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African Journal of AIDS Research 2010, 9(3): 249–259 Printed in South Africa — All rights reserved

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ISSN 1608–5906 EISSN 1727–9445 doi: 10.2989/16085906.2010.530178

The role of law in the regulation of HIV-vaccine research in South Africa and Kenya Pamela Andanda University of the Witwatersrand, School of Law, Private Bag 3, Johannesburg 2050, South Africa Author’s e-mail: [email protected] Law is an important regulatory mechanism, particularly for creating an enabling research environment. However, the manner in which law addresses issues related to medical research, and HIV-vaccine research in particular, is at times inadequate and of great concern to the stakeholders involved in such research. The challenges for law as a regulatory mechanism in this regard are twofold: the complexity of issues related to HIV-vaccine research, and the apparent disconnection between the legal and ethical frameworks that are applied in the regulation of these issues. This article analyses the extent to which these challenges have been addressed in South Africa and Kenya. Especially, it highlights the lessons that can be drawn from the two countries in establishing a suitable ethical-legal framework for HIV-vaccine research. Keywords: drug research, ethics, guidelines, HIV/AIDS, legal aspects, legislation

Introduction It is apparent that no specific regime of law governs medical research in general at the international level or in most jurisdictions. Concerted efforts have been made over the years to regulate medical research using ethics guidelines as well as legislative provisions. However, close scrutiny shows that law, as a regulatory mechanism, tends to move slower than advances in medical research (Andanda, 2006). In this regard, Justice Windeyer’s orbiter dictum in Mount Isa Mines Ltd v Pusey (1970), describing the pace at which law moves in relation to medicine — as “law marching with medicine, but in the rear and limping a little” — may still be relevant today. The judge in the above case had to determine whether the defendant could be held liable for the plaintiff’s schizophrenic condition, which was set off by shock as a result of witnessing two fellow employees being severely burnt due to the defendant’s negligence. Noting that the law had come a long way in its ‘march’ with medicine, the judge handed down a rather progressive judgment in holding that it was sufficient that the type of injury was foreseeable as a possible consequence of a particular conduct, and on this basis the defendant was liable. This case is more relevant for delictual claims, but it does give an indication that law ought to bring itself up to speed with other areas, such as biomedical research. This possibility informs the discussion here, hence the metaphorical manner of describing the pace of law. This article focuses on HIV/AIDS preventive vaccine research because it is one field of biomedical research that poses challenges based on the fact that 1) the candidate vaccines are often tried out on potentially vulnerable communities and participants, and 2) because high levels

of discrimination and stigma still surround HIV and AIDS (Slack, Lindegger & Vardas, 2002). Most importantly, “Regulatory challenges are likely to accompany approval criteria for vaccines with low efficacy or trials with unconventional clinical endpoints, such as lowered viral setpoint and consequent delayed disease progression” (Berkley & Koff, 2007, p. 98). HIV-vaccine research has equally generated a lot of controversy in both Kenya and South Africa in comparison with research on vaccines for other diseases (Patel, 2006; Nienaber, 2008). The second part of this article provides an overview of the legal frameworks that regulate clinical research in Kenya and South Africa, with a view to establishing the extent to which these frameworks are relevant for regulating HIV-vaccine research. The unique challenges that are involved in regulating HIV-vaccine research are discussed in the third part, while lessons that can be learnt from attempting to deal with the challenges are considered in the fourth part, with a view to suggesting ways of improving the role that law currently plays in the regulation of HIV-vaccine research. The legal framework for regulating research in Kenya and South Africa Regulatory frameworks in Kenya An audit of regulations for HIV-vaccine research in Africa, conducted by Grant, Lewis & Strode (2005) between 2003 and 2004, revealed that no concise legal framework was in place in Kenya to govern clinical research and the rights of trial participants. As such, researchers and stakeholders tended to rely on relevant provisions from the Constitution, statutory laws, as well as common law for research governance and regulatory purposes. Subsequently, a lot of progress has been made in Kenya, particularly since

African Journal of AIDS Research is co-published by NISC (Pty) Ltd and Routledge, Taylor & Francis Group

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late 2004. Before discussing the new developments, it is important to explain the nature of the legal framework that researchers and other stakeholders had to rely on. This is helpful for appreciating the inadequacy of the framework before it was improved. Pre-2004 ethical-legal framework As mentioned above, during this period researchers and stakeholders in Kenya had to rely on relevant provisions from the Constitution, statutory laws, as well as the common law for research governance and regulatory purposes. Chapter 5 of the Constitution provides for fundamental rights, such as the right to life (section 71); liberty, security of the person and the protection of the law (section 72(1)); freedom of conscience, expression, assembly and association; and protection of the privacy of one’s home and other property and from deprivation of property without compensation (section 70). No specific provision in the Constitution deals with clinical research. Kenya’s common law is based on English common law, and the extent of the application of such law is governed by the Judicature Act of 1967. Section 3(1) (c) of the Act provides that common law “shall apply so far only as the circumstances of Kenya and its inhabitants permit and subject to such qualifications as those circumstances may render necessary.” This in essence means that established principles from the law of negligence can be used in the research context. Apart from the above legislation, the only glimmer of an attempt to establish an ethical-legal framework for biomedical research in Kenya was the enactment of the Science and Technology Act of 1979 (Chapter 250 of the Laws of Kenya), which established the National Council for Science and Technology (NCST) to coordinate all research in Kenya and to advise the government on all matters related to research. Thus, the NCST is responsible for assessing the technical and ethical aspects of the proposals submitted for clearance and authorisation. It is equally under this Act that the Kenya Medical Research Institute (KEMRI) was established, in 1979, as the national body responsible for carrying out health research in Kenya (Patel, 2006). Institutional ethical clearance committees provide ethics clearance, but, surprisingly, only KEMRI had research guidelines (see NCST, 2005, p. 2). In 1984, the NCST published the Research Clearance Procedures and Guidelines; these guidelines dealt with clearance of all research conducted in the country and not specifically with research on humans. There is only one reported case where Kenyan courts had to deal with an application relating to research concerning HIV/AIDS. The case of Kenya AIDS Society v Arthur Obel (1998) was not directly related to HIV-vaccine research, but it concerned HIV/AIDS treatment using a drug that had not been subjected to conventional clinical research before being supplied to the public. The appellant was a non-governmental organisation lobbying for the recognition and protection of the rights of people with HIV or AIDS, and — among other aims — lobbying for legislative reform and initiative, and generally undertaking advocacy work in all areas affecting HIV/AIDS, as well as liaising with relevant

