Download Animal Testing and Clinical Trials

Varaporn Podprasart
ACKNOWLEDGEMENT
I would like to express my sincere gratitude and deep appreciation to
Professor. Dr. John Essigmann, Associate Professor Ram Sasisekharan, Dr.
Ganesh Venkataraman, Dr. Maria Kartalou from MIT, and Dr. Suvit Loprasert
from CRI for their guidance, supervision, and valuable advice throughout this
course. They were always nice and kindness. My equally grateful thanks are
extended to Dr. Praphan Phanupak from Thai Red Cross and Chulalongkorn
University, who has kindly provides me with constructive comments and
criticism in relation to the ethic problems in HIV/AIDS in Thailand. Special and
sincere appreciation are given to Mr. Pornchai Sornsathapornkul, a staff in
TAVEG-SIRIRAJ, for providing an excellent information about HIV/AIDS
vaccine clinical trials in Thailand. Finally, I would like to thank all of the CRI’s
staffs and my friends in “Bioengineering and Environmental Health” course,
especially in the ethics group, according to wonderful friendships.
Varaporn Podprasart
July 2000
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Varaporn Podprasart
SUBMITTED ABSTRACT
Acquire Immunodeficiency disease (AIDS), a major infectious disease, has
currently emerged rapidly and the infection, HIV, can be occurred in a wide range in
humans; newborn up to old age or even in pregnancy women. The AIDS epidemic is
likely to continue to spread with a potential to become one of the most lethal diseases.
Therefore, many researchers must be rapidly deal with this problem. According to not
only variety of HIV types but also rapidly change of them, no specific treatment for
HIV/AIDS patients are completely developed. Normally, the testing of new drug(s)
and vaccine to prevent or cure this dreadful disease has been initially in vitro follow
by in vivo and finally study in humans. Hence, there are many moral and ethical
arguments on using animals and humans for experimental purposes. Animal is one of
the living populations, like us, so many questions have raised such as: Is animals
exactly serve as valuable model to solve the HIV problems? Is it necessary to use
them? Are there any alternative choices? If not, how can we take more benefits on
using them? In addition, the evaluation of new drug(s) or vaccine against HIV/AIDS
must be pass through clinical trials to determine their efficacy in humans. So, is it
right to carry out the experiment in human subjects both in normal healthy people and
HIV/AIDS patients? Is the placebo necessary to use as a control in this life-threatened
disease? Who will responsible for the result if there are many side effects occur?
Furthermore, I will focus on the ethics between health care professionals and
HIV/AIDS patients. By duty, they can not abandon these patients but if they contact
the blood or any secretions from HIV-infected patient, what will they do? Who will
support them and can they continue their works? In contrast, if they can go on their
careers, how about the health care professional-to-patient transmission? Is it right to
let them work? All of these questions involve in both moral and ethical problems in
HIV/AIDS. Normally, ethics issues deal with an uncertainty and conflicting responses
about what we should do or should not do. It is difficult to justify that what is right or
wrong since all issues are abstract. Therefore, I try to recruit the ethical information
that cover all questions above as you can see in this report.
Varaporn Podprasart
9 June 2000
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CONTENTS
Page
Acknowledgement
I
Submitted abstract
II
Introduction
IV
Ethics
1
- Ethics and researchers
1
Ethics of using animal as a model for HIV/AIDS research
1
- The role of experimental animals and the development of
candidate HIV/AIDS vaccine
2
- Supportive ideas for the use of animal models for research
purposes including HIV/AIDS research
3
- Arguments the use of animal models for research purposes
including HIV/AIDS research
3
- Ethical problems involved the use of animal as a model
for HIV/AIDS research
4
- Alternative choices in the HIV/AIDS research study
6
- Principles for the utilization and care of vertebrate animals
used in testing and research
7
- The use of experimental animals in Thailand
8
Ethics of using human as a model for HIV/AIDS research
11
- Clinical trials: general ethics principles
11
- Ethical problems involved the use of human as a model for
HIV/AIDS research
12
- The protection concerning with the ethical problems in using
human model
16
- HIV/AIDS and human research in Thailand
16
Ethics in health care professionals (HCPs) and HIV/AIDS patients
17
- Patient-to-health care professional (HCP) transmission of HIV
17
- Ethical problems involved in patient-to-HCP transmission
of HIV
17
- Health care professional (HCP)-to-patient transmission of HIV
21
- Ethical problems involved in HCP-to-patient transmission of HIV
21
Conclusion
24
References
25
Appendix
Appendix I : The opinions of our classmates about the using of
animal as a model for research studies
28
Appendix II : The opinions of our classmates if someone ask them
to be volunteers in HIV/AIDS clinical trials
29
Appendix III: The reasons of volunteers, who have joined in
HIV/AIDS clinical trials in TAVEG-SIRIRAJ
30
Appendix IV: The reasons from people, who do not to join in
HIV/AIDS clinical trials
30
Appendix V : The example of informed consent for research study
31
Appendix VI: Deciding to enter an HIV/AIDS drug trial
33
Appendix VII : The example of medical accidental report for health care
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Professional
Appendix VIII: Questions from the audiences after presentation
INTRODUCTION
36
37
Ethical issues are one of the most problems associated with human
immunodeficiency virus (HIV) infection. HIV will develop the disease named
“acquired immunodeficiency disease” or “AIDS”, which is currently incurable.
Therefore, there are numerous and varied studies that try to develop new antiHIV/AIDS drugs and vaccines for prevention, control, and treatment. All of the new
treatments, which involved in HIV/AIDS therapy must be initially tested in animals to
determine the safety and efficacy of the drugs (or vaccine). If the results are
promising, they will move the study into human subjects, who are or are not infected
with HIV. Many experimental animals, especially chimpanzees and some type of
monkeys, were infected with HIV or even some type of infectious virus and were
observed by the investigators. Those animals received not only pain but also
uncomfortable. Some died from the infection. Some died from the drug or vaccine. If
the animal experiments for HIV/AIDS research must be conducted, the main ethical
issue involves about animal rights and animal welfare must be realized and addressed
by the all researchers. Similarly, the experiment that is conducted in human subject
must account for the human rights. Even though the HIV/AIDS research is set up for
the social purpose but the well-being of the animals and human subjects in the
research are important as well. Therefore, the ethical issues in this aspect must be
compare d between benefits and risks, social rights and animal or human rights as I
will mention in this topic. Another ethical issue is due to the gradually increase in the
rate of HIV/AIDS patients. The more HIV infection, the more patients admitted in the
hospitals. And now it was found that the health care professionals, who take care with
the patients can be infected with HIV during their duty. Thus, many ethical aspects
between health care teams and patients such as right to know and right to refuse are
complex and difficult to justify that who did the right things. The decision concerning
the human rights is also ethical problem as well. Therefore, the topic of ethics on
health care professional and HIV/AIDS patient is included.
Ethics
The word “ethics” comes from the Greek ethos and ethica, which evolved to
mean an academic discipline that provides a set of intellectual instrument (theories,
categories, and principles) for the analysis of morality. Morality comes from the Latin
mos-moris meaning a person’s behavior that is open to judgement of right and wrong.
The original meaning of ethics was “inner being” or a person’s character and the
oldest ethical theory focuses on good and bad in terms of the attitude and habit that
render a person good or bad. Social ethics deals with a social order and specifically
with what’s right and good in the organization of human communities (1). Therefore,
ethics concerned with values related to human conduct, the rightness or wrongness of
certain actions, and the goodness or badness of the motives or ends of such actions.
Ethics invites us to use reasoned analytic and critical approaches and precedents to
answer questions about how we ought to behave in given situations and why (1).
Consider with this topic, the most obvious difference between the ethics of using
animal and human testing is the “informed consent”. In human subjects’s experiment,
they can know about their situation and express informed consent. The decisions are
often made on behalf of the subjects, who is interested in the outcome of the tests or
procedures. But when the subjects of the experiment are animals, they can not deny
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all dangers we give to them. The whole picture of ethical decision-making, therefore,
is difficult for these subjects.
Ethics and researcher
There are 2 distinguish ethics that are involved in research (2);
1. Radar Ethics: Moral constraints are thought of as something coming from “the
outside” to which the person in question has to adjust.
2. Gyroscope Ethics: Moral constraints are self-imposed, on the basic of the person’s
own moral reflections.
If the researchers follow the radar ethics, they will help the society to gain
important knowledge and the ethical limits depend on the society decide. But many
researchers are still suspicious of the idea of engaging in moral inflections, which are
subjective and emotional, whereas the scientist is supposed to be objective and
emotionally unbiased. This fundamental moral question is the major problem to
justify the use of animals in biomedical research.
