Implications of the ethical-legal framework for adolescent HIV vaccine trials--report of a consultative forum.

The ethical-legal framework in South Africa is in a period of transition, with a number of new developments changing the substantive principles and procedures for health research in the country. Some of the changing dynamics include both law reform and the review of ethical guidelines. This changing environment poses many complexities for researchers, research ethics committees and participating communities involved in planning, implementing and reviewing research with child participants, including HIV vaccine trials. This paper presents the major themes and outcomes of a consultative meeting convened by the HIV AIDS Vaccines Ethics Group in July 2004 for key stakeholder groups. At this forum participants discussed the complexities posed by a transitional and sometimes contradictory ethical-legal framework and how the framework could be improved to simultaneously promote critical research and the welfare of child participants.     

The South African Medical Research Council's Guidelines on Ethics for Medical Research--implications for HIV-preventive vaccine trials with children.

Children are at risk of HIV infection, stand to benefit from the development of HIV preventive vaccines, and therefore should be enrolled in trials of HIV vaccines in order to generate relevant safety, immunogenicity and efficacy data. In South Africa, the national vaccine initiative is considering the future conduct of trials involving children; this requires an analysis of the current ethical framework, including elements that facilitate or constrain the conduct of such trials. In this article, we examine the Medical Research Council (MRC)'s Guidelines on Ethics for Medical Research: General Principles (Book 1), and their provisions on research involving children. We argue that this set of influential guidelines includes provisions on research with children that are conceptually problematic and may prohibit critical research with healthy (but at-risk) child participants, including trials of HIV-preventive vaccines. We recommend that Book 1 provisions should be redrafted to reflect a balance between protecting children from research-related risks and testing interventions critical to their health.     

The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of xenocorneal transplantation

To develop an international consensus regarding the appropriate conditions for undertaking clinical trials in xenocorneal transplantation, here we review specific ethical, logistical, scientific, and regulatory issues regarding xenocorneal transplantation, and propose guidelines for conduct of clinical xenocorneal transplantation trials. These proposed guidelines are modeled on the published consensus statement of the International Xenotransplantation Association regarding recommended guidelines for conduct of clinical islet xenotransplantation. It is expected that this initial consensus statement will be revised over time in response to scientific advances in the field, and changes in the regulatory framework based on accumulating clinical experience.     

Publication ethics

The editor of any medical journal has to be aware of the ethical and legal framework within which medical research is conducted. When research and publications relate to children, then particularly high standards are required in the design, conduct, and reporting of research in order to protect the rights of children and their families. Authors have a number of duties and responsibilities that are mirrored by those of editors and publishers. Of particular importance are the principles of transparency and integrity. Authors should be explicit about who carried out the work and who funded the study. They should declare whether the work has been published before and is not being considered for publication elsewhere. The authors must protect the rights of research participants including their anonymity. Editors and publishers have a duty to ensure high editorial standards and efficient and effective peer review systems. They should follow ethical and responsible publication practices and should safeguard the intellectual property of the authors. This review discusses in detail the duties and responsibilities of authors, editors, and publishers in modern medical publishing.     

Voluntary informed consent and good clinical practice for clinical research in South Africa: ethical and legal perspectives

Most differences, shortcomings and contradictions regarding voluntary informed consent for participation in clinical research relate to the South African-specific guidance documents, i.e. South African Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa (2006) and Ethics in Health Research: Principles, Structures and Processes (2004). These documents do not fulfil all the ethical and legal requirements for voluntary informed consent for clinical research participation in South Africa. International guidance documents reflect the minimum of the ethical requirements for the conduct of clinical research. Country-specific documents should be updated and aligned with relevant legislative and legal principles of that jurisdiction to ensure that research participants are adequately protected. The South African-specific guidance documents therefore require revision to address these deficiencies.     

Pharmacologically active: clinical trials and the pharmaceutical industry.

Multinational pharmaceutical companies ( 'pharmas') import and produce pharmaceuticals and also conduct clinical trials which are an important aspect of research and development (R&D). This may raise the question: Is South Africa a guinea pig for the pharmas? The Department of Trade and Industry National Industrial Policy Framework(1) designates chemicals, plastic fabrication and pharmaceuticals as a key value chain. So a second question could be: Can South Africa be a manufacturer for the pharmas, or can it leverage strengths in medical research and the conducting of clinical trials so as to develop a discovery-led industry? This paper analyses and quantifies the state of the clinical trials industry in South Africa, and concludes that: (i) a sizeable clinical trials industry exists, and that these trials are predominantly phase 3 and global in scope; (ii) South Africa is not a specific or unique guinea pig--a range of conditions is studied as part of global trials; and (iii) while South Africa has excellent prospects for increased clinical trials activity, R&D investment is too low to make it a major pharmaceutical contender.     