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government departments in handling HIV/AIDS issues. The respondent in the case was a registered medical practitioner, researcher, professor of medicine at the University of Nairobi, as well as a clinical pharmacologist. The appellant had approached the High Court at Nairobi seeking an injunction to restrain the respondent from manufacturing, distributing, offering for sale, selling, administering or in any manner dealing with a substance known as Pearl Omega, pending the determination of the case. The appellant alleged that the respondent, through the print media, had held out to members of the public that he had found a cure for HIV/AIDS which he called Pearl Omega. The appellant’s members had bought Pearl Omega and discovered that it was ineffectual. The appellant conducted additional investigation with the relevant bodies and established that the respondent was in total violation of various Acts of Parliament controlling the research, production or manufacture of drugs. The Acts that the appellant cited were the Pharmacy and Poisons Act (Chapter 244 of the Laws of Kenya) and the Rules made under the Science and Technology Act. It should be noted that the Pharmacy and Poisons Act regulates the practice of pharmacy, and since the respondent was not a pharmacist, the most relevant provision of the Act in this case is section 19(1) (b), which prohibits people who are not registered as pharmacists from preparing, mixing, compounding or dispensing a drug in the course of their trade or business, except under the immediate supervision of a registered pharmacist. The rules under the Science and Technology Act in this context refer to the NCST 1984 guidelines, which did not specifically deal with research on humans. Those guidelines are accurately described in the NCST 2005 guidelines as “weak with many loopholes, which have been exploited in the past…by people who do not want to do sound scientific and ethically acceptable research” (NCST, 2005, p. 2). In determining the application for an interim injunction, the High Court judge applied the established legal principles (from the case of Giella v Cassman Brown & Company Ltd [1973]). The principles are that an applicant must make out a prima facie case with a probability of success, and if a prima facie case is made out but it is established that damages would adequately compensate the applicant, then an injunction ought not to be granted. In applying these principles, the judge held that the appellant had not made out a prima facie case with a probability of success, and, furthermore, that even if such a case were made out, damages would adequately compensate the appellant. On appeal, the court (comprised of three judges) had to determine whether the High Court judge had properly exercised his judicial discretion by refusing to grant the appellants an interim injunction. The Court of Appeal (in a four-page ruling) agreed with the decision of the High Court by holding that the judge had applied the correct legal principles in deciding not to grant an order for injunction. The court went on to state the following: “We suppose it is in the interest of the appellant to ensure that all the laws regarding research into drugs, their manufacture and distribution are complied with, but even if the appellant were to prove in the impending trial that such laws were not

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complied with, the appellant would still be required to prove loss to it and its members arising from the failure to comply with the law. The only loss we can see is that the appellant and its members would have spent money buying a concoction that is ineffectual against the malady it was intended to cure” (pp. 3–4 of the judgment). The court also expressed the view that the appellant was aware that Pearl Omega was ineffectual even before filing the case and was not therefore obliged to buy it. The appeal was therefore dismissed. The appellant’s application in this case failed on purely technical grounds — that is, because the requirements in terms of the legal principles governing the granting of injunctions were not satisfied. It is clear that the courts did not delve much into the substance of the application — particularly the issue of a prominent researcher publishing his alleged research findings in the print media instead of in a peer-reviewed journal. The courts did not equally appreciate the effect of the respondent’s conduct on the public, as well as the fact that his alleged research did not comply with the statutory requirements or follow conventional procedural requirements for clinical research. The ruling by both courts clearly illustrates the disconnection that can emerge between law and medical research — particularly when judges stick to procedural rules in total disregard of the substantive issues that are raised by the parties. During the hearing of the application before the Court of Appeal, the appellant’s advocate argued that “a man like the respondent must of necessity be restrained when addressing the public in the area of his specialisation, and that if for some reason of his own, such as personal gain, he chooses to make unsubstantiated claims likely to be believed and to be injurious to the public, then courts ought to intervene and stop him” (pp. 2–3 of the judgment). The court simply registered the advocate’s concern and noted that the respondent was a highly trained man and that what he said in his area of training was very likely to be taken seriously, particularly by ordinary members of the public. Apart from noting the advocate’s concern, the court did not reckon with the argument in handing down its ruling. What is disturbing in this ruling is that the court was of the view that any loss that members of the appellant may have suffered as a result of the respondent’s conduct could be easily quantified and remedied by way of damages. One wonders how adverse reactions and possible harm to the public from taking Pearl Omega, which had not been subjected to clinical research, could be quantified and remedied by way of damages. Apart from the court ruling, the issue of Pearl Omega also featured in parliamentary debates after Arthur Obel announced in his book (Pearl Omega: The Anti-Illusive AIDS Agent: Obel, 1996) that the product had converted the HIV-positive serostatus of seven patients. The government was initially willing to support additional clinical trials, but just one week after the Assistant Minister of Health announced this proposed plan in Parliament, the Minister of Health denounced Pearl Omega as a herbal concoction and stated that the author Obel had ‘bent the rules’ (Dodd, 1996).