Ethics of using animal as a model for HIV/AIDS research
The use of animals for research purposes must be a concern for many
individuals as well as for society. While some people feel that animal experiments
should be abandoned, others are more moderate and accept to use them but they
suggest that certain limitations are necessary. Normally, a common classification of
animal experiments is according to scientific purpose (3);
1. To search for new knowledge
2. To diagnose disease
3. To test new therapeutic technique and new medicines
4. To detect and analyze drugs and others biological compounds
5. To produce and test vaccines, sera, and other biological compounds
6. To test for toxicity, carcinogenicity, and teratogenicity of new and old drugs and
chemical compounds
In addition, animal experimentation has lead to an increase understanding of
disease process and of normal body functions. Using animal models has made
significant theoretical and practical advances and also they are great potential in
vaccine and therapy studies. In other word, animal experiments can be condensed into
2 groups; (1) fundamental or basic research, and (2) manufacturing and testing. Even
though, there are some other “alternative methods” that try to use instead of using
animal model, which I will mention later, but the basic biological knowledge must
first be available. For example, if a biological problem is approached for the first time,
the question may be answered by means of using an animal experiment. There are
theoretically alternatives to the animal experiment that would change the basic
question (3). However, before using animals for research purposes, one might try to
answer these following questions;
1. Can the researchers list the advantages and disadvantages of using animals for
research?
2. Are there any circumstances in which the researchers would use animals?
3. Are there any circumstances in which the researchers would not use animals?
4. Would the choice of animal used have any bearing on the above e.g. mouse, rat,
cat, dog? If so, are there moral rather than scientific reasons for the choice of
animal model?
5. Overall, do the researchers think animals should be used for research purposes?
A survey of our classmate’s opinions on the use of animal as a research model
as shown in Appendix I.
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The role of experimental animals and the development
of candidate HIV/AIDS vaccine
Since AIDS is a unique human disease, so the study of methods to control
HIV infection will ultimately have to be done in human subjects. Such studies must
confirm to ethical standards and thus raise the problems of research design. In patients
with clinical AIDS, the evaluation of potentially dangerous drugs can be justified. But
the testing of vaccines in uninfected populations or the testing of potentially harmful
drugs in seropositive yet healthy persons will pose major practical and ethical
problems, which I will emphasize later. Therefore, animal models are needed. Animal
models of HIV infection will be critical guides if we want to better understand and
combat HIV infection especially for vaccine and antiviral development programs.
Drug evaluation in animals also provides essential information about efficacy,
pharmacology, and toxicity as well. Thus, animal models provide an important
intermediate level of drug or vaccine evaluation between in vitro studies and in
humans testing. In case of HIV vaccine production, it would not be possible to
produce candidate HIV vaccine in the cells culture if we did not already know that
which compound and which properties we are looking for.
There are many steps in development of candidate HIV/AIDS vaccine
(therapeutic vaccine, prevention vaccine, and perinatal vaccine) and can be divided
into 4 steps including:
Step 1: basic science research
Step 2: HIV vaccine development
Step 3: HIV vaccine testing and evaluation
Step 4: Procurement
Especially in step 3, to prove the efficacy of the vaccine, the information must
be come from the testing in animal models and in human volunteers both normal and
HIV-infected subjects. The ideal animal model for HIV and AIDS research would be
one in which (4);
1. The test virus would be HIV itself
2. The host would small, inexpensive, genetically and immunologically well-defined
animal
3. The target receptor would be CD4
4. The tropism would be comparable with that observed in humans
5. Disease development and mode of transmission would be resemble the situation
observed in humans
Up to now, such an ideal HIV animal model does not meet all or even most of
those criteria even though HIV-1 and HIV-2 have been reported to infect in many
species of monkeys. However, AIDS-related diseases in the animals infected with
HIV-1 and HIV-2 still unreported. Chimpanzees are animal models that mostly use in
the study of the early stage of HIV-induced pathogenesis and they are the only
animals now that know to test HIV candidate before clinical application in humans.
They also play a crucial role in the evaluation of the ability of anti-retroviral drug to
prevent, limit, or cure HIV infection as well. The rhesus macaque monkey of Asia can
develop an AIDS-like disease but from the infection of another type of virus named
“Simian immunodeficiency virus” or “SIV” (5). So, this type of monkey has
extremely valuable model of human AIDS and has also been of value in
demonstrating that vaccinated animals may be protected against challenge virus
administered in the form of infected cells as with HIV and the chimpanzee model.
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Supportive ideas for the use of animal models for research
purposes including HIV/AIDS research
“Animal research is still important, especially in prevention of the diseases
such as polio, diabetes, for long time ago. For example, without research, surgery
would be a painful, the smallpox already killed about two million people. Even
though millions of animals have died from the studies but now more than 200 other
diseases can preventable. Thanks to animal research.” (6).
“Animals are needed for research because it is currently impossible to model
the complex interactions of the biological machinery used by mammalian systems by
others than experimental animals or man.” (7).
“For HIV/AIDS research, animal experiments have been able to reestablish the
feasibility of an AIDS vaccine by demonstrating that a number of the daunting
theoretical obstacles to vaccine development. For examples, virus variability,
intracellular location and even immune protection against the establishment of latent
infection can be overcome in practice. These preliminary finding in experimental
animal studies have lead to a great deal of pressure to commence human vaccine or
conclusive.”
Doctors of Medicine (8) have convinced the general public that
experimentation on animals is essential if we want to cures something. They said “Do
you want to cure for your child’s asthma, diabetes, polio, or AIDS, or do you care
more about some monkeys?” Somebody against the use of animal in some researches
such as cosmetics but they also claim that “the use of animals in such areas was
necessary or even helpful in achieving medical progress for humans. This can be done
but it must has limitation in using those animals such as good experimental design and
good training to obtain the maximum efficacy of the results.”
Arguments the use of animal models for research
purposes including HIV/AIDS research
The struggle against sickness and disease is not over, yet medical progress is
being threatened by activists, who would end the use of laboratory animals in the
search for treatments and cures. The argument may be put that “animals are living and
feeling (sentient) beings and so should not in any circumstances be used for
experimental purposes. It’s morally wrong to inflict pain on any living creature such
as the search for the cure of particular disease-affecting humans.” Some stated
“animals are not human, thus, any results obtained from them are not applicable to
humans anyway. So, the animal experiments are worthless.”(9).
Ethical problems involved the use of animal as a
model for HIV/AIDS research
Ethical Problem I: Is it right to involve animals in our efforts to safeguard our
position and let them pain or discomfort throughout the research’s period?
Every animal testing are thorny issue, for example, in case of a chimpanzee
named “Jerome”. He was used for HIV research at the Yerkes Regional Primate
Research Center and he was infected with 3 different strains of the HIV virus by the
age of five and left him suffer through chronic diarrhea, depression, and anemia for 11
years. Finally, he died in 1996. Thus, is it right for Jerome to be suffering for a long
time under the name of “human betterment”? Based on the “animal rights”, a
consideration of the moral status of non-human animals and also involves the idea
that animals have the right to life as well as not to be used by humans in any way
because that animals have equal rights to humans, and “animal welfare”, the idea that
animals should be treated kindly and without inflicting any pain or suffering upon
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them, the used of animals for research purposes can not be done like the story of
Jerome (10).
Ethical problem II: Can we rely and accept the result(s) obtained from animal
experiment? Do we really get the better scientific knowledge and come up with new
cures and/or medicines?
In development of anti-HIV/AIDS drug or vaccine by using animal models,
the chimpanzees were killed in huge amounts since chimpanzee is the only animal,
other than human, that can be infected with HIV in normal condition. However, it can
not develop AIDS-like symptoms or evidence of immune suppression. Then, the
rhesus macaque monkey, which can develop an AIDS-like disease but from the
infection “SIV” as mention earlier, has extremely valuable as the clinical elements of
the disease only that disease is identical to AIDS in humans. So, there are still doubts
whether the elements of SIV disease in the macaque are really biologically equivalent
to AIDS in humans or not because SIV itself does differ from HIV in some aspect
such as the organization of its genome (11). In addition, Rhesus macaques often
shows fear and defense response, or stress reflected in significant changes in “normal”
physiological status, when the people is around as shown in Figure 1 (12). This stress
behavior, therefore, may increase the variability of the data and decrease the
reliability of the results. So, one would need to be very cautions in attempting to
extrapolate the result obtained from the macaque model to those in humans. The
extrapolation from one species to another is rather difficult, so can we rely those
results?
Figure 1: Rhesus macaques often shows fear, defense response, and stress reflected in significant
changes in “normal” physiological status, when the people is around or try to remove it from its cage.
