AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 8, Number 8, 1992 Mary Ann Liebert, Inc., Publishers
Summary of International Trials Working Group NZILAMBI NZILA
Downloaded by Universitat de Barcelona CRAI from www.liebertpub.com at 01/12/19. For personal use only.
INTRODUCTION
DURING
THE PAST years, a dozen AIDS vaccines have been tested in humans in the United States and Europe. These Phase I and II studies are intended to evaluate the vaccine safety and immunogenicity in a small number of volunteers. Results have been encouraging. Current efforts to plan for Phase III (efficacy) trials with an AIDS vaccine in humans reflects the pressing public health need to rapidly find a solution to the AIDS crisis. However, there is no ideal vaccine yet and there remain many basic questions to be answered about the body's immune responses to HIV. Meanwhile, the AIDS pandemic continues growth. This session, chaired by Dr. Dale Lawrence, was developed to bring persons together with information to share about many practical issues to be negotiated in advance of conducting efficacy trials. Since several years are required to organize and implement activities necessary for successful efficacy trials, it is essential to start preparation now.
SCIENTIFIC ISSUES In
a
population
where the rate of
new
infections per year is
easily assess whether a vaccine works by following a relatively small number of vaccinated people over a shorter period of time. The greater the annual incidence, the smaller the required number of volunteers, or the
high,
researchers
can more
shorter the required duration of the trial. For this reason, researchers anticipate that the clinical trials may be expeditiously conducted in developing countries, where HIV infection is spreading quickly through the general population. Another reason is that, in spite of commitment by clinical trial investigators to provide counseling and other risk reduction methods, an AIDS vaccine has more opportunity to be challenged by HIV infection in developing countries. As an AIDS vaccine made from one HIV isolate may protect against only a limited range of genetically variant strains, isolation and characterization of regional HIV strains is an important issue to consider prior to conducting clinical trials.
Deputy Director, Project SIDA B.P.
For this and other reasons, it is certain that there will be multiple vaccines tested at multiple sites. Selecting potential efficacy trial sites is merely the beginning of a long implementation process. The World Health Organization (WHO)/Global Programme on AIDS (GPA) has identified four countries for strengthening with the goal of ultimate conduct of clinical vaccine trials: Rwanda, Uganda, Brazil, and Thailand. In addition, the U.S. National Institute of Allergy and infectious Diseases, the Walter Reed Army Institute of Research, the Centers of Disease Control, and other U.S. agencies and institutions (U.S. Agency for International Development. Fogarty International Center of the National Institutes of Health) arc hopeful that coordination with WHO GPA. other international institutions, national AIDS control programs and pharmaceutical firms will assist many investigators to establish potential overseas sites in the next few years. It was mentioned that large-scale clinical trials will likely take place in the U.S. also, in parallel or preceding international trials. Criteria for site selection may include the following: high HIV incidence in existing high-risk cohorts; existing prevention efforts, such as treatment for sexually transmitted diseases (STD) and counseling programs; existing trained personnel; and existing laboratory facilities. Since lowering the HIV incidence rate is the goal of the clinical trials, targeted populations will be those with documented high rates; these could include young gay men. intravenous drug users, patients with STD, and female prostitutes and their clients. Each candidate vaccine will be tested first in small pilot studies in targeted populations to make sure it is safe and immunogenic of these populations, even though such studies have already been completed in a developed country, or elsewhere.
LEGAL, POLITICAL, AND ETHICAL ISSUES Most scientists involved in research are acutely aware of the ethical problems and practical difficulties of running trials in poor countries where people are desperate. Concerns voiced during the session included the following:
8502 Kinshasa 1. Zaire.
1423
NZILA
1424
Downloaded by Universitat de Barcelona CRAI from www.liebertpub.com at 01/12/19. For personal use only.
1. Vaccine manufacturers may be concerned about the uncertainty of risks during clinical trials as well as the current unavailability of sufficient numbers of participants in the trials. 2. Medical investigators may be concerned about liability implications, the availability of participants in the trials and the preservation of confidentiality. 3. Participants in the trials may be concerned about their anonymity as well as receiving equitable treatment if they are seemingly harmed by the vaccine. In general, the attendees agreed that a fair and efficient system balancing the needs of all concerned parties must be developed. Foreseeable and emerging problems should be addressed as early as possible, including discussing what happens after the research is completed and how the benefits of that research can be shared by the participating populations. A suggestion was made that each participating country form a National Ethical Committee to adjudicate vaccine-related injuries. Recommendations of this committee should be seriously considered by persons concerned with clinical trials in the respective countries. For a host country, problems consistent with the public interest, to be as seriously considered as the ethical issues, include: The need to involve local people at the beginning of the trial. Host country personnel should take the lead in the study. The national sensitivity to taking samples out of the country. The need to test samples only for those agents/conditions that were originally agreed to (i.e., don't test for anything without prior approval). The need to address what happens after the trial. The need to do only those studies that meet ethical and safety standards which would apply to the trials conducted in the United States.