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Post-2004 ethical-legal framework As biomedical research involving humans rapidly expanded in the country “with the involvement of an increasing number of non-governmental institutions, as a result of the HIV/AIDS pandemic, the NCST…” realised the need to “… position itself strategically in order to be able to efficiently and effectively coordinate all research in this area” (NCST, 2005, p. 2). The NCST decisive step was to set standards to be complied with by those who wish to conduct research involving humans. These standards are contained in the NCST Guidelines for Ethical Conduct of Biomedical Research Involving Human Subjects in Kenya (NCST, 2005). In issuing these guidelines, the NCST expressed hope that they would seal the loopholes that had existed in the previous medical-research regulatory mechanism in Kenya. After decrying the weaknesses of the prevailing ethical-legal framework for research on humans, the NCST proposed a way forward: In such circumstances, the Council should have powers to audit such works and mete out appropriate sanctions on such individuals if found to be peddling falsehood. It is hoped that the development of ethical guidelines by the Council for sound conduct of biomedical research involving human subjects with HIV/AIDS will go a long way in assisting it to regulate research efficiently and effectively [emphasis added] (NCST, 2005, p. 2). The emphasis in the above quote testifies to the fact that an ethical-legal framework that provides an enforcement mechanism is preferred by the NCST as a better option compared to exclusive reliance on ethics guidelines. This is the case in view of the fact that the NCST considered its 1984 guidelines (which did not provide an enforcement mechanism) to be inadequate. The NCST 2005 guidelines take into account ethical issues that have arisen since the advent of the HIV pandemic, such as drug and vaccine trials on humans. (The specific manner in which the guidelines address issues related to HIV-vaccine research is discussed in the third part of this article.) Another relevant development is the enactment of the HIV and AIDS Prevention and Control Act 14 of 2006. Although the Act does not specifically deal with research, it provides an enforcement mechanism through which parties can refer matters relating to breach of the NCST ethics guidelines, issued under the Science and Technology Act, to a specialised tribunal, known as the Equity Tribunal. Section 39 of the Act provides that no person shall undertake HIV/ AIDS-related human biomedical research on another person, or on any tissue or blood removed from such person, unless such research conforms to the requirements under the Science and Technology Act or any other written law for the time in force. A very important development under the HIV and AIDS Prevention and Control Act is the establishment of the Equity Tribunal under section 25. In terms of this section, the Attorney General must appoint persons to sit on the tribunal. The composition of the tribunal’s members is as follows: a chairman who shall be an advocate of the High Court with at least seven years of experience; two advocates of the High Court with at least five years of

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experience; two medical practitioners registered with the Medical Practitioners’ Board; and two persons with the specialised skills or knowledge necessary for the discharge of the functions of the tribunal. Section 26 of the Act confers jurisdiction on the tribunal to hear and determine complaints arising out of any breach of the provisions of the Act. This section clearly demonstrates that a legislative intervention has been put in place to provide research participants and researchers with an avenue for redress in the case of breach of research ethics. The requirements under the Science and Technology Act are stipulated in the NCST (2005) ethics guidelines. The guidelines relevant for discussion are summarised here: • Guideline 2 requires the study design to be clearly formulated in an experimental protocol, which should be transmitted for consideration, comment and guidance to an independent ethics clearance committee. • Guideline 3 provides that the research must only be conducted by scientifically qualified persons and under the supervision of a clinically competent medical person who is responsible for the participants. • Guideline 6 stipulates the requirements for the procurement of informed consent, while • Guideline 7 provides the details of the information that must be disclosed to the participants in procuring their consent. The impression that one gets from the legislation and guidelines mentioned above is that Kenya has an ethical-legal framework that deals with research on humans. This impression is based on the fact that the ethics guidelines governing clinical research in Kenya can be directly linked to the legal framework. Moreover, an attempt has been made to prioritise HIV-vaccine research. For instance, in the HIV-vaccine research guidelines it is indicated that “policy and political issues regarding identification and recruitment of the study populations and future assurance regarding access to a successful vaccine need to be addressed” (Ministry of Health, 2005, p. 7). As the discussion in the third part of this article shows, an attempt has been made to provide specific modalities for addressing such issues through the NCST guidelines. One of the terms of reference for the Kenya HIV/AIDS Vaccine Subcommittee (VSC), which was constituted by the Director of Medical Services in January 2004, is to develop policies on pertinent issues in vaccine research — such as scientific and ethical review of HIV/AIDS preventive vaccine research proposals; regulatory approval of candidate HIV vaccines; and eventual licensing and use of a successful HIV vaccine. The subcommittee functions as an advisory body to the Ministry of Health in regard to HIV-vaccine research and development. And, from the discussion of the frameworks in place, it is evident that progress has been made with regard to mechanisms for scientific and ethical review of HIV-vaccine research proposals. Regulatory frameworks in South Africa Various statutes as well as ethics guidelines exist to regulate research on humans in South Africa. Apart from the Constitution, other relevant statutes are the National Health Act 61 of 2003 and the Medicines and Related Substances Act 101 of 1965. The ethics guidelines in place are the

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National Department of Health’s Ethical Considerations for HIV and AIDS Clinical and Epidemiological Research (Department of Health [DoH], 2000) and the South African Medical Research Council’s (2003) guidelines for ethics on medical research (HIV Preventive Vaccine Research). The latter guidelines are an adaptation of those by the Joint United Nations Programme on HIV/AIDS, entitled Ethical Considerations in HIV Preventive Vaccine Research (UNAIDS, 2000), and only apply in respect of research funded by the Medical Research Council or conducted under its auspices. As such this article focuses more on guidelines created by the DoH, which are binding at a national level. It should be noted that the ethics guidelines (i.e. DoH, 2000) are used together with the general guidelines (i.e. Guidelines for Good Clinical Practice in the Conduct of Clinical Trials in Human Participants in South Africa, DoH, 2006). This part of the article provides an overview of the ethical-legal framework in South Africa, while the specific manner in which the framework has been used to address issues related to HIV-vaccine research is discussed in part three. The Constitution generally deals with medical research under section 12(c), which protects the rights of research participants. That section provides that everyone has the right to bodily and psychological integrity, which includes the right not to be subjected to medical or scientific experiments without giving informed consent. The sections of the Constitution that provide for other rights are equally relevant: for example, the right to equality (section 9), the right to human dignity (section 10), the right to life (section 11), the right to privacy (section 14), and the right to access healthcare (section 27(1) (a)). The National Health Act specifically deals with research on humans, in sections 71 and 72. For instance, section 71(1) provides as follows: Notwithstanding anything to the contrary in any other law, research or experimentation on a living person may only be conducted — (a) in the prescribed manner; and (b) with the written consent of the person after he or she has been informed of the objects of the research or experimentation and any possible positive or negative consequences on his or her health. This provision is relevant for addressing the three issues that law needs to deal with (discussed further in part three of the article): the relevance of study design, the procurement of informed consent, and the possibility of exploitation. Section 72(1) of the National Health Act provides for the establishment of the National Health Research Ethics Council. The council’s functions are stipulated in subsection 6 and include, inter alia: • Determine the guidelines for the functioning of healthresearch ethics committees. • Register and audit health-research ethics committees. • Set norms and standards for conducting research on humans and animals, including norms and standards for conducting clinical trials. • Advise the national and provincial branches of the DoH on any ethical issues concerning research. One purpose of the Medicines and Related Substances

