Bioethical Challenges in New Hiv Prevention Technologies

By Calvin Gwandure and Ruth Gwandure

Ruth Gwandure earned her master of science degree in medicine (bioethics and law) from the University of the Witwatersrand, South Africa.
Her research and consulting fields include bioethics, health law, environmental bioethics, research ethics, HIV and AIDS, ethics and law, clinical ethics, and HIV counselling and testing in schools.

Calvin Gwandure has a PhD in psychology. He graduated from Nelson Mandela University, South Africa.

His research and consulting fields include HIV and AIDS prevention, new HIV prevention technologies, HIV risk behavior, and group behavior.

Clinical trials on HIV and AIDS prevention face challenges associated with infection of participants with HIV and sexually transmitted infections. Participants also experience adverse events associated with voluntary medical male circumcision and the use of microbicides and vaccines in clinical trials. The results obtained from clinical trials investigating the efficacy of microbicides and vaccines in preventing HIV infection are disappointing, but there is hope that one day a breakthrough could be made. Clinical trials on voluntary medical male circumcision and preexposure prophylaxis have shown positive results that warranted approval by the US Food and Drug Administration (FDA) and the World Health Organization (WHO). The major challenge experienced in new HIV prevention clinical trials that are underway and in approved interventions that are being scaled up apparently relates to HIV incidence that threatens the social value and scientific validity of the interventions. Paradoxically, the clinical trials and scale-up interventions have become the new sources of HIV infection although the hypothesized benefit to be realized in the end is conceptualized as outweighing the current risks involved.

• Language: English
• Publisher: Xlibris UK
• Release date: May 23, 2018
• ISBN: 9781543489644

Calvin Gwandure

Ruth Gwandure: Master of Science in Medicine (Bioethics & Law), (University of the Witwatersrand, South Africa). Research and consulting fields: Bioethics, Health Law, Environmental Bioethics, Research Ethics, HIV and AIDS, Ethics and Law, Clinical Ethics and HIV Counselling and Testing in Schools. Calvin Gwandure: PhD in Psychology (Nelson Mandela University, South Africa) Research and consulting fields: HIV and AIDS prevention, new HIV prevention technologies, HIV risk behaviour, and group behaviour.

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Copyright © 2018 by Calvin Gwandure; Ruth Gwandure.

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Rev. date: 05/14/2018

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CONTENTS

Chapter 1 Ethical Guidelines In New HIV Prevention Technologies

Chapter 2 Provision Of New HIV Prevention Technologies To Vulnerable Groups And Special Populations

Chapter 3 The Use Of Incentives In HIV Prevention Clinical Trials

Chapter 4 Antiretroviral Therapy As HIV Prevention In Serodiscordant Couples

Chapter 5 Vaccines In HIV And AIDS Prevention Clinical Trials

Chapter 6 Microbicides In HIV Prevention Clinical Trials

Chapter 7 The Invisible Condom In HIV Prevention Clinical Trials

Chapter 8 Pre-Exposure Prophylaxis In HIV Prevention

Chapter 9 Voluntary Medical Male Circumcision In HIV Prevention

Chapter 10 Medical Injury Compensation In New HIV Prevention Technologies

CHAPTER 1

Ethical Guidelines In New HIV Prevention Technologies

New HIV prevention clinical trials are carried out in different parts of the world. Some of the clinical trials in Eastern and Southern Africa were completed. Countries have the choice to conduct their own clinical trials to establish the efficacy and safety of HIV prevention technologies that were approved in other regions of the world. The results of HIV prevention clinical trials carried out in Africa on voluntary medical male circumcision were used to approve circumcision as a method of preventing HIV. Clinical trials are mainly conducted in Africa, Asia, Latin America and the US mostly among Africa-Americans. Voluntary medical male circumcision and pre-exposure prophylaxis were approved for public health use as new HIV prevention technologies. The next stage after approval of the new HIV prevention technologies by the World Health Organisation (WHO) and the Joint United Nations Programme for HIV and AIDS (UNAIDS) is the roll out of the interventions to the larger population. Ethical guidelines in clinical trials and during scale-up of the intervention are adhered to in order to protect participants from harm. The major ethical problem in new HIV prevention technologies is that they invite HIV-negative people to participate in risk experimentation where some of the participants acquire HIV. In most, if not all of the phase III clinical trials conducted in Eastern and Southern Africa, HIV was contracted by some of the participants in both the intervention and control group although researchers justify it as a reflection of what is happening in the natural setting.

