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Getting past consent and ethical issues endemic in underserved populations to ensure quality GCP.
Clinical trials conducted in developing countries are usually not legally bound to adhere to Good Clinical Practice (GCP), and GCP is not mandatory as long as the data are not needed for regulatory purposes by the sponsor. Nevertheless, sponsors usually require that clinical trials are conducted in accordance with the ethical principles and quality standards that underpin GCP. There is some debate about how stringent the implementation of guidelines should be in these circumstances.
In essence, GCP "is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are accurate and credible."1
(PHOTOGRAPHY: COMSTOCK ILLUSTRATION: PAUL A. BELCI)
In an attempt to unify the various standards of GCP formulated over the previous 30 years in the European Union, Japan, and the United States, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) provided a new, tripartite GCP guideline.1,2 The ICH GCP Guideline came into force in 1997 and is probably the most frequently referenced document pertaining to GCP in clinical trials. In the United States, Japan, and Europe, for example, the guideline is already implemented in national legislation.
The objective of the ICH GCP Guideline was to "facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions," but it was further suggested that the "principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects."1
Although GCP is well recognized in the ICH regions, it was questioned whether the ICH GCP Guideline is utilizable outside these countries.3 This article explores these issues in the context of studies carried out in sub-Saharan Africa, in general, and in The Gambia in particular. It addresses ethical issues surrounding informed consent, vulnerability of study participants, and post trial treatment, and also considers data quality issues in trials such as GCP, other needs in sub-Saharan Africa, and routine monitoring.
Fast Facts: Gambia Up Close
It has often been questioned how much and which information might be understood by a potential trial participant who is illiterate. According to an investigation by Krosin et al., in West Africa about 90% of trial participants did not understand withdrawal criteria and the existence of side effects, and nearly 75% did not understand that they were enrolled in a study as opposed to receiving therapy.4
These findings are in agreement with results of an interview with 189 parents who were asked to let their children participate in a trial of a Haemophilus influenza vaccine in The Gambia in 1995. Although there was good knowledge of the purpose of the vaccination, only 10% of those who participated in the trial were aware of the placebo control group.5
A comprehensive sociological study by the UK's Medical Research Council (MRC) of trial participation in The Gambia was recently published.6 The trial was designed to test the efficacy of a pneumococcal vaccine in preventing childhood pneumonia, and mothers attending infant welfare clinics throughout the eastern half of the country were invited to enroll their children. From 800 mothers whose infants were recruited, 45% of respondents in the sociological study later claimed that they did not know, had not been told or had forgotten the purpose of the study. Only 6% mentioned pneumonia or the phrase "pneumococcal vaccine trial."
But the understanding of information given to trial participants is not solely a matter of concern in developing countries. Caldwell et al. reported that many parents of children who were asked to participate in a clinical trial in Australia had little knowledge about randomized controlled trials, misunderstanding the concept of randomization and the rationale for placebo use.7
A major contributory factor to the poor retention of important information is likely to be the large amount of information presented; it is not uncommon for information sheets to run to 15 pages for industry-sponsored trials—a daunting amount of information for anyone to comprehend.8
This situation arises in part from Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) in sponsors' countries insisting on certain information being included, even though the ability of potential participants to understand may be limited, particularly those who are illiterate.
For example, information about compensation or data protection is unlikely to be understood or remembered by most people in developing countries. Detailed explanations of the possibility that a test product may protect against asymptomatic infection is also unlikely to make sense to someone unfamiliar with the germ-theory of disease. Presenting such information often leaves potential participants overwhelmed. Further high-quality studies comparing the trial consent process in developing and developed countries would be useful.
If informed consent concepts vary in different societies, then the best methods for obtaining it may also differ, and GCP procedures should be modified accordingly. For example, it is irrational to translate written subject information sheets into local languages for illiterate subjects, when such languages are usually only spoken. Tape recorded translations of the information given to subjects in their local languages and the means to replay them could help to improve the process, keeping in mind that a straight translation might not be understood by the people involved.