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Act has been to establish the Medicines Control Council, which has the responsibility of regulating the registration of medicines intended for use in humans and animals. As such, this statutory body plays the important role of ensuring that clinical trial protocols are assessed according to prescribed ethical standards. Specific regulations have been made under the Act to regulate clinical trials. For instance, Regulation 34(1) provides that “a person desiring to initiate or conduct a clinical trial in respect of an unregistered medicine, a new indication or new dosage regimen of a registered medicine or substance, shall apply to a Council on a form determined by the Council for authority to conduct such a clinical trial”, while Regulation 34(5) prohibits conducting clinical trials, referred to in subregulation (1), without the authorisation of the Council. The above-mentioned statutes and guidelines in South Africa clearly create an ethical-legal framework for research on humans insofar as they provide for the protection of the research participants’ rights. This is illustrated by the recent case of the Treatment Action Campaign and Another v Rath and Others (2008), where the concept of ‘clinical trial’ was judicially considered for the first time. The case also tested the provisions of the National Health Act, as the court had to determine whether unlawful clinical trials were being conducted by the first to seventh respondents and whether the government respondents in the case had failed to take steps to prevent such unlawful clinical trials (for detailed analysis and commentary on the case, see Andanda & Pretorius, 2010). In this case, the first applicant, the Treatment Action Campaign (TAC), and the second applicant, the South African Medical Association (SAMA, a representative body for medical doctors in South Africa), brought an action against the first to seventh respondents (i.e. ‘Rath respondents’), claiming that these respondents had been systematically contravening various provisions of the Medicines and Related Substances Act, 1965 (Act No. 101 of 1965) (hereafter ‘the Medicines Act’). The specific activities that the applicants accused the Rath respondents of included: the sale and/or distribution of the products Vitacor Plus, Epican Forte, Lysin-C Drink Mix, and VitaCell (‘the products’) in South Africa without complying with the provisions of the Medicines Act; the conduct of unauthorised clinical trials in the country; the publication of unauthorised clinical trials in the country; and the publication of false and misleading advertisements regarding the efficacy of the products in the treatment and prevention of HIV or AIDS. The applicants further contended that if the activities of the Rath respondents were unlawful, then the eighth and ninth respondents (‘government respondents’) were under a duty to take reasonable measures to prevent such unlawful conduct and that these respondents had failed in their duties to investigate the matter properly and to take reasonable measures to prevent them. On the basis of the above contentions, the applicants sought: “1. an order declaring that the distribution and/or sale by the first and second respondents and any of their agents of the products Vitacor Plus, Epican

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Forte, Lysin-C Drink Mix and VitaCell in South Africa is unlawful, and 2. an order declaring that the clinical trials conducted in South Africa by and/ or under the direction of first, second, third, fourth, and fifth respondents are unlawful. 3. an order interdicting the first and second respondents from either directly or through agents distributing and/or selling the products Vitacor Plus, Epican Forte, Lysin-C Drink Mix and VitaCell in South Africa except in accordance with provisions of the Medicines and Related Substances Act 101 of 1965; 4. an order interdicting the first to fifth respondents from conducting unauthorised clinical trials in South Africa; and 5. an order interdicting the first to seventh respondents from publishing false or misleading advertisements concerning vitamins, multivitamins and the products Vitacor Plus, Epican Forte, Lysin-C Drink Mix and VitaCell” (see paragraph 4 of the judgment: Treatment Action Campaign and Another v Rath and Others [2008]). During the hearing of the application, the Rath respondents denied that the products, which they were distributing, were medicines and equally indicated that they had stopped distributing the products long before the applicants filed the case. Consequently, no order was made in this regard, but the court stated that “the Rath respondents should stop making claims about [the] efficacy of VitaCell until it has been submitted to the MCC [Medicines Control Council] to review claims about its safety, quality and efficacy” (see paragraph 65 of the judgment). The applicants equally contended that the activity of the Rath respondents constituted clinical trials, and, in support of this contention, they relied on “copies of advertisements placed on behalf of some of the Rath respondents in various newspapers.” One such advertisement read as follows: “We conducted a clinical pilot study in HIV-positive patients with advanced AIDS. The goal of the study was to show that vitamins and other micronutrients alone reverse the course of AIDS, even in its advanced stage. Thus it was essential that none of the patients had received any ARV [antiretroviral] drugs before or during this nutritional programme…. Blood tests and clinical evaluations were performed at the start and after 4 weeks on the nutrient programme. The results of this pilot study were so profound after only one month that we decided to publish the data of the first 15 patients without delay” (cited in paragraph 74 of the judgment). Much as the Rath respondents described their activity as ‘a clinical pilot study,’ it does fit within Regulation 1 under the Medicines Act’s definition of ‘clinical trial’ as follows: “An investigation in respect of a medicine for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the medicine, identify any adverse events, study the absorption, distribution, metabolism and excretion of the