Sponsoring organisations, researchers and health professionals involved in HIV prevention clinical trials and the scale-up of interventions are bound by ethical codes such as The Hippocratic Oath for medical doctors, The Nuremberg Code (1947), Declaration of Helsinki (2013), Belmont Report (1979), CIOMS (2016) and the US Common Rule (1991) (National Institutes of Health (NIH), Clinical Center (2017).

The Hippocratic Oath is taken by medical students on graduation before they enter the medical field to practise as medical practitioners. The Hippocratic Oath is a vow taken by medical students to maintain medical ethics in the practice of medicine. The oath is named after the physician Hippocrates who lived between 460 and 380 B.C (Markel, 2004). The original translated version of the Hippocratic Oath is presented below.

The Hippocratic Oath

I swear by Apollo Physician and Asclepi-

us and Hygieia and Panaceia and all the

gods and goddesses, making them my

witnesses, that I will fulfill according to

my ability and judgment this oath and

this covenant:

To hold him who has taught me this art

as equal to my parents and to live my life

in partnership with him,

and if he is in

need of money to give him a share of

mine, and to regard his offspring as

equal to my

brothers in male lineage and

to teach them this art — if they desire to

learn it — without

fee and covenant; to

give a share of precepts and oral instruc-

tion and all the other learning to my

sons and to

the sons of him who has in-

structed me and to pupils who have

signed the covenant and have taken an

oath according to the medical law, but to

no one else.

I will apply dietetic measures for the

benefit of the sick according to my ability

and judgment; I will keep them from

harm and injustice.

I will neither give a deadly drug to any-

body if asked for it, nor will I make a sug-

gestion to this effect. Similarly I will not

give to a woman an abortive remedy. In

purity and holiness I will guard my life

and my art.

I will not use the knife, not even on suf-

ferers from stone, but will withdraw in

favor of such men as are engaged in this

work.

Whatever houses I may visit, I will

come for the benefit of the sick, remain-

ing free of all intentional injustice, of all

mischief and in particular of sexual rela-

tions with both female and male per-

sons, be they free or slaves.

What I may see or hear in the course of

the treatment or even outside of the

treatment in regard to the life of men,

which on no account one must spread

abroad, I will keep to myself holding

such things shameful to be spoken

about.

If I fulfill this oath and do not violate it,

may it be granted to me to enjoy life and

art, being honored with fame among all

men for all time to come; if I transgress

it and swear falsely, may the opposite of

all this be my lot.

Translated from Greek by Edelstein.

(Source: Markel, 2004, p. 2028)

The Hippocratic Oath has been revised in various countries to suit their health laws and policies. The fundamental precepts of the oath have to be preserved to protect patients and medical doctors in practice. According to Markel (2004), the mantra First, do no harm which is translated into Latin as