In many developing countries, permission from community leaders, elders or spouses must be sought before individuals can consent to take part in studies.5 Furthermore, patients in many societies in developing countries are not accustomed to questioning doctors, while locally employed fieldworkers may be perceived as being more approachable by the communities in which research is being carried out.9
An alternative approach would be to develop a multilevel consent process in which the local IRB assumes primary responsibility for ensuring that the information sheet content is sufficient to capture the most important points likely to be intelligible to the majority of study participants. The IRB/IEC reviews the information normally included in the information sheet and consent form and satisfies itself that there is an adequate rationale for the study and that sufficient safeguards are in place to protect participants. A brief statement to this effect would be included in the information sheet. Fundamental changes to the consent process may be required to maximize the value of the informed consent.
Vulnerable trial participants include not only children but also women of childbearing age, who may be asked to take drugs that could be damaging to the developing fetus. Trial monitoring has revealed both under and over inclusion of pregnant women in some studies. Screening for pregnancy is expensive, prone to error, and carries with it ethical dilemmas about pregnancy disclosure and cultural convention. It may be difficult or even impossible to ensure adequate contraception is used by participants in studies of potentially fetotoxic drugs, especially in cultures that esteem female fertility.10
Explaining the risks in this context is also problematic, particularly when the consent to participate in a trial may not be a simple matter of individual choice for women. On the other hand, these difficulties raise concerns about the exclusion of women and adolescent girls from some important clinical trials, limiting the later applicability of data to this group.
Another aspect of concern in this respect is the question of coercion due to poverty and lack of access to medical care. Reasons given for participating in a clinical trial in Australia, for example, included the fact that the trial participants were provided with free medication, which would otherwise be very expensive; that they had access to new and effective treatments not routinely available; and that the health of participants was being monitored more closely.7
To consider this coercion in poor countries, which spend little on health care for their citizens, may be unfair and may actually disadvantage trial participants. These concerns can be ameliorated to some extent by making benefits available to the whole community, such as improved laboratory services, regardless of their participation in a particular trial.
A further ethical issue is the treatment of patients when a clinical trial is completed. An additional principle for medical research combined with medical care stated in the revision of the Declaration of Helsinki in 2000 is that "at the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study." In developed countries, alternative and effective treatments for many diseases are available, but this is not often the case in developing countries.
It was argued recently that implementation of GCP might be unaffordable and unworkable by small groups in low-income countries; that GCP standards do not facilitate better patient care but rather encourage clinical investigators to refocus their attention on excessive and expensive bureaucracy; and that that valuable essence of GCP should be distilled into something simple and workable.11
There can be no doubt that a single framework for GCP is helpful. Nevertheless, practical standards for implementation of the principles of GCP are urgently required for use in the developing world.12 The accepted model should define precisely the responsibilities of the sponsors, host institutions, and investigators running trials. This is the only way to attempt to ensure that the basic and universal rights of vulnerable people taking part in trials are afforded some formal protection no matter where they live and that the data reported are accurate and true.
There is a good precedent for defining such minimum standards. When the directive on clinical trials was implemented in the European Union, concerns over increasing bureaucracy and costs were voiced throughout the Union within the pharmaceutical industry and especially in academic institutions.8,13 It is now widely recognized that the full provision of the ICH GCP Guideline is not appropriate for noncommercial trials as already laid down in the European Directive on clinical trials.14 The European Commission is going to provide specific modalities of GCP for clinical trials conducted by researchers without the participation of the pharmaceutical industry.
In addition to the minimum standard, it should be possible to develop a mechanism to award points reflecting the extent to which additional desirable attributes are handled within the trial. Such an approach will allow evaluation of the quality of different trials without the constraints of a minimum standard. It could usefully be born in mind what the UK's MRC recommends in their Guidelines for Good Clinical Practice in Clinical Trials: The principles of GCP should be implemented "without destroying the essential element of trust which underpins all research funding, or adding a cumbersome layer of bureaucracy that stifles legitimate research activity."15
Low-cost, innovative research is to be promoted and those working in developing countries should be encouraged to define practical guidelines that fit in these settings while ensuring appropriate quality standards.