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medicine or ascertain its safety or efficacy” (from the Medicines and Related Substances Act 101 of 1965). The court therefore found the Rath respondents’ conduct unlawful insofar as they did not have permission to run clinical trials (see paragraph 75 of the judgment). The other relevant contention by the applicants, which the court had to deal with, was that “the Government authorities are under a duty to take reasonable and effective steps to stop the unlawful activities of the Rath respondents but failed to take such steps even after the unlawful activities were brought to their attention” (paragraph 85 of the judgment). In terms of section 3 of the National Health Act, the Minster of Health, who was the eighth respondent in the case, has the responsibility to protect, promote, improve and maintain the health of the population and to determine the policies and measures necessary to protect, promote, improve and maintain the health and wellbeing of the population. The Minister of Health is assisted by the Director General in the department (the ninth respondent), who ensures the implementation of the National Health Policy and the enforcement of the provisions of the Medicines Act. Under section 26 of the Medicines Act, the Director General may appoint inspectors for the proper enforcement of the Act. The applicants relied on the above provisions to support their argument that the government respondents had failed to carry out their duties. The government respondents denied the allegation and informed the court that, on receiving the complaints, they instructed their Law Enforcement Unit to investigate the claims, but no independent evidence was found to support the allegations of unlawful acts by the Rath respondents. They also informed the court that the Law Enforcement Unit continued to monitor the activities of the second respondent (‘Dr Rath Health Foundation Africa’) in order to obtain independent evidence of unlawful conduct (see paragraph 91 of the judgment). The court found no merit in the government respondents’ defence and agreed with the applicants’ contention that the Law Enforcement Unit’s investigations were insufficient insofar as the unit failed to use the provisions of section 28(1) (a) (ii) of the Medicines Act to enter upon the premises where the clinical pilot study was being carried out in order to investigate the allegations made against some of the first to seventh respondents (see paragraph 93 of the judgment). Section 28(1) (a) (ii) of the Medicines Act empowers an inspector (appointed by the Director General) to enter upon any place or premises if there is suspicion, on reasonable grounds, that an offence in terms of the Act has been or is being committed thereon or therein, or that an attempt has been made or is being made to commit such an offence thereon or therein. The court therefore held that the government respondents had a duty to stop the unlawful clinical trials and that they had failed to do so. Comparison between the Kenyan and South African regulatory frameworks The two cases discussed in the preceding parts of this

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article provide a useful backdrop for comparing both countries’ regulatory frameworks, even though the issues in point did not directly deal with HIV-vaccine research. A major limitation in comparing the two court cases lies in the fact that the Kenyan case was decided before the 2004 ethical-legal framework was developed. If the same case were to be heard by the Equity Tribunal since established, then a different and more progressive decision could be expected based on the current ethical-legal framework. As the decision stands, it does not offer much insight into the role that law has played in the regulation of clinical research in Kenya. The South African decision on the other hand confirms that the country has an effective ethical-legal framework for regulating clinical research, which — as the case brought by the Treatment Action Campaign clearly illustrates — the courts are already applying to ensure the safety of the public. The decision is as progressive as that of the case of Mt. Isa Mines Ltd, mentioned earlier. This demonstrates that the South African courts, unlike the Kenyan courts, are more progressive in their approach to research-related issues. An interesting point in comparing both countries’ frameworks is consideration of the extent to which they aim at fostering good research governance. Good research governance is viewed as an outcome and a process: the outcome is “the attainment of the best achievable standard both in research quality and compliance with research ethics and human-rights standards in given settings” (Tarantola, Macklin, Reed, Kieny, Osmanov, Stobie & Hankins, 2007, p. 4869). Hence, the process emphasises agreement about the gains expected from research and compliance with optimum ethical standards, through “an informed, structured, negotiated, participatory and transparent mechanism” (Tarantola et al., 2007, p. 4869). In essence, “Good research governance should define what questions ethics research committees should ask or what issues they should look for in order to make decisions about whether a research project can be approved” (Tarantola et al., 2007, p. 4870). Good research governance in turn creates an enabling environment for the conduct of successful research. The type of enabling environment that stakeholders are yearning for can be equated with what the World Health Organization’s Initiative for Vaccine Research (WHO/IVR) consultations aimed at mapping out: namely, this should be an environment with “potential creative mechanisms and approaches to attainment of the highest possible synergy between scientific quality, outcome of research, and protection of participants” (Tarantola et al., 2007, p. 4863). Kenya’s current framework has satisfied this requirement chiefly with the establishment of an Equity Tribunal. Both South Africa and Kenya do have enabling legislative frameworks facilitating the work of ethics research committees through legislation that, as recommended in the literature, protect research participants and contain mechanisms for enforcing and monitoring legal rights and ethical standards (Strode, Slack & Tangwa, 2002). In essence, this means that ethical-legal frameworks are created to govern clinical research, instead of allowing exclusive reliance on ethics guidelines. Both South Africa and Kenya have made progress in the right direction. In Kenya, the guidelines for

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HIV-vaccine research and the NCST guidelines are directly linked to specific legislation, under which the relevant regulatory authorities (such as the NCST and KEMRI) are empowered to approve applications for clinical research. Prior to the enactment of the National Health Act in South Africa, it could be argued that the Kenyan framework was more ideal for regulating clinical research. With the National Health Act in place, the South African framework equally offers an ideal framework, which other countries can draw lessons from. The specific lessons from both countries are mentioned in the fourth part of this article. HIV/AIDS preventive vaccine research and challenges for the law Insofar as human participants are used as a means of securing knowledge in HIV-vaccine research, the participants are placed at risk of harm for the good of others, and such research has the potential of exploiting the participants (cf. NCST, 2005, p. 2). Equally, there is the issue of the type of care to be provided to the trial participants and whether there is an obligation for the researchers and sponsors to provide such care (Tarantola et al., 2007). Apart from the specific issues that are discussed below, there is an inherent challenge that law must contend with when dealing with issues related to biomedical research generally. This is the apparent mutual tension between medicine and the regulators’ use of law, which arises from the fact that “both medicine and the state view themselves as acting to protect the public’s interest, but neither gives the public anything other than a marginal role in the process of constructing the new world of medical regulation” (Salter, 2001, p. 873). This inherent factor aside, there is the crucial question of determining the extent to which medical decisions should be the object of legal scrutiny and control (Mason & McCall-Smith, 1999). The legacy of the Nuremberg trials cannot be overlooked in this regard. As Rothman (1991, p. 63) notes: Other articles that addressed the Nuremberg trial drew from it not the lesson that the state should regulate experimentation but quite the reverse — that the state should not interfere with medicine. Nuremberg became a stick with which to beat the idea of ‘socialised medicine,’ not the occasion to oversee research. The logic of the argument was that the atrocities were the result of government interference in the conduct of research (and here, the distinction between the Nazi government and all other governments was lost). Science was pure — it was politics that was corrupting. Hence, state control over medicine through regulations that intruded in the private relationship between doctor and patient or investigator and subject were likely to pervert medicine. The undercurrents that exist in the relationship between the law as a regulatory mechanism and the aims of biomedical research can be adequately addressed either by using a specialised tribunal to resolve disputes or through ordinary courts that are capable of viewing research-related issues in a progressive manner. Both approaches are currently used