"Primum non nocere" is often mistakenly ascribed to the oath, although it appears nowhere in the Hippocratic Oath. Markel (2004) elaborates that Hippocrates came closest to issuing this directive in his treatise Epidemics, in an axiom or principle which reads, As to diseases, make a habit of two things — to help, or at least, to do no harm. (Markel, 2004, p.2026). It is noted that there is a stark contrast between the original Hippocratic Oath and the revised versions that are adopted by medical schools globally. The Hippocratic Oath mentions allegiance to Greek gods an aspect which puts off medical practitioners and medical schools as they would not be interested in associating their work with religious beliefs. It is also interesting to note that religious terminology is still used in courts of law and the same practice is evident in the swearing in of high ranking government officials including ministers and judges despite the diversity in beliefs, philosophies and atheism. Terms such as My Lord, Your Worship, or So, help me God are still in use. The religious and gender bias is reflected in the Hippocratic Oath and the same bias is still reflected in the judicial system globally. A male judge is referred to as My lord while a female judge is called My lady. A male magistrate is addressed as Your worship and a female magistrate is addressed as madam although there is also a female law lord in countries such as the UK. The terms are used differently globally. Medical schools are reforming some of the ethical codes and practices in order to meet contemporary challenges. It was revealed in 1993 that at 147 U.S. and Canadian medical schools, only 11 % of the versions of the Hippocratic Oath invoked a deity (Markel, 2004).

The Hippocratic Oath is against euthanasia and abortion (Markel, 2004). The medical field is facing ethical challenges due to changing values, customs, and beliefs associated with new developments and discoveries in medicine. New diseases challenge the world order and how to prevent them. Medical ethics seeks to uphold the sanctity of life and to avoid involvement in any act of assisted suicide, murder, or manslaughter (Markel, 2004). It is argued that documentary evidence shows that Greeks and Romans who were confronted with terminal illness preferred a quick, painless death by means of poison to help patients die by assisting nature to take its course (Markel, 2004). Furthermore, it was common during the ancient times for physicians to recommend assisted suicide for patients with an incurable disease (Markel, 2004). Similarly, it was not uncommon for physicians to induce abortion, typically effected by means of a pessary that induced premature labour in ancient Greece and the Roman Empire (Markel, 2004). In new HIV prevention technologies, pregnant women are excluded from the clinical trials. Some medical schools in the U.S omit sections of the Hippocratic Oath that refer to abortion and euthanasia. As of 1993, only 14 % percent of the Hippocratic Oath versions prohibited euthanasia, and only 8% prohibited abortion (Markel, 2004). The ethical problem would arise when medical doctors from the U.S operate in developing countries with different versions of the Hippocratic Oath. Researchers on HIV prevention clinical trials in Africa are regulated by Data and Safety Monitoring Boards in the US and local research ethics committees. Parity is required in the ethical conduct of medical doctors in developing countries and developed countries and ethical standards that promote life should be upheld as a priority in clinical trials. The bowdlerised versions of the Hippocratic Oath should retain the essential components of the oath that compel physicians to do no harm to patients as a first priority.

A criticism levelled against the Hippocratic Oath concerning surgery is the use of the knife to remove kidney stones. Advances in surgery recommend operation of kidneys to remove stones. It could be interpreted as a precautionary measure for medical doctors not to resort to unnecessary surgical procedures even in cases where the application of medicine or therapy would suffice. In new HIV prevention technologies, surgical procedures are used to remove the foreskin but in some botched operations patients could bleed to death. Rings are more preferable than surgical procedures in removing the foreskin in voluntary medical male circumcision. There are reported cases of excessive bleeding and patients losing function of the penis in HIV prevention clinical trials in which voluntary medical male circumcision is used to prevent HIV infection (Galukande, Kahendehe, Buuza & Sekavuga, 2015). The patients had undiagnosed hemophilia A and it is common in the scale-up of voluntary medical male circumcision that circumcisers trained to perform voluntary medical male circumcision do not ask patients about allergies and underlying medical conditions that could compromise their health. The training manuals provide guidelines for providing voluntary medical male circumcision but most of the circumcisers are not medical doctors so they focus on cutting the foreskin to men who come looking for circumcision and not attend to other health conditions for which they are not trained to handle.

The Hippocratic Oath prohibits physicians from having sexual relationships with their patients. Medical doctors working with patients in new HIV prevention technologies are aware of the need to avoid sexual contact or sexual harassment of participants and patients. Health professionals are required to be accountable to patients and maintain confidentiality as a way of maintaining the good reputation of the profession.

