NB: This paper is for your information only. If you want to quote from this article, you should consult the original published in: AIDS and Public Policy Journal 1995:10;22-26. There are important differences between this version and the printed version.
Introduction
Questions concerning informed consent have been prominent in the literature on the ethical issues associated with preventive AIDS vaccine trials. First, it has been pointed out that there not only are medical risks associated with a vaccine trial, but also social and psychological risks for the persons taking part in the trial. These include seroconversion and possible discrimination because of that, as well as a false sense of security and subsequent increase in risk behavior (1). Second, it has been pointed out that the usual conflict of interest between the physician as clinician and the physician as researcher is heightened in the case of HIV vaccine trials. The physician who has only the best interest of his or her patients in mind should do everything possible to make sure that the patients do not get infected, including using every appropriate educational means to ensure that the patients do not engage in any risk behavior. If the physician succeeds in this endeavor, it would be difficult to get any results from the trial because very few would become infected. The physician as researcher, however, is interested in results from the trial as quickly as possible, and would therefore want, although not necessarily consciously, the subjects to engage in high risk behavior. This conflict is absent from most other vaccine trials.
Careful attention therefore needs to be paid to informed consent requirements. Before a potential participant is included in the trial, he or she must understand the risk involved and understand the need to continue to avoid high risk behavior. Little is, however, known about whether the standard informed consent process is adequate in the context of AIDS vaccine trials. There are some studies in other areas of medical research which have documented deficiencies in the informed consent process (2).
The aim of this pilot study was therefore to address the question of whether it is possible to design a study of the informed consent process in the context of preventive AIDS vaccine trials, and to draw some preliminary conclusions about what aspects of the informed consent process need particular attention.
Methods
This is a pilot study with the purpose of testing out a questionnaire aimed at exploring issues important for informed consent to preventive AIDS vaccine trials. There were fixed answer alternatives to most questions, a few were open ended. The questionnaire was administered as a semi-structured interview, where the interviewer read out the questions and noted the answers. The questionnaire consisted of three parts. First, questions about individual characteristics, such as age, sex, residence and educational level were asked. The second part consisted of questions probing general knowledge and conceptions about vaccines, and of their relationship to physicians and to research in general. The third and main part of the questionnaire was a sample informed consent form for preventive AIDS vaccine trials. The text was based on existing informed consent forms for AIDS vaccine trials. The participants in the study read through the form. After having read it, they were asked to underline phrases in the text which seemed important to them, and to put a plus sign or a minus sign beside them, depending on whether they felt this would motivate them to participate or to discourage them from participating in the vaccine trial. They were then given eight statements taken directly or slightly modified from the informed consent form. For each of these eight statements, four interpretations were given, only one of which was correct. An open-ended 'other'-category was also provided. This design is similar to the one used by Sutherland et al (1990) for cancer clinical trials (3).
A first version of the questionnaire was tested among members of a self-help non-governmental organization for HIV-positives in Brazil (Pella Vida). In particular, they were asked about their concepts of key components of clinical trial design. Some of the answers given in these sessions were subsequently incorporated in the questionnaire design used in this pilot study. Results from a previous study of the concepts of vaccines among mothers in Rio de Janeiro were also used in the construction of the answer alternatives (4).
Even though this questionnaire was not addressed to a specific group, the pilot study was applied to 20 homosexual and bisexual males. The participants were recruited from a group of people taking part in a co-hort study initiated by one of the institutions responsible for the vaccine trials in Rio de Janeiro as a preparation for a future vaccine trial in Brazil.
The protocol was submitted and approved by the appropriate research ethics committees in both Norway and Brazil.
Results
The average age of the participants was 25.6 years. 2 of the respondents had some university education. About half had finished primary school (8 years of school), the others had some high school education, or had finished high school. All but one, who volunteered that he was HIV positive, would take a vaccine against AIDS if its effectiveness had been proven and if it were available today. 15 did not think that they would be completely protected against infection if there were vaccinated and 19 said that they needed to protect themselves against infection after they had been vaccinated. 14 of the 20 participants would take part in a trial if they were asked. All of them said that they needed to continue to avoid high risk behavior even if they participated in a vaccine trial as described in the informed consent form.
Table 1 lists some of the phrases the participants felt were important, and table 2 lists the answer alternatives to questions about their understanding of key phrases in the informed consent form. A total of eight such questions about key phrases were given. Results from four of these are given in table 2.
TABLE 1: This table shows some of the statements marked positive or negative by the participants. Positive meant that they felt this information would motivate them to participate, negative that they would be discouraged to participate. The percentages of respondents marking each statement positive or negative are also given.
Statements considered positive
Expenses for transport, lunch or even loss of a work day's wages, if necessary, will be covered - 50%.
To all participants will be granted medical treatment, as well as compensation, from the health care institutions, in case of any injury caused by the research - 45%.
The Brazilian Government through the Health Ministry and the World Health Organization will also be behind these trials - 30%.