The application of GCP in trials conducted in developing countries is often complicated by additional logistic challenges imposed by working in such an environment. Imaginative and effective solutions are possible but expensive.16 Research teams usually consist of members from different cultural and linguistic backgrounds from developing and developed countries working in partnership. The management of such a group is a complex undertaking for which few are trained.
The provision of messaging and email services for communication between researchers and trial staff working in different sites and the use of online training might be of help, since most main research centers are equipped with power supply and telecommunication facilities.
The use of source documents and the creation of a virtual Case Report Form (eCRF) are likely to decrease transcription errors. There is increasing experience with the use of Personal Digital Assistants (PDAs) for electronic data capture (EDC) at the point of collection.17,18 PDA-based data capture has benefits over paper-based systems: It prevents illogical data being entered, ensures that realistic ranges are respected, enhances the completeness of data (the user cannot move to question Y before question X is completed), and ensures skip patterns are obeyed. The use of modern technology to increase the quality of data is particularly valuable when less-educated field staff is employed to work in relatively remote settings. However, EDC systems may not meet all GCP requirements, as few leave an audit trail.
The involvement of data, safety, and steering committees from local settings rather than only members from major institutions overseas might be more cost effective.12
Trials and their systematic review are increasingly being used to provide the evidence base for recommendations given to clinicians, policy makers, and other providers of health care. Foundations and academic institutions can help to ensure that research findings move into clinical practice in low-resource areas.19 It is important that such recommendations are made on the basis of robust data. GCP and considerations of data quality have so far been largely confined to trials generating data for licensure.
However, there is an aching need for quality assurance standards in monitoring and evaluation of interventions in the postmarketing phase. Routinely generated Health Management Information data is notoriously unreliable, but there is no framework or agreed set of standards to indicate the reliability of such data. Similarly, various surveys (e.g., Demographic and Health Surveys, and Multiple Indicator Cluster Surveys) are taken as gold standard but without the benefit of external, standardized validation of data quality.
We believe that external clinical monitoring has an important role to play in reassuring data users that postmarketing evaluations and health surveys generate reliable data. This is particularly relevant in an era when many new interventions are beyond the financial capacity of less-developed countries that instead turn to the GAVI Alliance, GFATM grant, multilateral donors, and others to support new programs.
It is important to ensure that resources are used optimally and that decisions on what to implement, depending on the burden of disease in a country and the effectiveness of a strategy, are based on robust information. This argument can be extended to the role of General Budget Support from bilateral and health basket funding in decentralized health services. Nationally defined health priorities should be defined on the basis of reliable routine data.
The particular difficulties surrounding health research in developing countries should not prevent such research from being conducted—research is the only way to improve responses to health care needs and remains primarily the responsibility of national governments.
Data used to inform policy decisions must be robust and evaluated against a set of accepted standards. However, the industry-standard GCP benchmark should be assessed in relation to individual projects and not the other way around. Under this model, GCP represents a generic toolbox from which individual components can be selected and modified for the specific task in hand. This approach requires a flexible, realistic attitude from sponsors, review panels, and, crucially, by the journals publishing the results of such studies.
Trials should be assessed on their own GCP merits just as much as on other aspects of their design. A true appreciation of GCP rather than its rejection is therefore vital. This should include an understanding of the principles and commercial context that underpin current GCP guidelines and how they can facilitate good research rather than restrict it.
There are an increasing number of large, high-quality studies addressing important topical research questions conducted using high GCP standards in poorer parts of the world. Such studies can be expensive and complex to carry out, requiring the strong financial and managerial support of wealthy organizations, well-established in richer countries, that may well be working to their own political, ethical, and scientific agenda. It would be a mistake to reset the bar at a lower level in order to make it easier for smaller groups in resource-poor settings to carry out the work themselves. Instead, capacity needs to be built over time to raise the bar at least to the minimum standard everywhere.
Wealthy institutions and partners in the pharmaceutical industry have an obligation to support good science everywhere, conducted to high ethical standards, and generating robust data to solve the most important global health problems.