It is contended that physicians and other health professionals should not be involved in capital punishment or the use of poison to kill people even in advisory capacity (Curfman, Morrissey, & Drazen, 2008). Medicine as a profession dedicated to healing the sick should not be used in the process of execution (Curfman et al., 2008). Lethal injection was introduced in 1977 in the U.S to replace hanging, electrocution and chemical gassing which were considered to be inhumane executions (Curfman et al., 2008). Medicalisation of executions involves the use of lethal drugs and using medically trained personnel to administer the poison. Capital punishment through lethal injection is different from euthanasia through lethal injection in that it is forced on the person whereas euthanasia is death by consent, assisted dying, killing of a patient in an irreversible coma or killing of a person suffering from an incurable disease. If a patient autonomously requests to be killed through lethal injection in the case of euthanasia and if a prisoner on the death row autonomously consents to being killed through lethal injection, the physician would administer the lethal injection to relieve the patient from suffering and to serve the medical interests of third parties including the prison authorities, the justice system and the public (Valerius, 2007). The physician would administer the lethal injection with the intention of helping others, not of punishing the prisoner or patient (Valerius, 2007). In practice, the execution of prisoners does not require their consent in many countries although a priest could be called to legitimise and sanitise the killing.

Euthanasia could be abused by spouses, children and relatives when they request medical doctors to end a patient’s life so that they inherit the wealth left by the patient killed through the application of euthanasia. Anti-euthanasia activists regard all methods used to end a patient’s life as unethical. Similarly, lobbyists against capital punishment or death sentence view lethal injection as gruesome, cruel, inhumane and inappropriate in modern civilisation. The removal of life support in intensive care unit or the use of drugs to allow the patient to die calmly with less pain does not respect the sanctity of life. Patients who develop life-threatening health complications during HIV prevention clinical trials would pose an ethical dilemma to physicians if the laws of the country in which they conduct clinical trials are against euthanasia. If a physician comes from a country or a U.S state that approves euthanasia she/he could recommend euthanasia on dying patients in clinical trials. Euthanasia or assisted dying relieves the pain and the patient dies peacefully. The situation would be resolved by consulting with the Ministry of Health in the country in which clinical trials are conducted for guidance and compliance with health laws and codes of ethics on euthanasia and handling of the dying.

The Nuremberg Code (1947)

After the Second World War, it was realised that heinous crimes against humanity and gross violations of human rights and medical ethics were committed. The Nuremberg Code was formulated in Nuremberg, Germany in 1947 to try medical doctors who were involved in murderous and torturous human experiments in the concentration camps (Shuster, 1997). The trial of the medical doctors is referred to as the Doctors’ Trial. The ethical code sets standards for medical ethics and medical research including clinical trials. General Telford Taylor who was the chief prosecutor believed that one of the three U.S. judges, Harold Sebring, was the author of the Code. It is believed that two American physicians who helped prosecute the Nazi doctors at Nuremberg, Leo Alexander and Andrew Ivy, have each been identified as the Code’s author (Shuster, 1997). It is apparent that the authorship of the Nuremberg Code is not explicitly stated but implied. It is believed that the ten principles of the Nuremberg Code were developed from the trial itself (Shuster, 1997).

The Doctors’ Trial was conducted by an International Military Tribunal which comprised judges from allied powers. The allied powers were the United States of America, Britain, France, and the former Soviet Union (Shuster, 1997. The judges did not come from neutral countries, they were an interested party. Furthermore, the U.S conducted 12 additional trials of representative Nazis from various sectors of the Third Reich, including law, finance, ministry, and manufacturing, before American Military Tribunals at Nuremberg (Shuster, 1997). Of the 23 defendants, 20 were physicians accused of murder and torture in the conduct of medical experiments on concentration-camp inmates (Shuster, 1997). Of the 23 defendants, 16 were found guilty and 7 were sentenced to death by hanging (Shuster, 1997). Five got life imprisonment, two were to be imprisoned for 25 years, one was sentenced to imprisonment for 15 years and one was sentenced to imprisonment for 10 years (Shuster, 1997). Seven of the accused were found not guilty. The U.S. Supreme Court declined to review the case; the executions were carried out at the Landsberg prison (Shuster, 1997).