Apolitical climate supporting AIDS research is essential. The potential influences on the trial of political disfavor, or of a change in government that takes place while conducting a clinical trial, must be discussed in advance. Where relevant, it might be advantageous to establish firm institutional collaborative relationships with stable organizational structures, such as a National Ethical Committee, which may be less subject to transient political influences than a Ministry of Health. The role of WHO/GPA current activities in developing ethical guidelines of relevance to vaccine trials and clinical research in developing countries was described.
FINANCIAL ISSUES Some manufacturers and insurers seem to believe that the of vaccine development will be high, the chances of scientific success low, and commercial success uncertain. All these factors can weigh heavily against proceeding into this arena. However, at least 10 companies are engaging in AIDS vaccine research and development. Final access and broad distribution of AIDS vaccines may be facilitated through nego-
costs
by WHO with successful vaccine manufacturers. The underlying concern was that a safe and efficacious vaccine may prove too expensive for the Third World. Although brief descriptions of general approaches of the National Institutes of Health and others to support forprevaccine epidemiology studies were provided, the larger questions of support for vaccine availability were phrased as follows: tiations
Who takes the risks of experimentation and who gets the benefits? How can vaccine availability be assured for the needy? Who is going to distribute the vaccine? Who is going to pay for vaccine distribution?
CHARACTERISTICS OF TRIALS The informed consent process provides information to an individual about the rights and responsibilities he/she acquires by choosing to participate in a clinical trial. Some participants shared instructive experiences on other additional approaches which may apply depending on the phase of the trial, the types of personnel available to interact with potential participants in the informed consent process, and the country in which the trial occurs.
The study must be designed as a randomized, double-blinded, placebo-controlled clinical trial, meaning that not all participants actually will receive the vaccine and that neither the participant nor the clinical study personnel will know whether the participant has actually received the vaccine until the results of the clinical trials are analyzed. Whether a participant receives the HIV vaccine or a placebo will be determined randomly (by chance) (e.g., by a computer-generated code). In order to provide some benefit to placebo recipients, the placebo could be another vaccine (not the AIDS vaccine), such as the licensed hepatitis B vaccine. Furthermore, since STDs
represent risk factors for HIV transmission,
an STD control program which results from the procedures associated with the vaccine trial, could represent a great and lasting benefit for the
study participants. Every attempt will be made to protect the confidentiality of the results and the anonymity of the participant. In addition, it is essential that volunteers be considered to continue to avoid any high-risk behavior that might put them at risk for HIV infection. It is likely that the study protocols will be reviewed for approval locally in the host country as well as outside (e.g., U.S.) by ethical review bodies. Site-specific protocols seem more appealing to some than international, standard protocols. The important role of the U.S. Food and Drug Administration or other relevant regulatory bodies in the many issues of efficacy trials was emphasized. Routes of administration of a vaccine must be taken into account: a vaccine with an easy administration route, for example oral administration, is preferable to an injection. Also a single-dose vaccine will be preferable for large-scale clinical trials. Type of vaccine must also be considered, since vaccines with live vectors seem to be more immunogenic in
general.
SUMMARY OR INTERNATIONAL TRIALS OF WORKING GROUPS
OBJECTIVES FOR 1992
Assisting potential sites to identify sources of funding Providing genetic variation information such as isolation and
This session's goal was to identify specific, useful tasks for 1992. These include support (partially or completely) for one or more projects in 10 high-risk countries. Immediate objectives will include:
characterization of HIV strains Providing about two prototypic isolates from 10 countries to 10 AIDS vaccine manufacturers.
Identifying through WHO, academic research institutions and others, host country public health scientists, countries with high
HIV incidence in
geographically
tions, for assistance and funding
Downloaded by Universitat de Barcelona CRAI from www.liebertpub.com at 01/12/19. For personal use only.
1425
available
popula-
Offering, receiving, reviewing, and awarding grants in a minimum of 3-4 sites for prevaccine epidemiology Reviewing and awarding additional grants for related studies Advising potential grantees on programs in HIV-related sciences (networking) Providing scientific and technical information to prospective trainees
In summary, participants at this international trials working group session agreed that since AIDS is just one of the many public health threats to developing countries, AIDS activities may be usefully integrated into all AIDS prevention control activities, including sexually transmitted diseases in general and
family planning programs. Address
reprint requests
to:
Nzilambi Nzila Deputy Director Project SIDA B.P. 8502 Kinshasa I. Zaire
Summary of International Trials Working Group NZILAMBI NZILA
Downloaded by Universitat de Barcelona CRAI from www.liebertpub.com at 01/12/19. For personal use only.