In addition, animals hinder development of new cures/medicines because
animals just do not work well enough as human models due to different species react
differently. As the Nature of Wellness (13), in 1997, stated that “Animal research can
not work and the reasons are simple: every species of animal is a different
biomechanical and biochemical entity. Non-human animals are different not only
from humans but also from each other. Thus, animals react differently to different
drugs, vaccines, and chemical substances.” Furthermore, the Nature of Wellness also
represented that “Animals can not get human infectious diseases. In spite of massive
efforts aimed at creating “an animal model of human AIDS”, the researchers have
never been able to infect a single-non-human animal with human AIDS. Besides, a
non-human animal can not have a human disease because it is not a human. Among
other reasons, there are huge differences between the immune system of humans and
that of other animals.” One study (8) examined the differences in species reaction and
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found that there is 5-25% correlation between harmful effects in people and the results
obtained from animal experiments. In 1983, for example, the drug company, Pfizer,
carried out a study to test the efficacy of animal tests. Humans finding were compared
with the experimental data from rats and mice for all chemicals known to cause
cancer in people. In most cases animal tests had given the wrong answers (8). This
finding may be used to support that human medicines can not be based on veterinary
medicines and if they work we will go to the vet when we feel sick. Drugs are always
tested on humans after they are developed and tested on animals. This can be implied
that the results obtained from animal experiments are too unreliable to work in real
life (13). It is impossible to predict whether a drug will or will not harm one species,
human or not, no matter how many animals you test it on. Consequently, as you see
every year, the FDA is forced to pull off the shelves thousands of pharmaceutical
drugs, which had been found “safe” based on animal tests but they caused serious
health problems in human being. The Nature of Wellness (13) suggested that “The
only way to deal with our mounting health problems is to abolish the medieval ritual
of experimental research on animals and engage in real medicine, a medicine based on
prevention, clinical research (the observation and treatment of actual human diseases
in the patient) and, above all, logic and common sense.”
Ethical problem III: Religion ethics
In Buddhism, there are “Five Precepts”, which could be considered to play a
similar role as the “Ten Commandments” do for Jews and Christians. The injunction
against destroy life is known as the First Percept and in Buddha also tells us not to
hurt “living being” rather than persons. The beings referred to be sentient beings: All
beings tremble before danger, all fear death. Therefore, animals and mammals could
not be killed or otherwise hurt according to the First Percept and other teachings,
which protect sentient beings. Many people tried to justify killing animals because of
the benefits it brings, whether economic benefits or potential medical benefits, which
might arise from vivisection. But the Buddha says “He who for himself or others
craves not for sons or power or wealth, who puts not his own success of
righteousness, he is virtuous, and righteous, and wise”. That is doing the righteous
thing (obeying the Percepts) has a higher priority over worldly “success”.
Furthermore, Dhammapada stated that “killing animal (a violation of the First
Percept) can not be justified by the claim that it will prolong human life. Moreover,
Dhammapada does not claim that “humans are superior to or more important than
other animals” (14). However, Rosemary AA (14) contradicted that “It is difficult to
see how Buddhists, who do participate in activities which kill animals can justify the
discrepancy between their practice and the word of the Buddha. Although the goal of
animal rights is by and large consistent with Buddhism, too often the actions taken to
achieve these goals are not. Therefore, it is the best way to keep the use of all products
to a minimum, both to minimize our monetary contribution to killing and keeping
with the Buddhist ideal.”
Alternative choices in the HIV/AIDS research study
There are many researches using animals such as in nutrition, physiology,
pharmacology, virology, psychology, surgery, and toxicology. There are
strengthening voices that say the numbers of experimental animals are too high. So,
they should but cut drastically. For example, in 1986, 1,400 chimpanzees were used
for all biomedical research in United State. However, the chimpanzees were not
enough for AIDS studies (15). Nowadays, chimpanzees are an endangered national
resource that will be irreplaceable if squandered. Therefore, if they are necessary to be
use in AIDS-related experiments, the NIH committee stated that the experiment
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proposed, which involves the use of chimpanzees, must be broad consensus among
the interested scientific community and is critically important to development of
vaccines or antiviral agents and can not be conducted in any other species or by other
means. The use of these animals must be under extreme caution (15). Not at all, in
U.S.A, the Nation’s Primate Centers should be strengthened to permit the expansion
of the appropriate biocontainment facilities and the education of appropriate trained
investigators, when using them (15). Later, the interest in alternative choices for
animal researches has arisen because of a high concern for animal rights and animal
welfare. The Animal Welfare Institute strongly supports the “Alternative”, which
refers to 3R. The meaning of alternative covers these following techniques (16);
1. Replaces the uses of experimental animals by change from one species to another
or change to other techniques such as using human cell culture instead of using
animal cell culture
2. Reduces the need or number of animals used in a particular test as low as possible
by trying to use computer simulation model before initial study in animal or use
the statistics to calculate the minimum number of the animals used
3. Refines housing, handling, and existing procedures to reduce discomfort, pain,
fear, stress, and suffering endured by animal.
An enlarged interpretation of alternative includes the replacement of one
animal species with another, particular if the substituting species is non-mammalian
(16). Thus, the alternatives to animal experiments are not experiments without
animals but experiments on animals that are less painful (refined) and involving fewer
animals (reduced). Dr. Andre Menache (8) reported that over the last 10 years, there
has been an intensive effort to find alternatives to whole-animal testing. It has been
estimated that animal experimentation worldwide has decreased by 30-50% in the last
15-20 years due to reduction and replacement techniques. For example, genetic
engineering techniques are largely used today to test vaccines in place of whole
animals. A major breakthrough in scientific progress has been made possible by the
ability to now grow and culture human cells. Human cells more closely resemble
human beings than do animal cells resulting in more reliable and more predictive
results for human studies than were previous animal cells. The only problems
encountered so far with human cells are those associated with culture techniques and
the availability of human donor organs and tissues. The latter problem needs to be
considered with human’s rights. The source of human tissue is the spontaneously
aborted human fetus. Therefore, it would be necessary to provide a legal framework
involving informed consent before such tissue could be used. Thus, in the field of
research and testing, animal experiments is gradually replaced by more sophisticated
methods of biomedical research involving human cells culture, advanced laboratory
techniques as well as computer simulations. Furthermore, one (17) suggested that the
demand for animal experiments can be limited if humans accept and enforce the
following 3 principles:
1) If it is possible to replace a harmful animal experiment with one where humans
are caused only limited pain and inconvenience. This method should be done by
means of human volunteers.
2) If it is possible to replace a harmful animal experiment with one using organs or
tissue from dead humans, aborted human fetuses, or the like. This method should
be done.
3) If doing without a harmful animal experiment involves only a slight risk or loss to
humans. We should do without it.
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However, some activists (18) still believed that the use of 3R’s is nonsense.
Reducing the number of animals or refining the methods used do not eliminate the
problem that animal tests just are not a valid way of testing. And “Replacing” is
usually taken to mean, “replacing” one type of animal testing to another type of
animal testing. These groups need to abolish the use of animals by humans for
research.
Principles for the utilization and care of vertebrate
animals used in testing and research
One way to improving the conditions of animals used in the experiments is by
means of “legislation”. Laws for the protection of animals used in research must
include (17);
- specify minimum standards for the accommodation and care of research animals
- prescribe the use of anesthetics and pain-killers
- prescribe that animals involved in potential harmful experiments should be killed
as soon as possible
- prescribe the other ways aim to limit the suffering and other kinds of harm
inflicted on the animals
This legislation is certainly important element in bringing ethical standards to
bear on the conditions of animals used in experiments. In addition, the U.S.
Government Agencies develop the principles requirement for testing, research, or
training procedures involving the use of vertebrate animals as follow (19);
1. The transportation, care, and use of animals should be accordance with the Animal
Welfare Act (7 U.S.C. 2131 et. Seq.) and other applicable Federal Laws,
guidelines, and policies.
2. Procedures involving animals should be designed and performed with due to
consideration of their relevance to human or animal health, the advancement of
knowledge, or the good of society.
3. The animals selected for a procedure should be of an appropriate species and
quality and the minimum number required to obtain valid results. Methods such as
mathematics models, computer simulation, and in vitro biological systems should
be considered.
4. Proper use of animals including the avoidance or minimization of discomfort,
distress, and pain when consistent with sound scientific practices is imperative.
Unless the contrary is established, investigators should consider that procedures
that cause pain and distress in human beings may cause pain or distress in other
animals.
5. Procedure with animals that may cause more than momentary or slight pain or
distress should performed with appropriate sedation, analgesia, or anesthesia.
Surgical or other painful procedures should not be performed on unanesthetized
animals paralyzed by chemical agents.
6. Animals that would otherwise suffer severe or chronic pain or distress that can not
be relieved should be painlessly killed at the end of the procedure or, if
appropriate, during the procedure.
7. The living conditions of animals should be appropriate for their species and
contribute to their health and comfort. Normally, the housing, feeding, and care of
all animals used for biomedical purposes must be directed by a veterinarian or
other scientist trained and experienced in the proper care, handling, and use of the
species being maintained or studied. In any case, veterinary care shall be provided
as indicated.
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8. Investigators and other personnel shall be appropriate qualified and experienced
for conducting procedures on living animals. Adequate arrangements shall be
made for their in-service training including the proper and humane care and use of
laboratory animals.
9. Where exceptions are required in relation to the provisions of these Principles, the
decisions should not rest with the investigators directly concerned but should be
made, with due regard to Principle II, by an appropriate review group such as an
institutional animal care and use committee. Such exceptions should not be made
solely for the purposes of teaching or demonstration.