The chief prosecutor regarded the case as a murder trial and a crime against humanity. It was pointed out by the chief prosecutor that this was not a mere murder trial since the accused persons were physicians who had sworn to do no harm and to abide by the Hippocratic Oath (Shuster, 1997). The Hippocratic Oath was used to convict the physicians. The aggravating circumstances highlighted by the chief prosecutor were that the world needed to know with conspicuous clarity the ideas and motives that led the physicians to treat fellow human beings as less than beasts (Shuster, 1997). The tribunal wanted to know what brought about such savageries and the chief prosecutor implored the tribunal to weed out or cut out and expose the war criminals before they became a spreading cancer in the breast of humanity (Shuster, 1997).

War crimes facing the world today are biological weapons including deliberate poisoning of communities, soldiers and freedom fighters. The wars in the Middle East have reports about alleged use of chemical weapons which are banned under international law. During Apartheid in South Africa, some of the physicians were involved in war crimes relating to the manufacture, distribution and administering of poison on enemies of the state (Bateman, 2016). In Rhodesia, clothes laced with poison were distributed to targeted communities and freedom fighters. In countries that use chemical weapons, the army employs medical doctors to carry out the chemical assassination in violation of human rights and medical ethics.

The tribunal at the Nuremberg trial assessed the complementary roles of the Hippocratic Oath and human rights in clinical trials. Hippocratic ethics or Hippocratic moral ideas should safeguard the human rights of subjects in human experimentation. The ethical values should guide research ethics. The application of Hippocratic ethics to human experimentation and Hippocratic moral ideals without human rights would not be enough to protect participants in clinical trials. The tribunal explored ideas that shaped medical-research ethics led by Leo Alexander, an American neuropsychiatrist, Werner Leibbrand, a German psychiatrist and medical historian, and Andrew Ivy, a renowned American physiologist (Shuster, 1997).

Alexander’s contribution to the tribunal was that he gave the chief prosecutor, Taylor a memorandum detailing ethical and non-ethical experimentation on human beings. He identified three ethical, legal, and scientific requirements for the conduct of human experimentation (Shuster, 1997). The first requirement is the right of the competent experimental subject to consent or refuse to participate in the experiment. The researcher should establish that the subject is willing to undergo the experiment of his or her own free will (Shuster, 1997). The second requirement is that the physician should, based on the Hippocratic Oath, prohibit an experiment if the foregone conclusion, probability or a priori reason to believe exists that death or disabling injury of the experimental subject will occur (Shuster, 1997). Clinical trials on new HIV prevention technologies report adverse events such as deaths and they are continued with minor modifications to address the adverse impact. If some of the participants in the previous clinical trial were infected with HIV that does not stop new investigations on a new sample. The common reason given is that non-adherence results in HIV infection. Sometimes the Data and Safety Monitoring Board stops the clinical trial but in some situations the clinical trial continues up to the end even though the investigators are aware that some of the participants are being infected with HIV. The clinical trial would be reported as a failure when it fails to protect participants from HIV infection or success with casualties, that is, with some of the participants acquiring HIV. The scale-up of new HIV prevention technologies happens against a backdrop of reported HIV infections among participants during clinical trials. Statistical significance is used to justify the continued exposure of participants to HIV infection during HIV prevention experimentation. If less people are infected with HIV in the experimental group than the control group and the difference is statistically significant, then the new HIV prevention technology is regarded as efficacious in reducing HIV infection.

