, meetings etc.

19. Why do Clinical Trials in Low Resource Settings? • To accumulate data that allows the efficacy and cost-benefit ratio (efficiency) of any feasible interventions in the natural history of a disease to be assessed • Because evidence is context sensitive – therefore, what applies in one population or environment does not necessarily apply in another

20. Why do Clinical Trials in Low Resource Settings? • The questions (hypotheses) that need to be addressed to improve care in low resource settings frequently differ from those that are given highest priority in high resource settings • More than half of all cancer is in developing countries – this represents a valuable, but largely untapped source of potentially unique knowledge of value to all

21. In Addition, Clinical Trials Can: • Simultaneously provide effective prevention or treatment • Provide a focus for training and education • Improve clinical care – quality assurance needs (monitoring and audits) detect problems, provide supervision; instill good practices • Provide improved professional circumstances and new career opportunities – with added incentives to improve results

22. Phase II/III Clinical Trials can Improve Care • Clinical research demands high standards of care and expertise in the disease in question: • Accurate diagnosis • Appropriate treatment (or early detection) design • Discipline in adhering to protocol; good supportive care • Documentation of results (follow up essential) • Quality assurance – of care and data • Studies must be designed with available resources and study populations in mind • Performing clinical trials will help to identify infrastructural inadequacies, stimulate the search for solutions and increase precision and discipline • Ethical principles must be adhered to

23. Examples of Clinical Trials that Result in Improved Care • Comparison of relative toxicity, cost or scheduling of standard regimens optimization studies • Identification of risk factors in a local context, or characterization of disease or its epidemiology (generally one arm studies) • Early detection studies, particularly using direct visualization techniques and simple treatment strategies of early lesions

24. Value of Inter-Institutional Clinical Projects • Improved access of patients and professionals to the local (few) and international experts: • Increased communication and hence learning among all participants (community of practice) • Greater acceptability of quality control potentially healthy competition among participating institutions • May identify problems that are specific to populations, regions or institutions

25. High Priority Clinical Trials in Low Resource Settings • Questions of national or local importance: • Treatment of high priority diseases; high incidence with a known effective intervention (may be uncommon in the affluent world (e.g. hepatoma, bilharzial bladder cancer) Preventable or curable • Study of toxicity, efficacy and practicality of therapies developed in high income countries • Impact of resource sparing modifications (detection methods, e.g., VIA, VILI, altered drug regimens or X-ray fields, simpler surgery) • Standard therapies associated with evaluation of risk factors, characterization or epidemiology

26. Developing Necessary Infrastructure • Will nearly always require international collaboration – ideally, direct participation • To provide the necessary propositional and procedural knowledge • To provide training and education • To monitor conformity to protocol, quality of data and confirm results of the intervention • To encourage inter-departmental and inter-institutional collaboration

27. Benefits to All • Translational and clinical research will be more rapidly accomplished if a larger number of patients were accessible (applies particularly to uncommon cancers or stages of cancer) • Developing countries provide unique opportunities for understanding the epidemiology and pathogenesis of cancer and exploring the efficacy of low cost or resource sparing interventions • Research in developing countries may be relevant to minority populations in affluent countries

28. Obstacles to Research in Developing Countries • Little or no research training of physicians; promotion generally based on seniority • Protocols often viewed as guidelines which can be modified at will • Limited research infrastructure • Concept of data quality rudimentary • Published data often unreliable • Lack of professional or financial rewards: lack of incentive to perform research • Can be seen as “limiting” freedom • Follow up often poor

29. Knowledge Transfer: The Standard Model • High level meetings in developing countries (with predominantly Western faculty) • Utility depends on content, but audience unselected and no outcome measures • Training in Western institutions • Benefits the West more than low and middle income countries, although has created some excellent leaders in developing countries • Provision of written guidelines • Essential, assuming based on relevant evidence, but limited or no assessment of use or value

30. Communicating Information Sender – information put in language that recipient understands Recipient – must have sufficient experience for information to be meaningful Information of no value unless acted upon

31. Standard Model; Guidelines • Many organizations develop “best practice guidelines” • May be created with minimal knowledge of local resources and populations (feasibility?) • Based on information derived, for the most part, from high income countries (applicability?) • Read only by a small fraction of practitioners and not necessarily used as written – (utility?) • Usually no measures of use, performance or outcome (i.e. evidence of utility) • May be used by non-specialists with the potential for serious harm

32. Applicability of Guidelines • The pattern of disease differs – incidence and stage distribution (different priorities re: cancers to be studied) • Cancer biology may differ – e.g., bilharzial associated bladder cancer (different approaches to prevention or treatment), genetic lesions may differ • Resources and facilities differ – differences in staff expertise, and availability or access to products • Patients differ - illiteracy and poverty impact upon adherence to treatment, genetic and environmental factors (pharmacogenetics, comorbidities, malnutrition, hygiene) may change outcome

33. Clinical Trials Actively Build Capacity • Training/continuing education can be accomplished in the context of clinical trials for health professionals • Infrastructure is developed, with additional staff, improved use of IT etc. that should impact on non-research clinical care • Trials foster collaboration and communication, both nationally and internationally • Quality assurance provides an assessment of effectiveness of educational methods