The use of experimental animals in Thailand
In 1987, The use of animal models for research in the universities, for example
Mahidol, Chulalongkorn, and Karsatsart Universities, were still low. So, the user
could buy anywhere such as from Sanamloung (for rabbit, rat, and mouse), from the
government for a dog, and from the temple for a cat. Dr. Pradon Jatikavanit was
responsible for the use of those animal models in the faculty of Science, Mahidol
University. At that time, the use and care of animals were not only unsystematic but
also uncontrollable. No one concentrated and realized on these important things. After
1987, Biomedical research rapidly increased especially in Mahidol University. So, the
numerous needs and uses of experimental animals in parallel went up while the
supply of animals did not keep up. Until on 29 July 1991, Mahidol University was
assigned by many universities to responsible for supply both quality and quantity
animals and also dealing with these topics e.g. produce, care, and transport the
animals. The name of this place is the “International Animal Research Center,
Thailand” located at Salaya, Nakornpratom province (20). The use of animals for
researches, which supplied by the International Animal Research Center, Thailand,
during 1981-1993, is shown in Table 1. Fortunately in Thailand, no one is severely
against the use of animals for research purposes. However, the use of them is partially
under control of Thai law, which identify that “the one who makes the animals pain or
kill them with unnecessary purposes, he or she will be in jail not more than 1 month
or pay the money, not more than 1,000 baht, or all of above.” The relationship
between the ethics and use of animal for research purposes can be summarized in the
Figure 2 (20).
Table 1
The use of experimental animals, which supplied by The International
Animal Research, Thailand, during 1981-1993.
Years
Rat
Mouse
Total
1981
247
3,014
3,261
1982
6,977
26,491
33,468
1983
11,453
68,242
79,695
1984
9,503
87,880
97,383
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1985
15,264
75,546
90,810
1986
19,575
133,506
153,081
1987
18,550
116,986
135,536
1988
20,159
117,572
137,731
1989
22,219
193,462
215,681
1990
19,686
208,468
228,154
1991
19,429
172,601
192,030
1992
20,523
167,274
187,797
1993
18,837
151,322
170,159
Ethics of using human as a model for HIV/AIDS research
The Declaration of Helsinki (21) stated that the purposes of biomedical
research involving human subjects must be to improve diagnostic, therapeutic,
prophylactic procedures, and the understanding of the aetiology and
pathologenesis of disease. The HIV/AIDS clinical trials, the prospective
experiments involving human subjects, can be conducted after anti-AIDS drug
or HIV candidate vaccine were evaluated for their safety both in vitro and in
vivo. Classically, anti-AIDS drug clinical trials are categorized into phase I, II,
and III (22).
Phase I study: to define optimal dose not as the maximum tolerated dose or even safe
dose. This phase uses a variety of laboratory and clinical measurements to search for
the most effective dose or dose strategy.
Phase II study: to determine whether the antiviral activity is active against the
disease or not. This study is often randomized to ensure the balance among the
treatment groups.
Phase III study: to compare the experimental therapy with the current standard
therapy (or no treatment-placebo). This phase is the key in the determination of
optimal therapeutic strategies worldwide.
Similar to anti-AIDS drug trials, the clinical trials for HIV candidate vaccine
are divided into 3 phases;
Phase I vaccine trial: assesses the safety of a candidate vaccine and evaluate its side
effects in humans.
Phase II vaccine trial: assesses immunogenicity (the ability and the efficacy in elicit
an immune response).
Phase III vaccine trial: assesses the protective efficacy by observing the rate of
infected in vaccinated subjects as compared to that in control non-infected subjects.
There are reported in 1994 (23) that there are 16 phase I and 2 phase II HIV
candidate vaccine trials conducted in 1,000 volunteers in the U.S.A and Europe.
However, the study design and volunteers in ant-retroviral drug or HIV vaccine trials
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must be followed the general and ethical guidelines, which are recommended by
WHO in 1989 including (24);
Phase I trial: should be conducts in the producing countries on HIV-seronegative
individuals with no risk behavior. The vulnerable groups such as children, pregnant
woman, and confined populations e.g. prisoners, military personnel, and
institutionalized persons should not be included.
Phase II trial: should be conducts on HIV-seronegative person, who will avoid risk
behaviors. Trial in adults should precede in those “below the age of consent”.
Representatives of all major routes of infection as well as HIV-seropositive person
may also be included.
Phase III trial: representative of all major routes of infection should be conducted
simultaneously and should be large-scale. “Geographical sites should have adequate
resources for education about the preventive of HIV infection; national, qualified,
experienced personnel; the necessary infrastructive in terms of laboratories and field
capacity”.
Clinical trials: general ethics principles
The ethical issues surrounding HIV/AIDS research involving human subjects
have been debated since the beginning of the AIDS pandemic. During 1986-1991, the
Global Program on AIDS or GPA (25) has carried out a series of activities and
consultations to address the ethical issues surrounding AIDS-related research such as:
- Consultation on AIDS vaccine efficacy trials in human populations
- Consultation on criteria for international testing of candidate HIV vaccines
- Development of proposed international guidelines for the sentinel surveillance of
HIV infections (unlinked anonymous testing)
- Development of draft guidelines for AIDS clinical and vaccine trials
- Consultation on guiding principles for the conduct of international collaborative
AIDS research
- Support to Council for International Organizations of Medical Sciences (CIOMS)
to develop guidelines for ethical review procedures for epidemiological research
and practice
- Development of a checklist of practical and ethical considerations in research
involving human subjects
In order to protect the human volunteer in clinical trials research, the research
investigators must follow these regulations (26);
1. Risks to subjects are minimized
2. Risks to subjects are reasonable in relation to anticipated benefit, if any, to
subjects, and the importance of the knowledge that may reasonably be expected to
result.
3. Selection of subjects is equitable
4. Informed consent will be sought from each prospective subject or the subject’s
legally authorized representative, in accordance with, and to the extent required by
Sec.46.116.
5. Informed consent will be appropriately documented
6. Where appropriate, the research plan makes adequate provision for monitoring the
data collected to insure the safety of subjects
7. Where appropriate, there are adequate provisions to protect the privacy of subjects
and to maintain the confidentiality of data
8. Where some or all of the subjects are likely to be vulnerable to coercion or undue
influence such as persons with acute or severe physical or mental illness, or
persons who are economically or educationally disadvantaged. Appropriated
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additional safeguards have been included in the study to protect the rights and
welfare of these subjects.
However, the study involving HIV infectious disease in humans still confronts
us with the ethics problems between the public’s right and the individual’s right. To
clarify the ethical problems in using human as a research’s subject, I will focus on the
use of humans as volunteers in HIV vaccine trial, which present a number of difficult
logistical challenges and start from the problems mostly founded in phase I up to the
last phase.
Ethical problems involved the use of human as a model for HIV/AIDS
research
# Ethical problems in phase I trial
As mention earlier, this phase of vaccine evaluation must be carried out in
normal volunteer populations with no risk of infection. I have some list of the
opinions of our classmates, if they were asked to be volunteers in HIV research trial
(Appendix II). In addition, I have the reasons of normal healthy volunteers, who are
decided to join the HIV candidate vaccine trials in Thailand and the opinions of some
Thai people, who are still in question and deter this trial as you can see in Appendix ,
III and IV, respectively.
The participants, who agree to join this project are assured on safety and also
confident for the test result. In contrast, there are a lot of issue that deter population.
The main reason of those people is about the risk of the vaccine. Thus, the ethical
issue involved liability for harm from the experimental vaccine must be considered in
the clinical trials. Therefore, all of the ethical requirements are set up in the form of
“informed consent”, which is necessary not only in this phase but also all of phases
in HIV/AIDS clinical trial. The informed consent is usually expressed in words like
those of the example in Appendix V. The crucial information in the informed consent
include:
1. A statement that the activity involves research.
2. An explanation of the scope, aims, and purposes of the research.
3. A description of any reasonably foreseeable risks or discomforts to the subjects.
4. A description of any benefits to the subjects or to others which may be reasonably
expected.
5. A disclosure of appropriates alternative procedures or courses of treatment, if any,
that might be advantageous to the subjects.
6. A statement that the subjects will be notified of new information developing
during the course of the research that might affect his participation in it.
7. A statement describing how confidentiality of records identifying the subjects will
be maintained.
8. An offer to answer questions the subjects may have about the research or the
subjects’ own rights.
9. An explanation as to whether compensation and medical treatment are available if
injury occurs in research involving more than minimum risks, and who shall be
contacted if harm occurs.
10. A statement that the participation is voluntary and refusal to participate will
involved no penalty and will not prejudice the subject’s right to receive continuing
medical care.
In addition to the federal regulations, IRBs must consider whether consent
forms should include the fact of randomization in the case of prospective randomized
clinical trials as well. When the volunteers or patients sign the consent form agreeing
to join in the drug or vaccine protocol, they permit the investigator to perform
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laboratory tests and treatment as well as to administer the new therapeutic agent to
them. Every steps of the protocol are explained to the subjects. The investigators must
never hesitate to answer all questions the subject asks, thereby creating a general
atmosphere of congeniality, mutual trust, and also respect (27).