The vaccine needs to be tested with a large number of participants - 30%.
The participants need to avoid any behavior that could increase their chance of becoming infected with the virus that causes AIDS - 25%.
Statements considered negative
If seroconversion develops, it may lead to discrimination against the participants - 25%.
The group which receives the active vaccine may test positive by conventional screening methods (i.e. the ELISA test) -15%.
An HIV+ person will be excluded from this trial - 20%. (But 25% had indicated this as a positive issue)
They cannot expect protection from the vaccine to be tested - 20%.
Neither the participants nor their physician will know whether they have actually received the active vaccine as long as the trial is going on - 25%.
There may be side effects which may be associated with any vaccine which involves injection into a muscle, such as local discomfort including pain, redness, and swelling at the injection site - 20%
Other theoretical side effects may occur, some of them may be potentially serious or entirely unknown at this time - 20%.
TABLE 2: This table gives the interpretations to some of the statements in the informed consent form. Participants were asked to choose one of the alternative interpretations. The percentages of participants who answered each alternative are also given.
I - "A process called randomization is used to select the participants in this vaccine trial, with a placebo ".
1 - The process will select the best treatment for the participant (30%)
2 - Each individual participant has exactly the same chance of receiving the vaccine, or the inactive control preparation, as any other participating individual. (30%)
3 - One vaccine is given one time, another is given another time. (10%)
4 - The doctor decides which vaccine is the right one for the participant. (10%)
5 - Other, I don't know (20%)
II - "Participants must continue to avoid any high risk behavior that might increase the chance of being infected with the AIDS virus"
1 - The participants must avoid any risk behavior in order to not compromise the performance of the trial. (10%)
2 - This statement refers only to the participants which will not receive the active vaccine. (5%)
3 - This statement refers to all the participants independent of whether he/she has received the active vaccine or not. (75%)
4 - People with high risk behavior are automatically excluded from this trial. (10%)
5 - other, do not know
III - "Those who receive the active vaccine may not be able to take advantage of other potential AIDS vaccines which may be available in the future"
1 - Those who receive the active vaccine, could be excluded from any other vaccine trial in the future. They will need to wait till the production of an effective vaccine in order to be protected against the AIDS virus. (35%)
2 - Those who receive the active vaccine, don't need to be worried about receiving other vaccines in the future. (0%)
3 - Those who receive the active vaccine could be excluded from receiving any other vaccine against AIDS, whether in a test or not, even if it proved to be of more effective than the vaccine in this test.(30%)
4 - Those who receive the active vaccine do not need any other vaccine that may become available in the future. (15%)
5 - other, do not know (20%)
IV - "It is also possible that the participants in the trial will be more susceptible to infection by the AIDS virus if they are exposed to it later".
1 - Those who receive the test vaccine may have their defenses against the AIDS virus more weakened, it can increase the possibility of developing the disease quickly, if they are exposed to it later. (25%)
2 - Those who receive the test vaccine, even if it does not prove to be highly effective, will be more protected against the AIDS virus, if they are exposed to it later. (5%)
3 - The organism can resist the presence of the AIDS virus better, if it is exposed to it later, once the organism has already been stimulated by the vaccine. It will improve survival, even if he/she will develop the disease. (60%)
4 - Because it is a question of a virus vaccine it could work like the virus itself, making the person develop the disease.(5%)
5 other, do not know (5%)
Discussion
This pilot study, with results from only 20 people, can of course not be used to draw conclusions about what potential participants in preventive AIDS vaccine trials are able to understand about central elements of informed consent. Nevertheless, one can say something about what issues a study about informed consent in this context needs to address.
The results from this pilot study indicate that people are motivated to take part in vaccine trials (14 out of 20). This is higher than was found in a recent study of drug users' willingness to enroll in HIV vaccine trials, although both the population and the phrasing of the question were different in this study (5). It is also interesting to note that all answered that it would be necessary to continue to avoid high risk behavior even if they participated in a vaccine trial.
One may be tempted to conclude from this that the worry some have expressed about participants in vaccine trials not being able to understand that they may not be protected against infection, is unfounded. It is, however, important to observe that only a few respondents give correct answers to fundamental points of trial design and to questions about their understanding of the risks involved in taking part in vaccine trials. One may therefore suspect that information regarding safe sex has become a kind of a slogan, almost a dogma. It does not make any difference concerning the context where it appears, when asked people will always say that they should avoid high risk behavior. We do not, therefore, think that the answer about avoiding risk behavior should necessarily be taken as evidence of a high awareness of the need to protect themselves once they are taking part in a vaccine trial.