INTRODUCTION
DURING
THE PAST years, a dozen AIDS vaccines have been tested in humans in the United States and Europe. These Phase I and II studies are intended to evaluate the vaccine safety and immunogenicity in a small number of volunteers. Results have been encouraging. Current efforts to plan for Phase III (efficacy) trials with an AIDS vaccine in humans reflects the pressing public health need to rapidly find a solution to the AIDS crisis. However, there is no ideal vaccine yet and there remain many basic questions to be answered about the body's immune responses to HIV. Meanwhile, the AIDS pandemic continues growth. This session, chaired by Dr. Dale Lawrence, was developed to bring persons together with information to share about many practical issues to be negotiated in advance of conducting efficacy trials. Since several years are required to organize and implement activities necessary for successful efficacy trials, it is essential to start preparation now.
SCIENTIFIC ISSUES In
a
population
where the rate of
new
infections per year is
easily assess whether a vaccine works by following a relatively small number of vaccinated people over a shorter period of time. The greater the annual incidence, the smaller the required number of volunteers, or the
high,
researchers
can more
shorter the required duration of the trial. For this reason, researchers anticipate that the clinical trials may be expeditiously conducted in developing countries, where HIV infection is spreading quickly through the general population. Another reason is that, in spite of commitment by clinical trial investigators to provide counseling and other risk reduction methods, an AIDS vaccine has more opportunity to be challenged by HIV infection in developing countries. As an AIDS vaccine made from one HIV isolate may protect against only a limited range of genetically variant strains, isolation and characterization of regional HIV strains is an important issue to consider prior to conducting clinical trials.
Deputy Director, Project SIDA B.P.
For this and other reasons, it is certain that there will be multiple vaccines tested at multiple sites. Selecting potential efficacy trial sites is merely the beginning of a long implementation process. The World Health Organization (WHO)/Global Programme on AIDS (GPA) has identified four countries for strengthening with the goal of ultimate conduct of clinical vaccine trials: Rwanda, Uganda, Brazil, and Thailand. In addition, the U.S. National Institute of Allergy and infectious Diseases, the Walter Reed Army Institute of Research, the Centers of Disease Control, and other U.S. agencies and institutions (U.S. Agency for International Development. Fogarty International Center of the National Institutes of Health) arc hopeful that coordination with WHO GPA. other international institutions, national AIDS control programs and pharmaceutical firms will assist many investigators to establish potential overseas sites in the next few years. It was mentioned that large-scale clinical trials will likely take place in the U.S. also, in parallel or preceding international trials. Criteria for site selection may include the following: high HIV incidence in existing high-risk cohorts; existing prevention efforts, such as treatment for sexually transmitted diseases (STD) and counseling programs; existing trained personnel; and existing laboratory facilities. Since lowering the HIV incidence rate is the goal of the clinical trials, targeted populations will be those with documented high rates; these could include young gay men. intravenous drug users, patients with STD, and female prostitutes and their clients. Each candidate vaccine will be tested first in small pilot studies in targeted populations to make sure it is safe and immunogenic of these populations, even though such studies have already been completed in a developed country, or elsewhere.
LEGAL, POLITICAL, AND ETHICAL ISSUES Most scientists involved in research are acutely aware of the ethical problems and practical difficulties of running trials in poor countries where people are desperate. Concerns voiced during the session included the following:
8502 Kinshasa 1. Zaire.
1423
NZILA
1424
Downloaded by Universitat de Barcelona CRAI from www.liebertpub.com at 01/12/19. For personal use only.
1. Vaccine manufacturers may be concerned about the uncertainty of risks during clinical trials as well as the current unavailability of sufficient numbers of participants in the trials. 2. Medical investigators may be concerned about liability implications, the availability of participants in the trials and the preservation of confidentiality. 3. Participants in the trials may be concerned about their anonymity as well as receiving equitable treatment if they are seemingly harmed by the vaccine. In general, the attendees agreed that a fair and efficient system balancing the needs of all concerned parties must be developed. Foreseeable and emerging problems should be addressed as early as possible, including discussing what happens after the research is completed and how the benefits of that research can be shared by the participating populations. A suggestion was made that each participating country form a National Ethical Committee to adjudicate vaccine-related injuries. Recommendations of this committee should be seriously considered by persons concerned with clinical trials in the respective countries. For a host country, problems consistent with the public interest, to be as seriously considered as the ethical issues, include: The need to involve local people at the beginning of the trial. Host country personnel should take the lead in the study. The national sensitivity to taking samples out of the country. The need to test samples only for those agents/conditions that were originally agreed to (i.e., don't test for anything without prior approval). The need to address what happens after the trial. The need to do only those studies that meet ethical and safety standards which would apply to the trials conducted in the United States.