Ethical problem I: It’s the fact that normal people, who receive HIV candidate
vaccine, should develop (false) antibodies to HIV. So, it seems to be they infected
with HIV at that time. This is because the currently used HIV tests detect antibodies
in the blood. This status may affect their life if no one knew the real reason. For
example, they will;
- refuse to provide education, housing, and funeral services
- have HIV testing without the subject’s consent
- attempt to segregate infected individuals in isolation facilities
- ban on travel to some countries or barriers to immigrant or resident status
- dismissal of workers, who have become infected or reject of job applications
- receive inadequate care delivery on the part of some health professionals and may
be refusal to treat the patient
- indiscriminate disclosure of positive results of HIV tests
One of the HIV vaccine trials research project in Thailand named “TAVEGSIRIRAJ” suggested that after vaccination, if you have an immune response, you will
develop antibodies to HIV, which is the result of the activation activity of the used
protein in vaccine and finally, the volunteers will have HIV-seropositive. However,
this seropositive result, refers as “vaccine positive”, has specific characteristic that
make it different from natural HIV-seropositive. These differences can be
distinguished by using the specific method called “ Western Blot tests”. The vaccine
positive will persist not more than 1 year after vaccination. The research investigator
will give an “evidence form” to confirm that your HIV-seropositive really comes
from the effect of injected-candidate HIV vaccine, not from real HIV-infection (28).
Ethical problem II: Who will be responsible for the side effect(s) that may be
experienced from the HIV candidate vaccine?
Like the side effect(s) after others vaccination, the volunteers may feel pain,
edema, and redness at the site of injection or you may develop fever for 1 or 2 days.
Up to now, no report about the serious side effect of the tested vaccine has been
published. However, the research investigator will enthusiastically deliver appropriate
care to anyone who suffers from the adverse reactions of the vaccine until they feel
normal. In addition, if your blood test represents seroconversion (HIV-positive from
the natural HIV, not from the tested vaccine) during trial period, the project will be
responsible for all of the insurance involving HIV/AIDS therapies all of your life. The
details about insurance due to the vaccine also are clearly clarified in the consent form
before the subjects agree to join in the project (29).
Suggestion: If someone want to participate in HIV/AIDS drug trials (or apply
for vaccine), I suggest that you must read and understand or ask the research
investigator all about the questions that are showed in Appendix VII.
# Ethical problems in phase II and III trials
The ethical issues of the phase I trial are fairly straightforward. In contrast, in
phase II and III trials, the subjects are in a difficult and often ambiguous position. So,
the investigators must take extra care to protect their human’s right. In these phases,
subjects may be high-risk cases or have HIV-seropositive to determine the antiretroviral activity of the tested drug or candidate vaccine compared to the placebocontrolled group selecting by randomization. Randomization technique is the
treatment allocation mechanism in which each subject or patient has the same chance
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of receiving any of the treatments under study (22). Placebo means an inert material
disguised to resemble the test drug as closely as possible. Some patients and
physicians may not desire to participate in a randomized trial. They said “it is difficult
to believe in the reality of equipoise (the ethical requirement of randomized trials that
both treatments are equally desirable) and there is no evidence that any other therapy
should be preferred”. To support this opinion, I will give 3 examples involving the use
of placebo in HIV clinical trials. First, look back in the early clinical trials of
azidothymidine or AZT, 286 patients with AIDS and ARC were divided equally into a
group receiving AZT and a group-receiving placebo. After administration for 6
months, an interim analysis revealed a highly significant reduction in mortality in the
AZT-treated group, only 1 death compared to 19 deaths in the placebo group. These
findings led to the abandonment of the placebo group and all patients involved in the
trials were then provided with AZT treatment (14). Second, in 1990, Volberding et al
(30) studied the side effect of AZT in adult asymptomatic AIDS patients with
CD4+<500 cells/cubic millimeter. They divided those patients into 3 groups including
a placebo (428 patients), 500 mg/d of AZT-treated (453 patients), and 1,500 mg/d of
AZT-treated (457 patients) groups and administrated for 55 days. The results showed
that the most side effects found in the 1,500 mg/d of AZT-treated group and most of
them developed anemia and neutropenia. In contrast, no any side effects observed in
the placebo group. For last 4 years, Cohen and Noormohamed (31) studied the
preventive effect of the same drug, AZT, in HIV transmission from mother to child.
They gave AZT to 365 HIV-pregnant women at 14-34 weeks of gestation (CD4+>200
cells/cubic millimeter and never received anti-AIDS drug). They divided into 2
groups: 180 AZT-treated and 183 placebo treated groups. They found that in AZTtreated group, the vertical transmission rate of HIV was only 8.3% and that in placebo
group was higher, 25.5%. No significant side effects obtained from the treatment in
both two groups.
Ethical problem III: Concerning of placebo-treated group’s result, the question is
generated in my mind that is it important to use the placebo? What is the importance
of it? Can we avoid using it in case of the life-threatening disease like AIDS?
As you see, the use of placebo-controlled trials was not only unjustifiable but
also unethical because of its obvious denial of effective therapy. But if a placebo
control group is required as a means of assuring the validity of data. Ethical
considerations would suggest that the trial be designed for the possible benefits of
patients, who has availed themselves of all conventional therapy without success, or
for whom there are no other reasonable alternatives with a grater degree of putative
effectiveness (32). However, it believes that randomized clinical trails using a placebo
control group are required until the first agent is identified that it is both safe and
effective. After an effective agent is discovered or we call it “standard therapy”
newer drugs can be and should be compared to it rather than to a placebo (32).
Factors to be considered in reviewing placebo research
The use of placebo is always a troublesome issue. The risks of deterioration of
the patient’s condition due to withdrawal of needed medication must be kept to an
absolute minimum even though they are clearly informed of these risks and of the
techniques to minimize them. Therefore, the IRB generated the following questions
for evaluate a new drug protocol involved in using placebo as control (32);
1. How necessary is the proposed research in terms of what is to be gained in useful
medical knowledge in comparison to potential risks presented to the subjects?
2. Is a placebo necessary in that situation?
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3. What jeopardy is portended for the patient or subject by his participation in the
trial should he not receive the active agent?
4. Can the placebo control be kept small without compromising the integrity of the
data?
5. How will the investigator deal with subjects whose condition seriously
deteriorates as a result of participating in a placebo control group?
Consideration of these questions may help to avoid some serious breaches of
ethics involved in the experimental use of placebo that have occurred in the past. Dr.
Joseph Saba of the UNAIDS Program indicated that if one of the placebo-controlled
trials was positive, all of the trials would have to stop prematurely in their current
design (33).
# Social or public ethical problem involved in clinical trials
Ethical problem IV: How to determine the efficacy of candidate vaccine in the high
risk volunteer?
Due to the increasing of HIV-infection and AIDS patients nowadays, the
researchers and public try to protect every body from this disease as much as possible
and as fast as they can. But the choice of volunteers to take part in such a trial would
be highly problematic. Ideally, to assess the efficacy of a potential HIV vaccine,
which is concerning today rather than anti-HIV drug, they need one who had not yet
been infected, but were at high risk of becoming infected such as homosexual men
and intravenous drug abuser groups. Morally, after the subjects were selected, they are
received an adequate education to reduce high risk behavior and also received
condoms to decrease the risk of infection as well. This advise would already
substantially lower the risk of HIV infection irrespective of the effect of the vaccine
and would markedly bias the significant of any positive findings. By doing this, it is
difficult to distinguish whether the potential protective effect of a candidate vaccine or
better education.
The protection concerning with the ethical problems in using human model
The Consultation on Criteria for International Testing of Candidate HIV
Vaccines convened by the World Health Organization’s Global Program on AIDS in
Geneva in 1989 (34) made it clear that “AIDS vaccine (or even drugs) trials should
adhere to the 3 basics ethical principles of biomedical research in humans including;
1. Beneficence: the treatment that does not cause harmful to the subjects. It must be
maximize possible individual benefits or minimize possible individual risks.
2. Distributive justice: the requirement of equitable sharing of both risks and
benefits, and includes the social good expected from the research. Fairness
requires that persons who are vulnerable in morally relevant respects e.g. because
they have limited capacities to consent be accorded special protections against
exploitation as research subjects. Thus, persons as children, the mentally disabled,
and prisoners as research subjects requires special justification.
3. Respect for persons: this is a principle that incorporates two fundamental ethical
convictions. The first holds that autonomous individuals should be treated with
respect for their capacities for self-determination; this conviction creates the
obligation to conduct research only with the subject’s informed consent, a vital
component in research protocols to protect of privacy and confidentiality.
HIV/AIDS and Human research in Thailand
Research on human subjects has been conducted in Thailand for more than 50
years (35). The first “Research Ethics Committee” in Thailand was formed since 1968
in Chiang-Mai, the province in the north of Thailand. The decision to research human
subjects must be passed by this Committee. The used guidelines to determine the
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benefits and risks of the subjects is based on “Helsinki Declarations”. The research’s
protocol must have clear objective(s), which described the importance necessity to
conduct the study in humans. The results obtained from the study must give new
knowledge or provide more information that give advantage to mankind. The number
of the research subjects must be limited as minimum as possible under the statistical
analysis. All HIV/AIDS vaccines introduced to Thailand for research purposed must
first pass safety and immunogenicity studies in both animal models and human
subjects in the countries producing the vaccine or in other developed countries. The
vaccine must demonstrated evidences of immune response in animal models or
human subjects. There must be agreement in advance that if some complication or
harm occurs to Thai volunteers due to the vaccine, the vaccine producer will provide
funds for the treatments and rehabilitation. The researchers must coordinate with
hospitals and health care institutions to provide the necessary medical and
rehabilitation services. A surveillance system for long-term side effects in the
volunteers must be established and followed for at least 5 years after the study has
been completed (36).
