|UNAIDS-Sponsored Regional Workshops to Discuss Ethical Issues in Preventive HIV Vaccine Trials (UNAIDS, 2000, 52 p.)|
|ANNEX 1: CASE SCENARIO AND DISCUSSION QUESTIONS|
A pharmaceutical company, (the sponsor), is based in a developed, industrialized country (the sponsoring country). The sponsor is proposing to conduct a phase III vaccine efficacy trial of an experimental preventive HIV vaccine (the candidate vaccine). The sponsor has conducted pre-clinical trials in animals, and it has completed a phase I clinical trial for safety in human subjects in the sponsoring country. It has also completed a phase II trial for safety and immunogenicity in the sponsoring country. The results of these trials suggest that the candidate vaccine is safe, immunogenic, and potentially effective. They show that markers for humoral immunity are induced by the candidate vaccine, although cell-mediated immune responses are not consistently present. A safety board of the sponsor has determined that the candidate vaccine is safe for further trials. The companys position is that the only way to know if the vaccine is effective in preventing HIV infection is to study it in a phase III human-efficacy trial.
The sponsor claims that it will require a very specific population from which to recruit volunteers. The most important characteristic of this population is that it must have a relatively high number of new infections occurring over time (a high incidence). Otherwise, it would require a very long time and a very large sample size for any difference between the placebo-treated and candidate vaccine-treated groups to be observed. This population should be composed of individuals who have adequate social stability, so that they will be more likely to continue participating in the study until its completion, and will be capable of following the study protocol. They must be capable of providing informed consent. In addition, the sponsor points out that any HIV vaccine will ultimately have its greatest value in these same high-incidence countries, and that the need for a vaccine in these countries is urgent. It is important that the vaccine be effective against viral strains found in developing countries, and in the human genetic, nutritional, and environmental context of these countries. For all of these reasons, the sponsor proposes to conduct the trial in a developing country.
There is a potential host country with which the sponsor has been in discussion. The host country has been working for several years to identify an appropriate study population (a cohort) in anticipation of a possible vaccine trial. This was required to ensure that there is a reasonable estimate of the incidence of new infections in the population, that the population is one that can be followed at regular intervals, that predominant viral genetic strains are identified, and that baseline HIV risk behaviour in the cohort is described. There appears to be a cohort which is appropriate. However, there has been no phase I or phase II study of this candidate vaccine, or any others for that matter, conducted in the proposed host country. Investigators in the host country are convinced that the need for a rapid process of vaccine evaluation is great, and that delaying the process in order to conduct phase I and II trials in the host country will mean the loss of too many lives. They are advocating for a phase III trial to take place in the host country without phase I and II trials in that country.
The research protocol that the sponsor is proposing has resulted from several levels of collaboration. Clinical research physicians from the company have carried out discussions with investigators from a university in the host country. These are the same investigators who have been attempting to identify an appropriate cohort for the trial. Investigators from this university have been enthusiastic about the proposed trial, and do not feel that there are major obstacles. They have participated in the development of the protocol and of the informed consent procedure. Community consultation was carried out by host country investigators during the cohort development study, and HIV-infected individuals and people in high-risk groups were asked for their opinions on logistics and ethics related to carrying out the cohort study. Much of this consultation was facilitated by nongovernmental organizations (NGOs) involved in HIV education and prevention. Based on these consultations, the host country investigators have advised the sponsor on how the protocol should be designed. However, there has not been any consultation of the community specifically related to preventive HIV vaccine trials, or on this specific protocol.
The sponsor has completed the process of scientific review of the proposed trial protocol through a university-based scientific review board in the sponsoring country. However, there is not a comparable review board in the proposed host country. The sponsor is now pursuing ethical approval from an ethical review board, also in the sponsoring country. There is no capacity for formal ethical review in the host country. The investigators there do not perceive that this should be an obstacle to proceeding with the trial, provided that the protocol has been developed with consideration of the input given by the host country investigators. The host country investigators are satisfied with the scientific and ethical aspects of the protocol.
The sponsor has agreed to train local technicians and interviewers and to provide the host country with the necessary clinical and laboratory infrastructures for research requirements, including logistical support. There will be no expense to the host country for conducting the trial. Investigators there have put considerable effort and expertise into developing the potential trial cohort, and the actual details of the current trial protocol. Without their support, in fact, it is likely that the current trial proposal would not have been possible. They are concerned that, at the completion of the trial, they may have no right to the results of the trial as intellectual property.
The sponsor proposes a phase III efficacy trial in which the vaccine candidate will be given to some individuals, and a placebo will be given to others. Neither the participants, the investigators nor the sponsor will know who is receiving the HIV candidate vaccine and who receives the placebo until completion of the trial (a randomized, double blind design). The sponsor states that this is the only way to arrive at valid and powerful conclusions about the effectiveness of the vaccine. It claims that no other study design will be capable of contributing conclusive evidence.