Apolitical climate supporting AIDS research is essential. The potential influences on the trial of political disfavor, or of a change in government that takes place while conducting a clinical trial, must be discussed in advance. Where relevant, it might be advantageous to establish firm institutional collaborative relationships with stable organizational structures, such as a National Ethical Committee, which may be less subject to transient political influences than a Ministry of Health. The role of WHO/GPA current activities in developing ethical guidelines of relevance to vaccine trials and clinical research in developing countries was described.
FINANCIAL ISSUES Some manufacturers and insurers seem to believe that the of vaccine development will be high, the chances of scientific success low, and commercial success uncertain. All these factors can weigh heavily against proceeding into this arena. However, at least 10 companies are engaging in AIDS vaccine research and development. Final access and broad distribution of AIDS vaccines may be facilitated through nego-
costs
by WHO with successful vaccine manufacturers. The underlying concern was that a safe and efficacious vaccine may prove too expensive for the Third World. Although brief descriptions of general approaches of the National Institutes of Health and others to support forprevaccine epidemiology studies were provided, the larger questions of support for vaccine availability were phrased as follows: tiations
Who takes the risks of experimentation and who gets the benefits? How can vaccine availability be assured for the needy? Who is going to distribute the vaccine? Who is going to pay for vaccine distribution?
CHARACTERISTICS OF TRIALS The informed consent process provides information to an individual about the rights and responsibilities he/she acquires by choosing to participate in a clinical trial. Some participants shared instructive experiences on other additional approaches which may apply depending on the phase of the trial, the types of personnel available to interact with potential participants in the informed consent process, and the country in which the trial occurs.
The study must be designed as a randomized, double-blinded, placebo-controlled clinical trial, meaning that not all participants actually will receive the vaccine and that neither the participant nor the clinical study personnel will know whether the participant has actually received the vaccine until the results of the clinical trials are analyzed. Whether a participant receives the HIV vaccine or a placebo will be determined randomly (by chance) (e.g., by a computer-generated code). In order to provide some benefit to placebo recipients, the placebo could be another vaccine (not the AIDS vaccine), such as the licensed hepatitis B vaccine. Furthermore, since STDs
represent risk factors for HIV transmission,
an STD control program which results from the procedures associated with the vaccine trial, could represent a great and lasting benefit for the
study participants. Every attempt will be made to protect the confidentiality of the results and the anonymity of the participant. In addition, it is essential that volunteers be considered to continue to avoid any high-risk behavior that might put them at risk for HIV infection. It is likely that the study protocols will be reviewed for approval locally in the host country as well as outside (e.g., U.S.) by ethical review bodies. Site-specific protocols seem more appealing to some than international, standard protocols. The important role of the U.S. Food and Drug Administration or other relevant regulatory bodies in the many issues of efficacy trials was emphasized. Routes of administration of a vaccine must be taken into account: a vaccine with an easy administration route, for example oral administration, is preferable to an injection. Also a single-dose vaccine will be preferable for large-scale clinical trials. Type of vaccine must also be considered, since vaccines with live vectors seem to be more immunogenic in
general.
SUMMARY OR INTERNATIONAL TRIALS OF WORKING GROUPS
OBJECTIVES FOR 1992
Assisting potential sites to identify sources of funding Providing genetic variation information such as isolation and
This session's goal was to identify specific, useful tasks for 1992. These include support (partially or completely) for one or more projects in 10 high-risk countries. Immediate objectives will include:
characterization of HIV strains Providing about two prototypic isolates from 10 countries to 10 AIDS vaccine manufacturers.
Identifying through WHO, academic research institutions and others, host country public health scientists, countries with high
HIV incidence in
geographically
tions, for assistance and funding
Downloaded by Universitat de Barcelona CRAI from www.liebertpub.com at 01/12/19. For personal use only.
1425
available
popula-
Offering, receiving, reviewing, and awarding grants in a minimum of 3-4 sites for prevaccine epidemiology Reviewing and awarding additional grants for related studies Advising potential grantees on programs in HIV-related sciences (networking) Providing scientific and technical information to prospective trainees
In summary, participants at this international trials working group session agreed that since AIDS is just one of the many public health threats to developing countries, AIDS activities may be usefully integrated into all AIDS prevention control activities, including sexually transmitted diseases in general and
family planning programs. Address
reprint requests
to:
Nzilambi Nzila Deputy Director Project SIDA B.P. 8502 Kinshasa I. Zaire