The third requirement is that researchers should adopt good research practices (Shuster, 1997). Best practices in research should be guided by ethical codes and policies that promote the welfare and human rights of participants in clinical trials and research in general. When participants are harmed or exposed to HIV infection that defeats the purpose of conducting research.

Alexander gave Taylor a second memorandum in which he stated conditions for ethically and legally permissible experiments on human beings. The conditions included voluntary consent of the subject, absence of duress, sufficient disclosure on the part of the experimenter, sufficient understanding on the part of the experimental subject of the exact nature and consequences of the experiment, voluntary participation, and permitting an enlightened consent (Shuster, 1997). The other conditions related to the humanitarian nature and purpose of the experiment, scientific integrity and obligations of the investigator to the welfare of the subject or participant (Shuster, 1997).

Werner Leibbrand, a German psychiatrist and medical historian at Erlangen University contributed to the debate on medical ethics at the Nuremberg trial. He explained to the court that German physicians at the time had a biologic thinking which regarded a patient as a series of biologic events or biologic processes. The patient was nothing more than a mere object (Shuster, 1997). Leibbrand pointed out that such a view precluded any human relation between physicians and their patients and it was against the Hippocratic ethics and the objectification of the patient eroded morality and reverence for human life (Shuster, 1997). He condemned experiments with human subjects without their consent which was a result of biologic thinking (Shuster, 1997).

This perspective contributed to the adoption of the term participant as opposed to subject in research designs. Research proposals submitted for ethics approval no longer refer to people as subjects. The terms research subjects and human subjects are still used in scientific experiments but the overtone of treating people as objects is what discourages many researchers from including the word subject in the terminology. Other researchers prefer to use the term respondents in place of subjects. The Nuremberg Code contributes to the humanisation of experimentation with human beings. It accords dignity to participants in clinical trials and experimenters are bound to treat participants with unconditional positive regard and respect.

During cross-examination, it was pointed out by defence attorneys that developed countries such as France, the Netherlands, Britain, and the United States had performed dangerous medical experiments on prisoners, often without their consent (Shuster, 1997). The American malaria experiments are a case in point. A military-sponsored research project begun during the Second World War exposed inmates of the Stateville Penitentiary in Illinois to infection with malaria. The prisoners were then treated with experimental drugs that sometimes had vicious side effects (Comfort, 2009). The inmates were made into reservoirs for the disease and they provided a food supply for the mosquito cultures (Comfort, 2009). The prisoners acted as secretaries and technicians, recording data on one another, administering malarious mosquito bites and experimental drugs to one another, and helping decide who was admitted to the project and who became eligible for early parole as a result of his participation (Comfort, 2009). It was noted that the prisoners were not simply research subjects; they were deeply constitutive of the research project (Comfort, 2009). The prisoner’s time on the project was counted as part of his sentence hence serving on the project could shorten one’s sentence. Participation in the project by prisoners was considered as simultaneously serving the functions of research and punishment (Comfort, 2009). This unethical medical experimentation was used by Leibbrand to illustrate that the U.S had erred in using prisoners as subjects or participants because they were in a forced situation and could not be volunteers (Shuster, 2007). The tribunal was challenged to broaden the scope of the trial by defining the conditions under which risky human experimentation is ethically permissible.

The defence lawyers brought to the attention of the tribunal that Nazi doctors were ordered by the state to conduct such experiments as the high-altitude hypothermia, and seawater experiments on inmates at the Dachau concentration camp (Shuster, 1997). The experiments were conducted to determine how best to protect and treat German fliers and soldiers (Shuster, 1997). It was contended that these experiments were necessary and that the good of the state takes precedence over that of the individual (Shuster, 1997). Leibbrand indicated that the state could order deadly experiments on human subjects, but the physicians remained responsible for carrying out the order or refusing to perform an unethical medical act (Shuster, 1997). In this regard, the physician was supposed to refer to the Hippocratic Oath for medical ethics and not perform unethical medical procedures. Since the argument was about physiological experiments, an expert who was a medical scientist and an authority on research physiology and whose wartime scientific interests corresponded to those of the Nazi doctor defendants was called to testify (Shuster, 1997). This expert was Andrew Ivy who shed more light on medical ethics during the trial.