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by Kenya and South Africa. Addressing complex issues in HIV-vaccine research in Kenya and South Africa A review of the literature shows that the following are complex issues in HIV-vaccine research in developing countries: relevance of study design, procurement of informed consent, and the possibility of participants’ exploitation (see Faden & Kass, 1998; Slack, Lindegger, Vardas, Richter, Strode & Wassenaar, 2000). These three issues are equally highlighted as the important factors that make clinical trials ethical. For instance, the NCST guidelines describe seven requirements that make a clinical trial ethical: the research must be valuable, it must satisfy methodological rigor, there should be fair selection of participants based on the study’s scientific goals and not their vulnerability or privilege, a favourable risk/benefit ratio must be established, it should be independently reviewed, informed consent must be procured, and the participants must be respected (NCST, 2005, pp. 2–9). Thus, the three chosen issues for this article are representative of the spectrum of factors that make a clinical trial ethical. The relevance of study design The points discussed in this section relate to randomised controlled trials, which involve a control as well as an experimental group. The participants “receiving the standard treatment, the placebo (dummy treatment) or no treatment are known as the control group, while those receiving the new treatment are known as the experimental group” (Foster, 2001, pp. 21–22). This design is commonly used in vaccine research. It has been argued, and rightly so, that “reliance on randomised controlled trials undermines alternative study designs that could provide adequate data without the risk inherent in randomization” (UNAIDS, 1998, p.17). The essence of this study design is the selection of controls to be used in a study. A fundamental question raised in this regard is: “If a host country has not adopted a vaccine that has proven effective elsewhere, would it be justifiable for a host country to use a placebo control arm?” (Bloom, 1998). International ethics guidelines indicate conditions under which placebos may be used as part of the study design in such circumstances. For instance, the Declaration of Helsinki states that: The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current, proven intervention, except in the following circumstances: • The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or • Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm (World Medical Association, 2008, paragraph 32). Guidance Point 11 of the UNAIDS guidelines (UNAIDS,

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2000) states that the use of placebo controls in phase-III HIV vaccine trials is ethically acceptable as long as there is no known effective vaccine. This point seems to echo the provisions of paragraph 32 of the Declaration of Helsinki (World Medical Association, 2008), though without justifying such use for methodological reasons. The South African guidelines equally adopt this position: It may be justifiable to use placebo in communities that do not have access to interventions that are the standard of care in resource-rich settings. In order to breach the ethical principle outlined above, the balance between potential harms and benefits should be such that the potential benefits to the community would considerably outweigh the harm (DoH, 2000, clause 3.2). This position seems to answer Bloom’s (1998) question in the affirmative (see previous paragraph). This is rather controversial insofar as the use of a placebo is justified on the basis of poverty or lack of access to effective treatment. Although the clause recommends widespread consultation prior to embarking on such studies, such a recommendation may be incapable of remedying the adverse consequences of using placebos (e.g. harm to the participants). It is equally worrying that instead of justifying this position on the basis of the methodological reasons proposed in paragraph 32 of the Declaration of Helsinki, the DoH’s 2000 guidelines emphasise the potential benefits to the community, which seem to be given priority over the potential harm to the participants. This position directly contradicts clause 2.2 of the same guidelines, advocating for the equal application of good research and ethical standards in vulnerable and non-vulnerable communities. A solution to the above contradiction can be found in the DoH’s 2006 guidelines: clause 2.3.12.1.2 provides that “as long as there is no known effective HIV preventive vaccine, a placebo control arm should be considered ethically acceptable in an HIV preventive vaccine trial.” The justification is based on compelling scientific reasons, however, which are stipulated in the clause as follows: i. Evidence that the HIV vaccine is highly unlikely to be effective against the virus that is prevalent in the research population; and ii. Convincing reasons to believe that the biological conditions that prevailed during the initial trial demonstrating efficacy were so different from the conditions in the proposed research population, that the results of the initial trial cannot be directly applied to the research population under consideration (DoH, 2006, clause 2.3.12.1.2). The DoH’s 2006 guidelines take precedence insofar as they are more recent and because the suggested scientific reasons are more plausible compared to the position in the DoH’s 2000 guidelines, even though the latter are intended to deal specifically with HIV-vaccine research. In Kenya, the guidelines by the NCST directly rule out the use of placebos by stating that: If there exists a consensus about what is the better treatment, there is no null hypothesis, and the research is invalid. In addition, without clinical equipoise, research that compares therapies is