Ethics in health care professionals (HCPs)and HIV/AIDS patients
# Patient-to-health care professional (HCP) transmission of HIV
Because of its means of transmission, AIDS poses a complex problem not
only for those who are suffering from it but also those in the general population, who
may come in contact with it and for the health care professions (HCPs). By duty to
provide dedicate and equal treatment, the HCPs must care both physical and mentally
of all patients especially HIV/AIDS patients, who fear of death, debilitation,
abandonment, and often face stress in their relationships with family, friends, and
others due to the stigma associated with AIDS disease. The HCPs can not turn away
or abandon them because of their prejudices or fears. From the Center of Disease
Control and Prevention (CDC) surveillance for occupational acquired HIV infection
in 1992 represented that the HCPs had the possibility to be infected with HIV only
0.3-0.5%, which is not statistically significant when compared with others
occupations in U.S.A (37). This low risk percentage may be because the health care
teams can safeguard their own health from any infection by using “universal
precautions”. However, they are directly close to those patients and more easily to
receive the infection accidentally during their work than other occupations are. The
risk to the HCPs over the life time career depends on several factors including; (1) the
risk of HIV transmission after a single contact, (2) the number of HIV-infected
patients treated by the HCPs, and (3) the number and type of blood contact
experienced by the HCPs (38). So, is it fair to risk their health and that of their
family? What will they do then? The London Report in 1989 showed that HCPs who
infected with HIV from the patients found 17 persons from 1 million of HIV-infected
patients (39). In 1990, 1 case of HCP in Australia had needle-stick, which used in
keeping blood from AIDS patient and finally she infected with HIV (40). The CDC
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had received reports of 13 HCPs in the United States who had seroconverted to HIV
after well-documented percutaneous, mucous membrane, or skin exposure on HIV. 11
persons were nurses and 3 persons were physicians. A more troubling case arises
when a health care professional sustains a percutaneous exposure to a patient’s blood.
(41). Some states in the U.S.A force patients to be tested for HIV and to disclose their
serologic status to a professional, who has sustained a blood exposure and most of
patients accept to be tested. In this situation, are the patient’s right to autonomy and
privacy more important than the worker’s right to know? This is a value judgement,
which policy-markers will have to ponder.
Ethical problems involved in patient-to-HCP transmission of HIV
Ethical problem I: Do the HCPs right to know the HIV status of the patients?
Normally, the main reason of the health care teams, who want to know the
HIV status of their patients, is to be more strictly careful with universal precautions.
But in this situation, it seems to be the specific obligations of health workers in that
they have the right to know about the infection status of patients regarding
HIV/AIDS. Simultaneously, the confidentiality of HIV/AIDS patients can not be
broken indiscriminately under the pretense of ensuring the safety of health care
workers. Since this kind of indiscriminate breach would violate the rights of patients.
And the patients may think that if their status were commonly known in the hospital,
they might be discriminated against their medical care either being refused or
receiving substandard care. For last 7 years (42), the CDC updated the
recommendations for HIV testing of patients, who are voluntary and confidential to
test, especially concerning in acute care settings. The CDC’s recommendations
emphasized conditions of voluntary testing that can been identified for 3 purposes.
First, for counseling to help people understand the test results. Second, for
establishment of an environment of nondiscrimination and third, for protection of the
confidentiality of the test results (42). However, a recent study of senior residents in
internal medicine and family medicine in 10 States indicated that 74% supported
surgeons knowing the HIV status of their patients (43).
Ethical problem II: If the HCPs exposed to a patient’s blood by needle-stick injury
and the patient refused to have HIV test. Can physicians obtain HIV antibody test
without the patient’s consent?
Normally, HIV testing without written consent form the patient is not only
illegal but also unethical. HIV testing over the patient’s objections violates the
patient’s autonomy and privacy as well as the spirit of informed consent. In addition
to respecting patient autonomy, consent for HIV testing is important because stigma
and discrimination may occur if other people know that the patient is seropositive.
The patient asserts a right to refuse HIV testing, while the physician claims a
countervailing right to know the patient’s HIV status. Therefore, an alternative
approach is anonymous testing of patient, who is the source of the blood. The result
obtained from that unethical way could be placed in the physician occupational
medicine file, not in the patient’s medical record. The name of the patient needs not to
be disclosed. An employee health program, rather than the patient’s insurer could pay
for the patient’s HIV antibody test. This approach maintains the confidentiality of the
patient, while the physician could know whether he is at risk or not, without waiting
for 2-3 months to see the seroconversion (44).
Ethical problem III: What do the HCPs do if they had an accident during their health
service to HIV/AIDS patients such as needle-stick or direct contact to the patient’s
secretion into their wound? And what will they receive if the HIV testing showed that
they already infected with HIV, especially in Thailand?
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To answer these questions, I want to show you about the trend of HIV
infection in patients in Thailand. It was found that recently, the AIDS and HIVinfected patients in Thailand increase dramatically as shown in Table 2 (45).
Table 2 The number of patients with HIV-infected and AIDS diseases, who were
admitted in the hospitals during 1984 – 1996 in Thailand
Patients
1984-1994
1995
1996
Cumulative
AIDS
6,291
18,240
21,867
46,398
Symptomatic
HIV disease
2,852
7,823
8,795
19,470
Even though the number of infected patients still increases, but the health care
professional can prevent and protect themselves by following the general universal
precaution as mention earlier. The HCPs must always keep in mind that all patients
have possibility of being HIV carrier without any sign of AIDS. The risk of
transmission of bloodborne virus (%) comparing between HIV and Hepatitis B Virus
that expose to health care workers are shown in Table 3 (45)
Table 3 The risk of transmission of bloodborne virus (HIV and Hepatitis B virus) to
health care professionals.
HIV
%
Hepatitis B Virus
%
Percutaneous exposure
0.40
Percutaneous exposure
9.30
Mucocutaneous exposure
0.05
The results showed that the possibility of HIV transmission via blood
contamination is rather low when compared to that of Hepatitis B virus. However, the
possibility of HIV infection depends on the amount and strain of the virus and the
primary care after exposure (46). The Article 12 of Technical Rule 324 in the Official
Journal of the Federation (17 November 1988), stated about the prevention and
control of HIV infection as follows (47):
Articles 12. In the event of probable exposure of health personnel to HIV as a result of contact with the
patient’s blood, through lacerations of the skin, through the mucosa, or through a prick or cut, a test
specific antibodies should be carried out immediately after the accident and repeated at intervals of 3,
6, and 12 months; seroconversion during this period shall be diagnosed as a case of “work-related
infection”.
Similarly, the CDC recommended that the one, who is directly exposed to HIV
must be follow these steps as primary protection and these recommendations are used
as guidelines to prevent HIV infection in HCPs in Thailand as well (48).
1. Primary prevention: if accidentally contamination of blood or other secretions of
patient occurs during work, the exposed HCPs must rapidly wash the exposure
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area with water and soap or chlorhexidine or 70% alcohol. In case of blood
exposure associated with needle-stick or cut wound, the blood must be expeled
immediately and then wash and clean again for 1-2 times. If the blood or secretion
get into the mouth, rapidly throw it away and wash with water or mouth-cleaning
solution. If the blood or secretion get into the eye, rapidly clean and rinse with
water or eye-washing solution. Alcohol, betadine, or chlorhexidine are not
recommended in the last situation.
2. Ask the patient who is the source of blood or secretion about the risk of HIV
exposure and ask for informed consent for HIV test.
3. Should be received at least 2 combination of anti-retroviral drugs. The first dose
must obtain within 24 hours or as fast as possible (1-2 hours are recommended) to
prevent infection in case of high risk exposure such as direct instrumental
laceration, needle-stick or spinal needle injury. If low risk exposure e.g. expose to
blood or secretion on normal skin (no wound), not recommend to take drugs
according to their adverse effects. The recommendation anti-retroviral drugs are
Zidovudine (AZT), Lamivudine (3TC), and the drug in protease inhibitor group
named Indinavir (IDV). However, the anti-retroviral drugs can not absolutely
prevent HIV infection, so you may be infected even though you received the
drugs. In 1996, the use of drugs to prevent HIV infection after exposure was
established as show in Table 4 (49).
4. Should be check for blood HIV testing start at the first time of exposure (0), then,
retest at 6, 12 weeks, and lastly at 6 months.
Table
4 Provisional Public Health Service, 1996, recommendations for
chemoprophylaxis after occupational exposure to HIV, classified by type of
exposure and source material.