Andrew Ivy was an internationally known physiologist and a noted scientist and he had first-hand knowledge of the Stateville Penitentiary experiments on malaria (Shuster, 1997). He came from the state of Illinois and was nominated by the American Medical Association to serve as a medical advisor to the Nuremberg prosecution (Shuster, 1997). Ivy presented to the judges three research principles that he had formulated at the request of the American Medical Association. The three principles concerning ethical experimentation with human beings included consent, evidence based on animal experimentation and the use of qualified personnel to carry out the experiments.

The document presented at the Nuremberg Trial which guides medical ethics today states that:

1. Consent of the human subject must be obtained. All subjects have been volunteers in the absence of coercion in any form. Before volunteering, subjects have been informed of the hazards, if any. Small rewards in various forms have been provided as a rule.

2. The experiment to be performed must be based on the results of animal experimentation and on knowledge of the natural history of the disease under study, and must be so designed that the anticipated results will justify the performance of the experiment. The experiment must be such as to yield results for the good of society, unprocurable by other methods of study, and must not be random and unnecessary in nature.

3. The experiment must be conducted only by scientifically qualified persons and so as to avoid all unnecessary physical and mental suffering and injury and only after the results of adequate animal experimentation have eliminated any a priori reason to believe that death or disabling injury will occur…

(Source: Shuster, 1997, p. 1438).

Clinical trials on new HIV prevention technologies request informed consent from participants, animal experiments are conducted in the early phase of the study before the study invites human beings to participate. The use of scientifically qualified personnel is not followed in voluntary medical male circumcision. Surgical removal of the foreskin is performed by paraprofessionals who are not physicians. This is rationalised as speeding up the process of circumcising large numbers of men in East and Southern Africa where qualified medical doctors are in short supply. The World Health Organisation endorses the use of less qualified personnel in voluntary medical male circumcision as justifiable and it provides guidelines on the scale-up of the intervention. In practice, WHO has no oversight role to supervise how men are circumcised by the trained circumcisers on the ground.

Ivy justified the American malaria experiments with 800 or more prisoners. He pointed out that the experiments were justified scientifically, legally and ethically even if they brought danger to human life. To treat malaria was an important scientific problem and as long as the subjects volunteered and hazards of the experiments were explained there is no ethical reason against it (Shuster, 1997). If prisoners condemned to death were volunteers, then the experimentation was ethical (Shuster, 1997). Ivy pointed out that it was not a written requirement in the US at that time that subjects could withdraw from risky experimentation. He indicated that subjects could be infected, severely injured or fatally harmed in dangerous experiments they consented to participate in (Shuster, 1997).

Sometimes consent is given by participants without having enough information on what the study entails. Participants could be rushed to sign informed consent forms if they are enrolled in large numbers. Participants could follow what others are doing and sign informed consent forms without reading the information and conditions of the clinical trial. There are participants who consent to participate but without suspecting that physicians could design risk experiments that could cause death as it is believed in society that medical doctors save lives. Consent could be abused when it is used as a reason to expose participants to risky research.

During cross-examination, Ivy agreed with Leibbrand that researchers must refuse to conduct dangerous experiments on human beings when ordered by the state in order to save lives (Shuster, 1997). He agreed and concurred with his German counterpart that researchers should not conduct research with non-volunteering participants. Ivy declared that there is no justification in killing five people in order to save the lives of five hundred people. He also declared that no state or politician under the sun could force him to perform a medical experiment which he thought was morally unjustified or unethical (Shuster, 1997). This illustrates independent thinking of a physician guided by the Hippocratic Oath.