The incorrect answers seem to reflect more than simple misunderstandings. When the respondents choose an answer, they not only choose an incorrect answer, but they also choose one which reflects a sense of trust in the researchers or in research itself. Let us give some examples: When questioned about randomization, 30% gave a correct answer, however, 30% answered that the process will select the best treatment for the participant; when questioned about the possibility to be excluded from other vaccinations against AIDS, 30% gave a correct answer, but 35% answered "Those who had received the active vaccine, can be excluded from any vaccine trial in the future, they need to wait for the production of an effective vaccine in order to be protected against the AIDS virus." 30% of the interviewees underlined as positive the fact that the Health Ministry and WHO will follow this process. When asked what is meant by "It is also possible that the participants in the trial will be more susceptible to infection by the AIDS virus if they are exposed to it later" 60% answered "that the organism can resist the presence of the AIDS virus better, if it is exposed to it later, once the organism has already been stimulated by the vaccine. It will improve survival, even if he/she will develop the disease". One conclusion one can draw from this is that a study of the adequacy of the informed consent process needs to go beyond asking simple questions about the trials, such as whether potential participants would take part, or whether they understand the need for avoiding high risk activities. It is necessary to probe deeper, asking questions about the details of the trial design, and about details of their understanding of possible benefits and risks. Only then can one say something meaningful about whether potential participants have understood enough to a truly informed consent.
The pilot study has thus demonstrated that the design used in this study, giving potential participants a sample informed consent form, and asking questions about their understanding of key issues, can capture some of the possibilities for misunderstanding. If the results from the pilot study are confirmed in a larger study, the results can be used to improve the informed consent form and the informed consent process.
One should, however, also go one step further and ask, what causes the high willingness to take part in this vaccine trial? As mentioned above, it seems that there is a feeling of trust, but we do not think that this is the more important reason. We also think that there is a kind of information, non-formal knowledge, that can easily escape the perception of researchers, but it can play an important role in the willingness to take part in such a vaccine trial. We are not talking about information of key conceptions of vaccine trial design, but information about AIDS itself instead. This information comes from their daily life, from how they perceive the disease and everything surrounding that. We could say that there is a kind of concern regarding the disease and because of that a willingness to help with everything that can fight the disease. They are not concerned with prevention only, they are concerned with AIDS with its broad meaning, and it is a reality in their life. We guess that the incidence of acceptance of preventive AIDS vaccine trials will be higher the worse the realities of AIDS are perceived.
The question here is not if they have enough information in order to take part in a vaccine trial against AIDS (the use of the AIDS term here instead of HIV is intentional). We do think they have a lot of information regarding AIDS (not necessarily academic information), probably more than many researchers, but they have also expectations from the vaccine. This is probably the point that plays an important role in the willingness to take part in this vaccine trial and one should pay attention to this issue as well when designing studies to capture the perceptions of potential participants, and when designing the informed consent process.
NOTES
1. For a critical discussion of the risks involved in preventive AIDS vaccine trials, see Mariner WK. Why clinical trials of AIDS vaccines are premature. Public Health and the Law 1989; 79: 86-91; Porter JP, Glass MJ, Koff WC. Ethical considerations in AIDS vaccine testing. IRB: A review of human subjects research 1989; May-June: 1-7; and Lurie P, Bishaw M, Chesney MA et al. Ethical, behavioral and social aspects of HIV vaccine trials in developing countries. Journal of the American Medical Association 1994;271:295-301.
2. See for example Cassileth BR, Zupkis RV, Sutton-Smith K, March V. Informed consent - why are its goals imperfectly realised? New England Journal of Medicine 1980; 302: 896-900; DCCT Research Group. Implementation of a multicomponent process to obtain informed consent in the diabetes control and complications trial. Controlled Clinical Trials 1989; 10: 83 - 96; Howard JM, DeMets D, et al. How informed is informed consent? The BHAT experience. Controlled Clinical Trials 1981; 2: 287 - 303; Llewellyn-Thomas HA, McGreal MJ, Thiel EC, Fine S, Erlichman C. Patients' willingness to enter clinical trials: measuring the association with perceived benefit and preference for decision participation. Social Science and Medicine 1991; 32: 35-42; Lynoe N, Sandlund M, Dahlqvist G, Jacobsen L. Informed consent: study of quality of information given to participants in a clinical trial. British Medical Journal 1991; 303: 610-613; Riecken HW, Ravich R. Informed consent to biomedical research in Veterans Administration hospitals. JAMA 1982; 248: 344-348; Sutherland HJ, Lockwood GA, Till JE. Are we getting informed consent from patients with cancer? Journal of the Royal Society of Medicine 1990; 83: 439-443.
3. Sutherland HJ, Lockwood GA, Till JE. Are we getting informed consent from patients with cancer? Journal of the Royal Society of Medicine 1990; 83: 439-443
4. Bercini, Marilia A. Nao Vacinacao: a fala das maes, um estudo de caso numa comunidade de baixa renda no muicipio do Rio de Janeiro. Dissertacao de mestrado - Institudo Fernandes Figueira, Fundacao Oswaldo Cruz, Ministerio da Saude, Rio de Janeiro, Brasil, 1992
5. Meyers K, Metzger DS, Navaline H, Woody GE, McLellan T. HIV vaccine trials: Will intravenous drug users enroll? American Journal of Public Health 1994; 84; 761-766