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unlikely to be of value because the research will not contribute to increasing knowledge about the best therapy, and the risk-benefit ratio is unlikely to be favourable because some of the subjects will receive inferior treatment (NCST, 2005, p. 4). The controversy relating to the position that Kenya has taken in accepting the concept of ‘clinical equipoise’ is highlighted below. Wendler, Emanuel & Lie (2004) have suggested a default requirement consisting of four conditions that ethics research committees can use in addressing this issue: 1) scientific necessity, 2) relevance for the host community, 3) sufficient host-community benefit, and 4) subject and host-community non-malfeasance. With regard to the first condition, the authors suggest that ethics research committees should allow research using less than the best methods only when scientifically necessary to answer an important question. In relation to the second point, the authors argue that when trials using lower standards of care “address an important health need of communities in developing countries, the moral importance of helping the poor provides a strong argument in their favor” (Wendler et al., 2004, p. 925). The explanation that the authors give in respect of the third condition — for purposes of minimising risks and maximising benefits to the host community — is that investigators should “focus their research on methods that the host communities can implement, if proved successful” (Wendler et al., 2004, p. 925). This proposal has been criticised insofar as it does not give any conceptual clarification of the idea of “methods that communities can implement, if proved successful.” Critics argue that this is a debated concept in health systems and that the proponents of the above proposal simply leave it as a theoretical construct without furthering the debate (e.g. Hyder, 2004, p. 2048). The requirement in respect of the fourth condition is that there should be clinical equipoise between the proposed new treatment and the local methods of care (cf. Wendler et al., 2004, p. 925). Clinical equipoise is the point at which a rational informed person would have no preference between two (or more) available treatments (Lilford & Jackson, 1995). Clinical equipoise has also generated heated debates (see also Andanda, 2006, pp. 28–33). At the heart of such debates has been the revelation, as described in one clinical review, that “a surprising number of doctors owned up to entering their patients [in trials] when the treatments in the trial were probably otherwise freely available but when patients harboured a personal preference for one of the treatments. Worse, doctors seemed to have been aware that their patients might not have fully understood what was going on” (Edwards, Lilford & Hewison, 1998, p. 1209). There are no established legal principles that govern this issue (i.e. the ethics of study design) — even in Kenya and South Africa, which have otherwise attempted to create ethical-legal frameworks. Procurement of informed consent The duty of obtaining a participant’s informed consent is “a requirement in research ethics, which is widely recognised in national and international guidelines as well

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as legislation” (Andanda, 2005, p. 14). For example, the South African Constitution provides for this in section 12(2) (c). The complication in obtaining informed consent arises from the rampant assumption that a prospective participant’s signature on the form signifies that the participant has understood the contents and has freely consented to participate (cf. Fitzgerald, Wasunna & Pape, 2003, p. 15). It has been equally noted that most ethics review boards rarely focus on “how the researcher will communicate the information to the volunteers who may speak a different language or come from a different culture” (Fitzgerald et al., 2003, p. 16). The concern in this regard is the capacity of a participant to comprehend the provided complex medical and scientific information (see also Andanda, 2005, p. 19). Diverse approaches to informed consent are currently used, and these approaches reflect various notions of informed consent — that is, informed consent in an institutional sense or as autonomous authorisation (Faden & Beauchamp, 1986). The first approach is essentially legal as it is concerned with liability, thus it requires that “all technical information be disclosed to patients as part of the process of providing legal indemnity to medical researchers” while the second approach “is more concerned with facilitating shared decision-making, which a burden of excessive information might undermine, and is based on the belief that the expert does not know everything and cannot know what is best for each person in a medical trial” (Lindegger & Richter, 2000, p. 314). In view of the various notions of informed consent, it has been suggested that the ethical and legal dimensions of informed consent should be carefully considered in HIV vaccine trials. Such trials should be based on sound ethical considerations since “the success of these trials is dependent on far more than protection of the legal rights of all parties. Rather it goes to the very heart of ethical concerns, particularly the autonomy of prospective participants and how their informed decision-making can be facilitated” (Lindegger & Richter, 2000, p. 314). Preventing the exploitation of participants An interesting observation has been made that research participants “continue to be exploited in the sense that their participation in research trials is obtained within conditions that the more fortunate members of our community would refuse to contemplate” (Brazier, 2008, p. 180). An exploitative trial is “one that takes unfair advantage by offering an unfair benefit level to research subjects” (Denny & Grady, 2007, p. 382). An overall agreement has emerged among people who are involved in vaccine research and clinical trials in that “it is important to do as much as is feasible to improve medical care to participants in trials as well as improve care in general in resource-poor settings where trials are conducted” (Tarantola et al., 2007, p. 4863). The concern in this case is to ensure that the participants in developing countries derive some benefits from participation in the research. The research ethics guidelines in both Kenya (i.e. NCST, 2005, p. 5) and South Africa (i.e. DoH, 2006, clause 1.2.4) consider this issue from the point of view of the assessment of the possible risks and benefits that are associated with the trial. What should be considered

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at a practical level is the extent of the possible risks and potential long-term benefits associated with the availability of the evaluated product, if it proves to be safe and effective (see also Andreopoulos, 2000, p. 188). Guidance Point 9 of the UNAIDS (2000) guidelines requires full specification of the nature, magnitude, and probability of all potential harm that may result from participation in an HIV vaccine trial. South Africa’s guidelines (i.e. DoH, 2000) specifically require the study’s design to include the costs of long-term provision of the drugs used in a study and of clinical monitoring. The information “should be clearly stated in the patient information section of the informed consent document” (DoH, 2000, clause 3.5). Kenya’s guidelines equally require that the participants in the research should be fairly selected to ensure that they benefit (i.e. NCST, 2005, p. 4). Guidelines may be in place but the challenge mainly lies in determining what amounts to fair levels of benefits. UNESCO’s Declaration on Bioethics and Human Rights states: “Benefits should not constitute improper inducements to participate in research” (UNESCO, 2005, Article 15[2]). Kenya’s guidelines on HIV-vaccine research explicitly recognise this problem and clearly state that “monetary benefit could be an inducement for participation in a trial and thus would negate free consent” (Ministry of Health, 2005, paragraph 7.3). One benefit usually emphasised in vaccine trials is access to an experimental drug that improves the participants’ health condition (Ballantyne, 2005). Such access can be facilitated by the granting of discounts on such drugs (Andanda, 2008). This certainly requires an appropriate legal framework — which can facilitate the granting of such subsidies — particularly the intellectual property-law regime of the host country. Apparent disconnections between ethical and legal principles The apparent disconnections in the manner in which legal principles and ethics guidelines address the issues discussed here (in the preceding section) are quite evident. For instance, study design and procurement of informed consent seem to be given totally different approaches by the two regimes of ethics and law, while no frameworks have been put in place in the two jurisdictions to determine the ‘fair level of benefits’ or to facilitate benefit-sharing with the research participants. Ethics guidelines do provide general ideas on how these issues ought to be addressed — but implementation strategies are needed. The key ethical principles that govern HIV-vaccine research are autonomy, beneficence, and justice (cf. Slack et al., 2000, p. 292). The relevant legal principles are equity, human rights, and protection of the powerful and powerless. It is important to underscore the importance of human rights since this encompasses individuals’ rights to dignity, life, equality, privacy, and access to healthcare. These rights have been translated to international documents and national Bills of Rights (see also Slack et al., 2000, p. 292). The legal principles mentioned above are usually relevant for protecting the rights of research participants, ensuring the approval of studies by designated regulatory bodies, and