Ivy under cross-examination stressed that the state may not assume the moral responsibility of physicians to their patients or research subjects (Shuster, 1997). He indicated that physicians should be acquainted with the Hippocratic Oath which represents the Golden Rule of the medical profession in the United States and globally (Shuster, 1997). When asked about his medical position on the Hippocratic moral maxim that forbids physicians to administer a poison to anyone even when asked to do so when conducting potentially lethal experimental interventions on volunteer subjects, Ivy pointed out that the Hippocratic commandment refers to the function of the physician as a therapist and not as an experimentalist. He explained that the Hippocratic Oath requires that physicians must have respect for life and the human rights of the experimental patients (Shuster, 1997).

At the conclusion of the Nuremberg Trial, the judges realised the importance of Hippocratic ethics and the maxim primum non nocere, but they found it necessary to include human rights in research ethics. The inclusion of human rights would protect human subjects in clinical trials. Finally, the judges articulated a sophisticated set of 10 research principles centred not on the physician but on the research subject and this culminated in the Nuremberg Code (Shuster, 1997). The research principles constitute the Nuremberg Code. The Nuremberg Code is presented in the box below.

The Nuremberg Code

1. The voluntary consent of the human subject is absolutely essential.

This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.

4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.

7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

(Source: Shuster, 1997, p. 1436)

The Nuremberg Code improved the Hippocratic doctor–patient relationship. Before, using the Hippocratic Oath, the patient was expected to be silent or passive and dutifully obedient to the beneficent and trusted physician (Shuster, 1997). The patient sought the physician’s help and initiated the therapeutic relationship with the physician (Shuster, 1997). Following the Hippocratic Oath, once patients agree to be treated, they trust that the physician will act in their interest, or at least will do no harm (Shuster, 1997). The relationship between a patient and a doctor in clinical trials is different from a therapeutic relationship. In research, trust may be misplaced because the physician’s primary goal is not to treat but to conduct an experiment to test a scientific hypothesis (Shuster, 1997). During the experiment, the physician follows the research design of the protocol without paying enough attention to the patient or subject’s best interests or feelings. The Nuremberg Code seeks to protect the rights of patients, subjects or participants in clinical trials or human experimentation. The attitude of the physician who believes in Hippocratic ethics tends to submerge the subject’s autonomy into what the physician-investigator thinks is best for the subject even though informed consent is sought from the patient or subject (Shuster, 1997). This is generally regarded as paternalism in the patient-doctor relationship. The doctor does not listen much to what the patient says but prescribes what he/she thinks is right for the patient. Researchers in HIV prevention clinical trials might not listen much to stories about side effects experienced by participants; they might regard the ailments as normal adverse events associated with medication or teething problems of the intervention.

The Nuremberg Code emphasises informed consent as a core value in protecting subjects’ human rights. The Nuremberg Code merges Hippocratic ethics and the protection of human rights into a single code (Shuster, 1997). It is a requirement under the Nuremberg Code that physicians or researchers in clinical trials protect the best interests of their participants. The Nuremberg Code empowers subjects to actively protect themselves in clinical trials or human experimentation by terminating their participation. In contrast, in Hippocratic ethics, the subject relies on the physician to determine when it is in the subject’s best interest to end his or her participation in an experiment (Shuster, 1997). The subject, patient or participant is passive and led by the experimenter. In the Nuremberg Code, the subject has much authority as the physician or researcher to end the experiment before its conclusion (Shuster, 1997). On either side the subject or experimenter gives notice to end the study without consequences.

The autonomy of the participant or experimenter promotes medical ethics and human rights in research with human subjects. Clinical trials should promote freedom of expression and independent decisions on continuing or quitting among participants. In new HIV prevention clinical trials, informed consent and voluntary participation are required and withdrawal from participation at any point is provided for but some of the participants are lost to follow up without giving notice or reasons about their withdrawal. When participants leave the clinical trial without trace it would be difficult for researchers to ascertain adverse events such as