Type of exposure
Percutaneous
Mucous membrane
Skin, increased risk
(high titer of HIV
prolonged contact at
extensive area)
Source material *
Blood
Highest risk
Increased risk
No increased risk
Fluid containing visible
Blood, other potentially
infectious fluid, or tissue
Other body fluid
Blood
Fluid containing visible
Blood, other potentially
infectious fluid, or tissue
Other body fluid
Blood
Fluid containing visible
Blood, other potentially
infectious fluid, or tissue
Other body fluid
Antiretroviral
prophylaxis
Antiretroviral
regimen
Recommend
Recommend
Offer
AZT+3TC+IDV
AZT+3TC+IDV
AZT+3TC
Offer
Not offer
Offer
AZT+3TC
AZT+3TC+IDV
Offer
Not offer
Offer
AZT+3TC+IDV
Offer
Not offer
AZT+3TC
AZT+3TC+IDV
* Any exposure to concentrated HIV e.g. in a research laboratory or
production facility is treated as percutaneous exposure to be with highest risk.
5. The doses of drugs intake are: Zidovudine sig 200 mg per oral, 3 doses/day
Lamivudine sig 150 mg per oral, 2 doses/day
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Indinavir sig 800 mg per oral, 3 doses/day
Saquinavir sig 600 mg per oral, 3 doses/day can be used instead of Indinavir.
6. Checked for the side effects of the drugs by checking complete blood count (CBC)
and hepatic functions test during administration and 2 weeks after terminate the
administration.
7. In Thailand, the AIDS Control Center had supported only AZT and ddI until in
1998. So, now there is no additional support in anti-retroviral drug for HCPs
except from the hospital that they employed (46).
8. Advise the exposed persons to control or change their behavior during waiting for
the result e.g. avoid blood donation, avoid pregnancy, and avoid or use condom
when sexual intercourse.
9. The exposed HCP must write the accidental report to their supervisors or
employers within 24 hours. The example of the “Medical Accidental Report” is
showed in Appendix VII.
10. If the HIV testing result of the exposed HCP show seropositive at the first time of
checking, this means that you have been infected with HIV before you contacted
the patient. In contrast, if the result represents HIV-seronegative within 72 hours
after exposure and then found the seroconversion later. It might be imply that you
are work-related HIV-infection (if you strictly followed the physician’s
recommendations). The HIV-seronegative result at the first test does not
guarantee that you are HIV-free. Since the body can take from 3-6 months after
exposure with AIDS virus to produce antibodies. Thus, periodically retest can be
found the positive result later.
The HCPs, who are work-related HIV infection should receive the same
insurance benefits and health care coverage as HCPs with other chronic or lifethreatening diseases.
The example case of accidental injury in HCP at Siriraj hospital
These are the information obtained from interviewed, on 20 June 2000, a 45year-old single woman nurse, who worked at the Siriraj hospital for more than 20
years. She said about 4-5 years ago, she punctured the blood from the patient and
accidentally had needle-stick injury on the finger. Fortunately, she knew the HIVseropositive status of the patient on the patient’s card, so she tried to expel the blood
off, washed her finger, and then treated it with betadine as primary care before
immediately went to see the doctor. She received the advice about the administration
of anti-retroviral drug since in some case as mentioned earlier the doctor said “the
treatment can be avoid. So, you must decide to take it or not”. The Siriraj hospital will
give only AZT if she decided to take the drug to prevent HIV infection. She decided
to take it because she thought that it was the best way to protect herself. After that she
started to have HIV test and retested about 3-4 times within 6 months. Finally, the
HIV testing’s result showed “no infection” but she was rather suffered from the side
effects of AZT such as nausea, severely headache, and vertigo. She said if the result
showed HIV-seropositive, she could continue her job and the hospital will support the
AZT for her. And if she died from AIDS, she could earn about 3 million baht at that
time.
Reports about accidental injury in medical students and HCPs in Thailand
In 1991 (50), the 5th and 6th year medical students of Faculty of Medicine,
Chiang-Mai University, were asked about accidental incidence during medical
procedure. It was showed that 96.8% of these students once had accidental exposure
(82.6% cutaneous exposure, 72.6% needle puncture, 49.2% mucous membrane
exposure, and 13.2% cut wound). After accidental, 59.5% of them did not consult
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Varaporn Podprasart
anybody and 23.4% are afraid of checking anti-HIV. Later, in 1994 (51), another
study was conducted in Siriraj hospital, Bangkok, by using questionnaires. The
investigator reported that from total 3,600 HCPs, there are 2,528 episodes of injuries.
61.6% of those injuries were needle-sticks, 24.5% by broken glasses, and 13.9% by
surgical instruments, which can be recalled during the past 6 months. About 98% of
them knew about the danger of acquiring infection in the accidents and knew how to
treat themselves after injuries. Although the incidence of HIV infection from
occupational exposure is small but the figure is real. Thus, this problem must be
concern.
Recommendation
The health care agency must have a responsibility to provide a safe work
environment for their employees, which includes access to adequate equipment and
supplies for health care workers to use in barrier precautions (right to safety) such as
double gloves, face shields. Universal precautions and safe management of shape
provided adequate protection for nurses and other HCPs for bloodborne infectious
disease like HIV/AIDS. At the same time, HCPs must exercise adequate professional
judgement about the protection required for the specific situation.
# Health care professional (HCP)-to-patient transmission of HIV
In the past, the patient’s main risk of HIV infection in health care setting was
from blood transfusion. More recently, the public became frightened of contracting
HIV infection from HIV-seropositive health care workers according to one tragic case
in Florida in 1990 (52). A 23-year-old college student, Ms. Kimberly Bergalis,
became the first report case of health care profession-to-patient transmission of HIV
during dental care. Her dentist contracted AIDS and requested information from the
CDC on the risks of continuing his work. The guideline at that time suggested that he
must used gloves and mask because it was reasonably safe for him to continue his
work. In 1987, he extracted 2 molar teeth from the college student. And two years
later, that student rapidly developed AIDS. Although this was a short time between
possible infection and disease progression to AIDS, it was still unknown for the
reason. The CDC investigators tried to eliminate other sources of infection and also
did DNA sequencing test at Los Alamos laboratories on samples of the virus from the
student and from the dentist. The result indicated that the dentist had been the source
of infection. Four other patients of this dentist also tested and the results showed that
all were HIV-seropositive. The way of transmission in this case still unconfirmed,
although most likely sources were inadequate cleaned instruments and nasocomial
HIV transmission. Ms. Bergalis harshly criticized publish health officials. “Whom do
I blame? Anyone who knew (the dentist) was infected and had full-brown AIDS and
stood by doing nothing about it. You are all just as guilty as he was.”
Similar to patient-to-HCP transmission, the risks of infection are much less
common but it evokes strong emotional reactions. The CDC calculated that 360
surgeons, 1,200 dentists, and 5,000 physicians in the United States were HIVseropositive in 1992 (53). The CDC has estimated that 13 to 128 patients may have
been infected during a span of 10 years, even though just only 6 cases above have
been reports. These finding raises many ethical questions, for examples, the HIVinfected doctor has to inform his patients about this fact? What will they do between
continue their practice or retire from their works? What is the right choice?
Ethical problems involved in HCP-to-patient transmission of HIV
Ethical problem I: Is it important to tell the patients that their physicians infected
with HIV? And can we prevent or decrease this way of transmission?
24
Varaporn Podprasart
Naturally, the contract between the patients and their physicians requires the
promotion of the well being of patients and the prevention of harm to patients. All of
the HCPs are aware of the potential destruction of their clinical work if they inform
their patients that they have HIV infection. In a 1991, Newsweek poll 94% of
respondents agreed that all physicians and dentists should be required to tell patients
if they are infected with HIV. 63% said HIV-infected surgeons should be forbidden to
practice, 60% said seropositive dentists should be so restricted, and 51% said all
seropositive physicians should not practice (54). Many nurses and physicians agree
with the general public that this event justifies mandatory testing of HCPs. The
compulsory testing of all health care workers, however, were too expensive and too
intrusive into privacy for the small margin of safety that might conceivable be added.
Therefore, the CDC’s recommendations for voluntary testing and minimal restrictions
on HCPs activity that involves exposure-prone invasive procedures represent a
compromise between recognition of differential risk assessment, political expediency,
awareness of public fear, and respect for the HCPs’s autonomy (55). The exposureprone activity such as using fingers and a shape object in a confined or poorly
visualized site, presents a risk of percutaneous HCP injury that is likely to bring the
HCP’s blood in contract with the patient’s body cavity, subcutaneous tissues, and/or
mucous membranes. All HCP’s who perform invasive procedures are recommended
to know their HIV status and to seek counsel from expert panels about clinical
activities. The CDC guidelines about seeking advice from expert panels for HIVinfected HCWs weighted HCW autonomy and right to privacy as less compelling than
nonmaleficence. Some people said hospitals have no legitimate reason to instill that
kind of fear in their patients, and informing patients that their physician has HIV or
AIDS because it does more harm than good. Penny Strong, a director of Public
Information for the Illinois ACLU in 1988 once said, “ We believe that by not telling
the patient, you are protecting the patient. Telling patient gives them the false
impression that if their doctor has HIV, they are going to get AIDS. But they will not,
assuming the doctor follows the guidelines. And secondly, you don’t know who else
in the hospital has the virus. By telling the patient, your doctor has HIV, you are not
promising the patients anything. It sounds as if you are, but you are really not.” (56).