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protecting intellectual property rights with a view to ensuring access of the researched vaccine to the participants if it proves effective (see also WHO/UNAIDS, 2004, p. 22). In practical terms, however, law seems to incorrectly view research as a highly risky business and the participant’s role as a hazardous occupation (Chayet, 1978). Chayet (1978, p. 97) correctly argues that these factors cause difficulties in communication with the public, lead to wrong conclusions in ethical analysis, and inappropriate ethical norms, guidelines and regulations are generated as a result. This weakness of law becomes evident when research-related issues are not resolved through an ethical-legal framework. Perhaps this is the main factor that still causes laws to ‘limp’ in their attempt to keep up with issues related to HIV-vaccine research. South Africa and Kenya have attempted to deal with this problem appropriately, consequently providing lessons that can help in improving the role of law. Lessons learnt from addressing the challenges There are two important lessons to be learnt from Kenya and South Africa. First, reliance on statutory laws as well as common law for research governance and regulatory purposes may not suffice without a close link to ethics guidelines. Second, having ethics guidelines alone without enabling legislation for ensuring compliance may not be helpful. Kenya has made a unique move by establishing an Equity Tribunal to deal with research-related disputes. This is a good means of ensuring that the ethical-legal framework in place is properly utilised. Though it may be argued that regular courts are equally capable of handling such issues, they do have their limitations, as demonstrated in the manner in which the Kenyan courts handled the 1998 case of Kenya AIDS Society v Arthur Obel. These courts could be used if they are progressive in their approach, as the South African court proved to be in the 2008 case of the Treatment Action Campaign and Another v Rath and Others. South Africa’s position equally highlights how these lessons can be implemented in practice: Section 90(1) (s) of the National Health Act provides for the making of regulations that govern health research, and compliance with current guidelines (i.e. DoH, 2006, clause 1.4) will be enforceable through the anticipated regulations. Conclusions It may be argued that the very nature of law as a regulatory mechanism is bound to make it lag behind modern medical research. However, the progress that Kenya and South Africa have made in creating ethical-legal frameworks for HIV-vaccine research clearly shows that this is not the case. In view of the two lessons pointed out in the preceding section, there is hope that the current role of law can be improved to make it more suitable for facilitating biomedical research. References Andanda, P. (2005) Informed consent. Developing World Bioethics 5(1), pp. 14–29.

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Andanda, P. (2006) The Law and Regulation of Clinical Research: Interplay with Public Policy and Bioethics. Nairobi, Kenya, Focus Publishers. Andanda, P.A. (2008) Human-tissue-related inventions: ownership and intellectual property rights in international collaborative research in developing countries. Journal of Medical Ethics 34(3), pp. 171–179. Andanda, P. & Pretorius, J.T. (2010) Miscellaneous contracts. Annual Survey of South African Law 2008, pp. 1153–1174. Andreopoulos, G.J. (2000) Declarations and covenants of human rights and international codes of research ethics. In: Levine, R.J., Gorovitz, S. & Gallagher, J. (eds.) Biomedical Research Ethics: Updating International Guidelines. A Consultation. Geneva, Council for International Organizations of Medical Sciences (CIOMS). Ballantyne, A. (2005) HIV international clinical research: exploitation and risk. Bioethics 19(5/6), pp. 476–491. Berkley, S.F. & Koff, W.C. (2007) Scientific and policy challenges to development of an AIDS vaccine. The Lancet 370(July 7), pp. 94–101. Bloom, B.R. (1998) The highest attainable standard: ethical issues in AIDS vaccines. Science 279, pp. 186–188. Available at: . Brazier, M. (2008) Exploitation and enrichment: the paradox of medical experimentation. Journal of Medical Ethics 34, pp. 180–183. Chayet, N.L. (1978) Research and the law: barriers and progress. In: Gallant, D.M. & Force, R. (eds.) Legal and Ethical Issues in Human Research and Treatment: Psychopharmacological Considerations. New York, SP Medical and Scientific Books Denny, C.C. & Grady, C. (2007) Clinical research with economically disadvantaged populations. Journal of Medical Ethics 33, pp. 382–385. Department of Health (DoH) [South Africa] (2000) Ethical Considerations for HIV and AIDS Clinical and Epidemiological Research. Pretoria, South Africa, National Department of Health. Department of Health (DoH) [South Africa] (2006) Guidelines for Good Practice in the Conduct of Clinical Trials in Human Participants in South Africa. Pretoria, South Africa, National Department of Health. Dodd, R. (1996) Patients sue ‘AIDS-cure’ Kenyan scientist. The Lancet 347(9016), p. 1688. Edwards, S.J.L., Lilford, R.J. & Hewison, J. (1998) The ethics of randomised controlled trials from the perspectives of patients, the public and healthcare professionals. British Medical Journal 317, p. 1209. Faden, R. & Beauchamp, T. (1986) A History and Theory of Informed Consent. New York, Oxford University Press. Faden, R. & Kass, N. (1998) Editorial: HIV research, ethics, and the developing world. American Journal of Public Health 88(4), pp. 548–550. Fitzgerald, D.W., Wasunna, A. & Pape, J.W. (2003) Ten questions institutional review boards should ask when reviewing international clinical research protocols. IRB: Ethics and Human Research 25(2), pp. 14–18. Foster, C. (2001) The Ethics of Medical Research on Humans. Cambridge, UK, Cambridge University Press. Giella v Cassman Brown & Company Ltd [1973] EA 358). Grant, C.J., Lewis, M. & Strode, A. (2005) The Ethical-Legal Regulation of HIV Vaccine Research in Africa: A study of the regulation of health research in Botswana, Ethiopia, Kenya, Tanzania and Uganda to determine their capacity to protect and promote the rights of persons participating in HIV vaccine research. Pietermaritzburg, South Africa, Ethics, Law and Human Rights Working Group (ELH), African AIDS Vaccine Programme (AAVP).

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