Reviewing independent access to HIV testing,counselling and treatment for adolescents in HIV‐specific laws in sub‐Saharan Africa: implications for the HIV response

Introduction : AIDS is a leading cause of death among adolescents in sub‐Saharan Africa. Yet, legal, policy and social barriers continue to restrict their access to HIV services. In recent years, access to independent HIV testing and treatment for adolescents has gained increased attention. The 2013 WHO Guidance on HIV testing and counselling and care for adolescents living with HIV (WHO Guidance) calls for reviewing legal and regulatory frameworks to facilitate adolescents’ access to comprehensive HIV services. As of 31 March 2017, some 28 countries in sub‐Saharan Africa have adopted HIV‐specific legislation. But there is limited understanding of the provisions of these laws on access to HIV services for adolescents and their implication on efforts to scale up HIV prevention, testing, treatment and care among this population. Methods : A desk review of 28 HIV‐specific laws in sub‐Saharan Africa complemented with the review of HIV testing policies in four countries using human rights norms and key public health recommendations from the 2013 WHO Guidance. These recommendations call on countries to (i) lower the age of consent to HIV testing and counselling and allow mature adolescents who have not reached the age of consent to independently access HIV testing, (ii) ensure access to HIV counselling for adolescents, (iii) protect the confidentiality of adolescents living with HIV and (iv) facilitate access to HIV treatment for adolescents living with HIV. Results : Most HIV‐specific laws fail to take into account human rights principles and public health recommendations for facilitating adolescents’ access to HIV services. None of the countries with HIV‐specific laws has adopted all four recommendations for access to HIV services for adolescents. Discrepancies exist between HIV laws and national policy documents. Inadequate and conflicting provisions in HIV laws are likely to hinder access to HIV testing, counselling and treatment for adolescents. Conclusions : Efforts to end legal barriers to access to HIV services for adolescents in sub‐Saharan Africa should address HIV‐specific laws. Restrictive provisions in these laws should be reformed, and their protective norms effectively implemented including by translating them into national policies and ensuring sensitization and training of healthcare workers and communities. This study reiterates the need for action in all countries across Africa and beyond to review their laws and policies to create an enabling environment to accelerate access to HIV prevention, testing and treatment services for adolescents.     

Urogynaecological research: current and future developments

The massive introduction of new products from device and drug industries together with a scanty device approval process and a growing scepticism about the reliability of drug trials call for new improved strategies in urogynaecological research. Device companies and physicians have a mutual ethical responsibility of contributing to create clinical data based on the framework of trials in surgery before new surgical products are implemented and disseminated. In respect of the patients' altruism and confidence, which make drug trials possible, the industry and academia have an obligation to conduct and report clinical results in accordance with the highest standards of scientific and ethical integrity.     

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40 , 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51 , 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.     

Comparative assessment of five trials of universal HIV testing and treatment in sub‐Saharan Africa

Design

Universal voluntary HIV counselling and testing followed by prompt initiation of antiretroviral therapy (ART) for all those diagnosed HIV‐infected (universal test and treat, UTT) is now a global health standard. However, its population‐level impact, feasibility and cost remain unknown. Five community‐based trials have been implemented in sub‐Saharan Africa to measure the effects of various UTT strategies at population level: BCPP/YaTsie in Botswana, MaxART in Swaziland, HPTN 071 (PopART) in South Africa and Zambia, SEARCH in Uganda and Kenya and ANRS 12249 TasP in South Africa. This report describes and contrasts the contexts, research methodologies, intervention packages, themes explored, evolution of study designs and interventions related to each of these five UTT trials.

Methods

We conducted a comparative assessment of the five trials using data extracted from study protocols and collected during baseline studies, with additional input from study investigators. We organized differences and commonalities across the trials in five categories: trial contexts, research designs, intervention packages, trial themes and adaptations.

Results

All performed in the context of generalized HIV epidemics, the trials highly differ in their social, demographic, economic, political and health systems settings. They share the common aim of assessing the impact of UTT on the HIV epidemic but differ in methodological aspects such as study design and eligibility criteria for trial populations. In addition to universal ART initiation, the trials deliver a wide range of biomedical, behavioural and structural interventions as part of their UTT strategies. The five studies explore common issues, including the uptake rates of the trial services and individual health outcomes. All trials have adapted since their initiation to the evolving political, economic and public health contexts, including adopting the successive national recommendations for ART initiation.

Conclusions

We found substantial commonalities but also differences between the five UTT trials in their design, conduct and multidisciplinary outputs. As empirical literature on how UTT may improve efficiency and quality of HIV care at population level is still scarce, this article provides a foundation for more collaborative research on UTT and supports evidence‐based decision making for HIV care in country and internationally.