The cohort that has been proposed is a population of discordant couples. These are heterosexual couples in which one of the individuals is infected with the HIV virus, and the other is not. It has been discovered that there is a relatively high incidence of new infections occurring in the previously uninfected partners, in spite of counselling on how to avoid transmission. In addition, this population appears to be capable of following a research routine and presenting for research visits.
The sponsor and investigators in the host country propose that couples such as these be invited to participate in the trial. There will be advertisements distributed to key sites inviting people to participate in the study. Those who contact the investigators will then receive both verbal and written information in their own language about what the study is, how it will be carried out, and what the potential risks and benefits to the participants are. Both members of the couple will receive this information, but only the HIV-negative member (male or female) will be invited as a study participant. They will be asked to provide their signature to consent to participate in the study if they have completely understood the trial procedures and agree with them. They will have the option of leaving the study at any time. The investigators have assured the participants that all information will be kept in confidential files with the investigators and not with the countrys health care system.
The following details will be described to the potential participants prior to consenting to the study. After they have signed the informed consent for testing (to determine if they are eligible for the study), both members of the couple will require an initial HIV test. This will confirm that one is positive and one negative. They will also need to answer several questions about their sexual activity within the relationship and outside of it. If both are found to be positive, then neither one will be eligible to enter the study, and both will be counselled on how to seek HIV care that is available in the host country. However, if one of the partners is confirmed to be HIV-negative, then this individual will be invited to participate in the trial. The HIV-positive partner may participate in the study visits, and will be encouraged to participate in preventive counselling, but will receive no further testing or questioning. After the HIV-negative partner has consented to participate in the study, he or she will answer a further questionnaire requesting more detail about sexual history, drug use, social activities, and many other personal details. The participant will then receive an injection in the arm. Neither the participant nor the investigators will know whether this injection contains the vaccine being tested, or the placebo. There may be some pain in the arm for the next couple of days, and possibly fever, but it will be mild and will subside. There are no other side-effects to be expected, but if any symptoms should arise that have not been described, the participant is asked to notify the investigators. There is no risk that the injection will cause infection with HIV, as the candidate vaccine is basically composed of inactive pieces of the virus. However, there is a possibility that any future tests for HIV will indicate a positive result even if the individual is not truly infected. If this occurs, the individual may have a positive test for some weeks even though they are not truly infected. For those who do have a vaccine-induced seropositivity test, they will need to take a special blood test (Western blot) to prove that they are not truly infected. This test is usually, but not always, available in laboratories doing screening. Participants who wish to have it will carry a card explaining to health workers that their HIV screening test is not evidence of infection. Finally, if this candidate vaccine is found NOT to be efficacious, then there is a remote possibility that another candidate vaccine that is found in the future to be effective may not be useful for an individual who has already received the current study vaccine.
The HIV-positive partner will receive no injection, and is not officially enrolled in the study, but both members of the couple will be offered counselling on how to avoid transmission. It is emphasized that there is a chance that the participant has not received the candidate vaccine, but that even if he or she has received the vaccine, it should not be assumed that it will provide any protection. The couple should use every possible method, including condoms, to prevent transmission of HIV, and condoms will be provided by the sponsor at no cost to the couple. Study visits will take place at 7 days, 14 days, and 30 days after injection, then every 3 months for the first year and every 6 months for another 4 years. These visits will include a short interview (which includes questions on sexual activity, number of partners, use of barrier techniques), a blood test and counselling on how to prevent transmission of HIV. The blood test will be for the presence of new HIV infection, as well as immunological markers (such as CD4 cell count and viral load). If the participant does become infected, they will be asked to continue with the research visits for at least 12 months following infection. Over these 12 months, they will continue to have blood tests every 3 months to see how much virus is in their bodies. During this time, they will also be encouraged to seek the treatment, which is available through the health system of their country.
The proposal does not include any provision for antiretroviral drugs, prophylaxis or treatment for opportunistic infections, physician visits, palliative care or monitoring of the immune system for the HIV-positive partners, or for the study participants should they become infected with HIV during or after the study. The sponsor does not take responsibility for any special testing required by those who develop a positive HIV test as a result of receiving the candidate vaccine. The HIV positive partners will be encouraged to pursue the standard clinical treatment that is offered in the host country, as will the HIV-negative partners should they become infected during the course of the trial. All costs for transportation to the research visits and any expenses related to the visit such as food and lodging will be covered by the investigators.
If there is any physical illness or injury to the participants that results directly from the research being conducted, the costs for treating this will be covered by the sponsor. However, the proposal does not include any provision for compensation for loss of employment or other social disruption related to involvement in the research, or for stigma or discrimination resulting from an altered HIV testing status, or acquiring HIV infection.
If, following the three years of the trial, this vaccine is found to be effective, the sponsor has agreed to enter into a discussion phase with the government and health authorities of the host country concerning provision of the vaccine to that country. It is recognized that a decision about how and for whom the vaccine should be provided will depend to large degree on results to be obtained from the study, such as side-effects and degree of effectiveness. A promise about providing the vaccine cannot be made until this information is available. However, the sponsor is willing to ensure that the vaccine is made reasonably available at affordable rates to the individuals in that country for whom the vaccine is most appropriate.