34. Designed for a specific population in the context of available resource Usually entails collaboration and mutual learning Associated with quality assurance and ethical review Identifies deficiencies Associated with outcome measures Generates new information Based on available evidence – usually from a high resource context Rarely entails collaboration or learning Rarely any quality control and no ethical review No identification of deficiencies No outcome measures No new information Comparison of Guidelines and Clinical Trials Research Guidelines

35. Dialogue; the Importance of Mutual Understanding The Sage, the person of wisdom, for whom knowledge is sacred is the fount of knowledge Sage • LISTEN: Chinese character includes those for heart, eye and ear • LEADS TO: deeper understanding and a sense of shared meaning Listen Dialogue: from Greek dia: across, logos: word,

36. Advantages and Opportunities re: Cooperative Trials in LRS • Improved access of patients and professionals to the limited number of experts involved in conduct of the trial • Increased communication and hence learning among all participants • Instills good habits of clinical care, and a research perspective in junior staff that extends beyond the trial in question • Provides a local data base that can be built upon – a step towards sustainability

37. Cooperative Groups in Low Resource Settings - Foreign • Can join existing groups based in affluent countries but… • Trials will not address locally important problems • Patients may not be comparable to those entered in a “western” setting • Limited opportunities to play a role in identifying or designing studies • Resources provided to group members in the wealthy country may not be available • Regulatory issues can create problems

38. Cooperative Groups in Low Resource Settings - Local • Can develop own groups but… • May lack appropriate leadership • Inter-institutional rivalries may exist • Entrenched views of senior members of institutions (lack of academic mindset) may limit studies that can be done • Will usually have limited infrastructure and ability to monitor quality • Therefore: will usually require outside assistance

39. Cooperative Groups in Low Resource Settings • Most cooperative groups in developing countries are in more advanced countries such as Latin America • GATLA, GATHEM for hematological neoplasms • Some relationships between US or European Groups have been established • Collaboration with external organizations or institutions who support the development of local groups increasing (e.g., INCTR)

40. Who Pays for Research? • The consumer – especially when combined with appropriate therapy • Out-of-pocket expenses, private or national insurance • The institution – where research is supported by grants, and/or institution is academic (education) • Charitable organizations/NGOs – which provide funds for disciplined patient treatment, professional education or research (not for individuals) • Government or Governmental Organizations – particularly when health/economic (closely linked) or international political benefit may result from the research or training • The Pharmaceutical industry – drug development

41. Pharma Sponsored Trials • If international pharmaceutical sponsor, ultimately directed to increased drug sales (initial incentives, e.g., donations of drugs or funds may be valuable) • Post-trial local price and availability are issues that should be addressed in drug development trials • Is it sufficient for only high income patients in the country to benefit? • Need to avoid charges of exploitation – esp. phase I • Can help to improve infrastructure and provide additional revenue for hospitals • Patients can benefit if trials address important local problems as well as special ethical considerations

42. Local Pharma Industry • Local pharmaceutical industries are growing • Local drugs much less expensive – Indian drugs now used widely in Asia and Africa; government subsidies • Increasing local development pipe-line with increased local needs for clinical trials, including phase I studies • May push international pharmaceutical companies out of the huge market in developing countries (at least for generics) – 55% or so of all cancer and climbing

43. Sponsorship by NGOs • Most cancer societies not involved in patient care, but may support salaries or provide grants • Some professional societies may sponsor studies • SIOP; Wilms’, hepatoblastoma • INCTR dedicated to cancer in developing countries: support; NCI, grants, Pharma • Clinical trials used to both immediately improve patient care and as a focus for capacity building

44. INCTR’s Network Offices and Branches Collaborating Units

45. Tenets of the Network • Focused on small number of centers in countries interested in clinical research and training programs • Includes active participation in identification and design of projects • Works with other organizations with overlapping interests • Once studies running effectively, add additional centers: use participating centers to provide training for others in the country or region • Modern capabilities re: IT for training, consultation, review of diagnostic images etc. gradually being enhanced

46. Active Clinical Projects • Reasons for late presentation of retinoblastoma – 16 centers in 11 countries • Survey of breast cancer management - 4 countries • Cx Cancer screening (with IARC) – 2 countries, 4 sites • Treatment of advanced cervical cancer (with Eli Lilly) – 10 centers in 10 countries (accrual complete) • Treatment and study of ALL in India - 4 Indian centers • Treatment and study of Burkitt’s Lymphoma in Africa - 4 centers in 3 countries (expanded access in Tanzania) • Palliative care; provision and training – 4 countries • Expansion of care for leukemia (Philippines)

47. Projects in Planning Phase • Treatment of locally advanced retinoblastoma (Philippines, Turkey) • Treatment of breast cancer (with IAEA) • Cervical cancer screening and treatment • Palliative care in Nicaragua (PACT) • Cancer control in Cameroon • Cancer control in Uzbekistan

48. ALL study: 1048 Patients Acute Lymphoblastic Leukemia MUMBAI (652) DELHI • DELHI (232) CHENNAI (168)

49. Improvement over time with MCP 841 at TMH

50. Research Projects PROJECTS INCTR Programs, Branches, Associate Members, Partners Scientific Review Ethical Review Disease Specific Strategy Groups Implementation