     

Protection of human participants in health research - a comparison of some US Federal Regulations and South African Research Ethics guidelines

In response to criticism of ethical review of a South African clinical trial, we contrast aspects of the United States Common Rule with South African research ethics requirements. In the USA the Common Rule does not apply to all health research and allows many exemptions from ethics review and waivers of informed consent. At a structural level research ethics review in South Africa is in many cases equivalent to the US institutional review board (IRB) and Office for Human Research Protections (OHRP) oversight system, is wider reaching, and has no exclusions.     

我国器官移植伦理委员会的建设与规范化运行思考

为适应我国器官移植的规范开展需要,器官移植伦理委员会的结构应科学合理,成员要多样性,且具有必要的伦理学知识,必须建立适应性广泛、合理和规范的道德原则和准则,制定系统、规范的伦理学审查操作指南。尸体器官移植的伦理学审查重点是器官分配是否公正公平,活体器官移植的伦理学审查重点则是捐献意愿的真实性、知情同意和风险受益比的评估。伦理委员会还应结合实际开展对从事器官移植医护人员的伦理教育和培训。     

How well does South Africa's National Health Act regulate research involving children?

Currently there are no laws in South Africa regulating the rights of research participants. The National Health Act is the first attempt by the legislature to use the law to protect research participants, including children. This article describes the strengths and limitations of the provisions, implications for researchers and research ethics committees, and makes recommendations. Strengths of the Section include that it enables the Minister of Health to issue regulations detailing protections for research participants, it supplements existing law on consent, it introduces the concept of the 'best interests' of the child and it creates procedural safeguards. Limitations of the Section include that it does not set an independent age for consent to research, it focuses on informed consent and not other protections, it is inconsistent with existing or draft legislation and ethical guidelines, and it retains the contested distinction between 'therapeutic' and 'non-therapeutic' research. Poor drafting and inconsistencies also impede interpretation. The implications for researchers are that it facilitates so-called 'non-therapeutic' research on children. However, procedural burdens for obtaining consent are created. Research Ethics Committees (RECs) will have to work with the 'therapeutic' and 'non-therapeutic' distinction as well as new concepts such as 'best interests' of the child, and ensure that consent procedures comply with the Act. We conclude that while the Act is an important development in the law, it is flawed in places. We recommend that amendments be made and that capacity development be provided to stakeholders.     

Randomised Clinical Trials in Surgery: A Look at the Ethical and Practical Issues

An ethically conducted randomised controlled trial (RCT) is the backbone of evidence based medicine. In surgical practice however, RCTs have taken a backseat, drawing much adverse comment. There are several reasons to explain surgeons’ disinclination to conduct RCTs. These include many practical difficulties such as the problem of blinding surgical procedures, design and funding issues. There are also many ethical issues which need to be considered including the concept of equipoise as well as the ethical issues associated with sham surgery as a control. While there is no doubt that RCTs are essential and in fact have helped to weed out several unnecessary surgical procedures, it is important not to lose sight of the fact that they may not be always necessary in order to obtain evidence in favour of a procedure. Possible solutions could be to follow guidelines that have been issued by learned bodies and a strict adherence to all ethical norms that have been recommended in the conduct of trials     

Biomedical publication for neurosurgery residents: a program and guide

One of the most pressing obligations in academic neurosurgery is the publication of clinical and basic science research results. Publication documents intellectual property and communicates findings among researchers working to improve neurosurgical treatment. It documents productivity, justifies funding for research, creates reputations, and builds careers. Nonetheless, the actual writing of reports is a skill often learned by osmosis in academic medicine. To give residents the tools necessary to negotiate the biomedical publication process successfully, we developed a publications program based on the premise that residents seeking an academic career must be prepared to generate publishable reports with maximum efficiency. The program consists of a "publication kit," a series of seminars, and one-on-one tutorials with academic biomedical editors that permit residents individually to improve the quality of their reporting. We describe this program, provide guidelines that can help residents write high-quality papers and publish their work more efficiently, and summarize important content regarding the framework for a successful paper, the elements of a conventional research report, brief guidelines for specific types of papers, reporting standards for clinical trials and meta-analyses, keys to citation in bibliographic indexes, and ethical and legal considerations related to research approval, confidentiality requirements, copyright law, permission to use previously published material, and conflict of interest. Residents who are able to view their work with a sharp critical focus and are educated about the standards of biomedical publication are better prepared to succeed in building a career in academic medicine.     

Patients with severe mental illness: a new approach to testing for HIV.