Jenny Mueller, * PhD, is clinical trials support manager, MRC Laboratories, PO Box 273, Banjul, The Gambia, email: firstname.lastname@example.orgDavid Schellenberg, PhD, DTM&H, is professor of malaria and international health, London School of Hygiene & Tropical Medicine. Stephen Owens, MBChB, MTropPaed, is a career development fellow with the nutrition program, MRC Laboratories.
*To whom all correspondence should be addressed.
1. ICH tripartite guideline. Guideline for Good Clinical Practice, Adopted for Step 4, 10 June 1996.
2. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), http://www.ich.org/cache/compo/276-254-1.html.
3. N.J. Dent, "Is ICH Exportable Outside the European Union," Quality Assurance, 8 (1) 19–31 (2000).
4. M.T. Krosin, R. Klitzman, B. Levin, J. Cheng, M.L. Ranney, "Problems in Comprehension of Informed Consent in Rural and Peri-urban Mali, West Africa," Clinical Trials, 3 (3) 306–313 (2006).
5. A. Leach, S. Hilton, E. Manneh et al., "An Evaluation of the Informed Consent Procedure Used During a Trial of a Haemophilus influenzae Type B Conjugate Vaccine Undertaken in The Gambia, West Africa," Soc Sci & Med, 48 (2) 139–148 (1999).
6. J. Fairhead, M. Leach, M. Small, "Where Techno-science Meets Poverty: Medical Research and the Economy of Blood in The Gambia, West Africa," Soc Sci & Med, 63 (4) 1109–1120 (2006).
7. P.H.Y. Caldwell, P.N. Butow, J.C. Craig, "Parents' Attitudes to Children's Participation in Randomized Controlled Trials," The Journal of Pediatrics, 142 (5) 554–559 (2003).
8. M. Salzberg and E. Müller, "Quality Requirements in Clinical Studies: A Necessary Burden?" Swiss Medical Weekly, 133 (31-32) 429–432 (2003).
9. W. Apateerapong and J. Ananworanich, "Participation in Randomized Trials in Developing Countries," The Journal of Pediatrics, 144 (1) author reply 140 (2004)
10. E. Mills, S. Nixon, S. Singh et al., "Enrolling Women into HIV Preventive Vaccine Trials: An Ethical Imperative but a Logistical Challenge," PloS Medicine, 3 (3) (2006), http://journals.plos.org/plosmedicine/information.php.
11. N.J. White, "Editorial: Clinical Trials in Tropical Diseases: A Politically Incorrect View," Tropical Medicine and International Health, 11 (10) 1483–1484 (2006).
12. D.J. Diemert and J.M. Bethony, "Debate: Letters to the Editors" (response to N.J. White's editorial) Tropical Medicine and International Health, 12 (3) 470–472 (2007).
13. J. Sweatman, "Good Clinical Practice: A Nuisance, a Help or a Necessity for Clinical Pharmacology?" British Journal of Clinical Pharmacology, 55 (1) 1–5 (2003).
14. Directive 20/2001/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, published in the Official Journal L, 121 (34) (1 May 2001).
15. MRC, Guidelines for Good Clinical Practice in Clinical Trials (1998), http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC002416 (accessed February 26, 2007).
16. F.T. Cutts, G. Enwere, S.M.A. Zaman, F.G. Yallop, "Operational Challenges in Large Clinical Trials: Examples and Lessons Learned from the Gambia Pneumococcal Vaccine Trial," PloS Clinical Trials, 1 (3) (2006) http://journals.plos.org/plosmedicine/information.php (accessed February 27, 2007).
17. K. Shirima, O. Mukasa, J. Armstrong Schellenberg et al., "The Use of Personal Digital Assistants for Data Entry at the Point of Collection in a Large Household Survey In Southern Tanzania," Emerging Themes in Epidemiology, 2007 (in press).
18. M.A. Missinou, C.H.O. Olola, S. Issifou et al., "Piloting Paperless Data Entry for Clinical Research in Africa," American Journal of Tropical Medicine and Hygiene, 72 (3) 301–303 (2005).
19. J.L. Deen and J.D. Clemens, "Issues in the Design and Implementation of Vaccine Trials in Less Developed Countries," Nature Reviews Drug Discovery, 5 (11) 932–940 (2006).