BACKGROUND: The prevalence of HIV infection in South Africa is approaching 20% of young adults. In severely mentally ill people it is probably higher. Testing for infection is subject to stringent ethical principles. Undiagnosed HIV infection in people with severe mental illness increases costs and morbidity. Since effective treatments are available, it is imperative to diagnose HIV infection early in this high-risk population. METHODS: A literature review established the prevalence of HIV infection in inpatient populations with HIV infection. The pattern of testing for HIV over 3 years at a major psychiatric hospital was investigated. We surveyed public sector psychiatrists in the Western Cape to establish their attitudes to HIV in their patients. RESULTS: The reported HIV seroprevalence in psychiatric inpatients ranges from 0 to 59.3%, with a mean of 10%. Data show a clear trend towards an increase in prevalence: before 1996 the mean HIV seroprevalence was 7.4%, while after 1996 the mean was 15%. State psychiatrists in the Western Cape do not test routinely for HIV infection, mainly owing to ethical constraints: 14.6% of patients at Lentegeur Hospital were tested in 2006. CONCLUSIONS: The high prevalence of HIV infection in South Africa, which is probably higher in patients with severe mental illness (most of whom are not competent to provide informed consent), and the availability of effective treatment require debate and a clear policy regarding testing for HIV infection to be implemented. We recommend a new approach to HIV testing in these patients.     

HIV infection in Africa. Clinical and therapeutical research

A MAJOR HEALTH PROBLEM: Human Immunodeficiency Virus (HIV) infection is a major public health problem in sub-Saharan Africa and the care of HIV-infected patients is limited by the lack of resources. Clinical research can play a major role to assess the benefit of preventive and/or curative measures adapted to the context of these countries. To illustrate advances and gaps in HIV/AIDS clinical research in Africa, we explored three issues relevant to this research: opportunistic infections in adults, mother-to-child transmission of HIV and the ethical questions. EPIDEMIOLOGY: Epidemiological African studies have shown: the omnipresence of tuberculosis, first cause of death among HIV+ patients; the frequency of bacterial infections, first cause of serious morbidity and second cause of death; the high frequency of toxoplasmosis, cryptococcal meningitis, isosporiasis, cryptosporidiasis, and other infectious syndromes of unknown etiology. More research efforts need to be done for improving tuberculosis diagnosis, compliance to treatment (evaluation of Directed Observed Therapy), resistance to treatment and primary chemoprophylaxis which has shown clear short term benefit but median term interest remains to be demonstrated. Chemoprophylaxis of opportunistic infections other than tuberculosis needs also to be evaluated: cotrimoxazole reduces the short term mortality of HIV+ patients with tuberculosis and the early serious morbidity of HIV+ patients without tuberculosis. TRANSMISSION: Mother-to-child transmission of HIV can occur during pregnancy, during delivery and the postnatal period by breastfeeding, a common practice in Africa. The overall risk of vertical transmission is estimated to be 30% but the attributable part of breastfeeding needs to be further explored. Beyond the prevention of sexual transmission of HIV among childbearing women and family planning for HIV+ women, interventions aimed to reduce mother-to-child transmission depend on the availability or not of a proposing and realising an HIV counselling and testing: antiretroviral treatments and/or breastfeeding alternatives which reduce efficaciously transmission require HIV testing, while vaginal disinfection and vitamin supplementation whom efficacy needs to be demonstrated do not. PREVENTION: Prevention of mother-to-child transmission and care of HIV+ adults in the area of opportunistic infections are feasible in Africa with an acceptable cost. This requires first to train and inform health care providers and the populations. Lots of uncertainties in these areas are likely to be alleviated by reinforcing clinical and therapeutic research of good quality including the questions of antiretroviral treatment. Ethical issues raised by the design and conduct of clinical research in Africa need a positive thinking to face the HIV African pandemic.     

Ethical considerations for innovations and clinical trials

The ethical imperative to improve practice through innovation and research finds justification in the requirements of physicians to help patients, minimize the harms of treatment and disease, and to bring the benefits of scientific medicine to those suffering from illnesses for which satisfactory treatment has not yet been developed. This article discusses the values and principles that underlie clinical trials; the need for evidence-based knowledge; the difference between research and therapy; the ethical duty to improve care through research; the challenge of conflict of interest; the relevance of clinical equipoise; the need for research review and postapproval monitoring; and the value of disseminating results to research subjects, colleagues, and the public. Public confidence and willingness to participate in clinical trials will continue if the ethical standards set by professional, government, and international bodies are met.     

HIV-positive status among surgeons - an ethical dilemma.

HIV/AIDS is a manageable disease with a reasonable expectation that affected individuals might be able to experience both reduced mortality and morbidity. Within the socio-political context of the illness there has been a very strong emphasis on human rights issues, especially in relation to discrimination, which has seemingly been influenced more by emotion than science. This article explores and addresses the potential risk of an HIV-positive surgeon transmitting the virus to a patient. We argue that the Centers for Disease Control (CDC) and Health Professions Council of South Africa (HPCSA) guidelines are too restrictive, especially against a background of limited transmission risk, and hence that these guidelines could be more harmful than beneficial to our health systems.     

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.