Ethical problem II: Is it possible to have a mandatory HIV testing in HCPs?
According to their autonomy and right to privacy are in conflict with activities
required to protect the patients. If public pressure continues to propose mandatory
testing, HCPs may choose to leave their professions for other work (57). Recruiting
new teamwork may be difficult and requires many years to develop competency and
knowledge that more experienced workers possess. Therefore, these losses could
result in a lower standard of health care.
Ethical problem III: Can those infected health care professionals be retired by their
supervisors if they claimed that it is the best way to protect the safety of the patients?
In medical setting, HIV can be transmitted to patients only during invasive
procedures in which a seropositive HCP’s blood might “contact the patient’s body
cavity, subcutaneous tissues, and/or mucous membrane”. The CDC, in 1992, has
estimated the risk that patient will contract HIV from a seropositive surgeon during an
operation as between 1 in 42,000 and 1 in 420,000 (58). Even though, the risk seems
to be low but HIV infection is fatal and can be transmitted to loved ones. Patients may
betray if a physician placed them at any risk beyond that caused by their illness. The
Consultation on AIDS and the workplace, organized jointly by the WHO’s Global
Program on AIDS and the International Labor Organization (11) concluded that it
must be distinguish between 2 distinct HIV situations in occupational;
25
Varaporn Podprasart
1. The vast majority of occupations and occupational environments (in which) the
work does not involve a risk of acquiring or transmitting HIV between workers,
from worker to public, or from client to workers.
2. The vast majority of occupations and occupational situations in which a
recognized risk of acquiring or transmitting HIV may occur. This category
basically refers to health workers such as physicians, nurses, laboratory personnel
etc. These persons have possibility either acquiring HIV, if infected, of
transmitting it to co-workers or their patients in the performance of their work.
Furthermore, the Article 36 of the Regulations of the General Health Law
Regarding with Medical Care Delivery (47) stipulates that;
Article 36: Personal who works with any medical care establishment shall under no circumstances
perform their duties if they are suffering from any of the compulsorily notifiable communicable
diseases.
From this article, it seem to be likely that they must be retire from their work
if they are infected with HIV even though that infection came during duty, not their
improper behavior. So, is it right pass judgement to them like that since it is
discriminatory? According to the recommendations of the World Health Assembly
Member stated on 13 May 1988 that; “Respect and protect the human rights and also
dignity of HIV-infected or AIDS people, and of members of population groups, and to
avoid discriminatory action against and stigmatization of them in the provision of
services, employment, and travel (47)”. Therefore, these recommendations seem to be
conflicted. If we consider that these persons have the right to be hired due to full
respect of their human’s right. So, it will be advisable to modify such rules. Therefore,
the CDC revised the recommendations again in 1991 (59), and recommended that;
“Seropositive health care workers would presumably be restricted from performing
invasive procedures if they violated infection control procedures or had significant
cognitive or neurolgical impairment. And the termination of the employer-employee
relationship can only take place when development of the AIDS symptomatology
makes it impossible for the workers to perform their duties.”
Ethical problem VI: What are the social problem belong to employ the HIV-infected
HCPs?
The specific problems that belong to the employment of HIV-infected HCPs
included;
1. Public fear of infection from HIV-infected HCPs in hospitals, clinics, long-term
cares facilities, or home care agencies that employ infected nurses, causing
patients to seek care elsewhere.
2. Increased group’s insurance rates of the employer or hospital that HCPs work
because HIV-infected staffs will use their insurance to much greater extent than
other employees.
3. Uneven workload distribution since the HIV-infected HCPs can not carry a full
workload due to their disease status.
However, these problems seem to be an economic concern rather than ethical
concerns.
CONCLUSION
For development of anti-HIV/AIDS drugs or vaccines, it is still important for
the researchers to use animal experiments although there are some ideas against their
use due to the animal rights and animal welfare. However, there are many ways to
help anti-HIV/AIDS drugs or vaccines development such as computer simulation
model and human cell cultures. The only use of human cell culture, the technique that
26
Varaporn Podprasart
seem to be effective to use instead of using animals, is not enough to predict the
efficacy of anti-HIV/AIDS drugs because the human cell culture can not mimic the
interactions between cells and the hundred of cells in the body. Those, who use
animals in the experiment must be follow guidelines including refine, replace, and
reduce to keep the amount of the testes animals as low as possible. The experimental
studies in volunteer human subjects are conducted after anti-HIV/AIDS drugs or
vaccines seem to be safe in those experimental animals. The clinical trials must be
under careful supervision, the volunteers are willing to sign the consent and well
informed about the vaccine or anti-HIV/AIDS drug, the results of earlier animal tests,
the risks and benefits of the trials, and these peoples are free to withdraw at any time.
The decision to use these models mostly depends on more benefits obtain as well as
low risks occur. There are many sophisticate ethical problems between the health care
professionals-to-patients and patients-to-health care professionals transmission of
HIV. The health care teams can prevent themselves from HIV infection by using
“universal precaution” to all patients. And if this lethal virus infects them, they can
protect the spread of infection to the patients by severely following the guidelines
during their practice.
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คณะแพทยศาสตร์ศิริราชพยาบาล
โรงพยาบาลศิริราช กรุ งเทพ
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APPENDIX I
The opinions of our classmates about the using of
animal as a model for research study
- Varaporn Podprasart (Thailand)
“I think I can not avoid in using animal as a model for research study
especially in the development of new drugs like anti-AIDS drug or even the study of
toxicity of new chemicals. I knew that it is immoral or unethical but they are still
important and useful. But I think the best way is how I manage them to obtain the
maximum reliable results as well as use them as minimum as possible.”
- Julaporn Srinha (Thailand)
“Animal experiments are important for the progress in scientific and medical
researches especially for prevention or cure some lethal diseases. Now, we can not
seek for any in vitro methods that can mimic systemic organization like the human
body.”
- Ulla Maria Luhtasela (Finland)
“I think it’s OK to use animals.”
- Wang Xiaofeng (China)
“It’s OK but be careful.”
- Tan Swee Huang (Chaina)
“The extrapolation of animal studies to human may not be useful in HIV case.
Thoroughly understanding on how virus work still have to rely on human study but
it’s difficult due to the ethical problems. Therefore, using animal model should be the
choice of no choice.”
30
Varaporn Podprasart
-
Aung Zaw Naing Lin (Burma)
“There will be positive and negative effects on the use of animals. Anyway,
it’s good to do for our mankind but the limitation must be concern.”
- Zhang Jianjun, Army (China)
“Animal can be used as a model.”
- Akhtar Ahmad (Bangladesh)
“It’s OK. But every care must be undertaken to minimizing the loss.”
APPENDIX II
The opinions of our classmates: if someone asks them to be volunteers
in HIV/AIDS clinical trials and claims that it’s safe
- Varaporn Podprasart (Thailand)
“Nothing in the world is absolutely safe. So, I will not be a volunteer until I
sure by myself that the vaccine has no risk or harm. Then, I will be willing to donate
myself in that project.”
- Julaporn Srinha (Thailand)
“I don’t want to be a volunteer even though it’s safe. Since everything that still
in trial may be harm or toxic.”
- Ulla Maria Luhtasela (Finland)
“If I was 100% sure that there is no risk to get infected and not too bad side
effects. I can do it.”
- Wang Xiaofeng (China)
“If I believes that it’s safe. I want to.”
- Tan Swee Huang (Chaina)
“I will not do it, unless they provide sufficient proof that the vaccine is safe or
sufficient insurance if there is any infection occurs.”
- Aung Zaw Naing Lin (Burma)
“It would be great if I have a chance to be a volunteer. But I want to make sure
that there is safe enough for me. So, I’ll not be the first man to be tested.”
- Zhang Jianjun, Army (China)
“Definitely “NO”. Unless I get enough information on the safety of that drug
or vaccine.”
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Varaporn Podprasart
APPENDIX III
The reasons of volunteers, who has joined in HIV/AIDS
clinical trials, Thailand (TAVEG-SIRIRAJ)
Interviewed on: June 2000
- Mr. A: “I clearly understand what will they do now and future and I certainly sure
that it will not be the problem.”
- Mr. B: “I quite sure that the vaccine is rather safe because they said it tested in the
animals for many times and there are many organizations join, support, and
responsible for this trial.”
- Miss. C: “They told me everything I want to know. I confident that it will be safe
and benefit for someone, who are infected with HIV.”
APPENDIX IV
The reasons from people, who don’t want to join in HIV/AIDS clinical trials
32
Varaporn Podprasart
Interviewed on: June 2000 (Outpatient department, Siriraj hospital)
- Mr. A: “I am not so sure about the efficacy of the vaccine although it already
tested on animals because animals are animals, not humans.”
- Mr. B: “I am not sure that vaccine itself will not make me infected with HIV. If it
can, what will I do? Who will responsible?”
- Mrs. C: “I think there is no clearly information about this vaccine. I never find or
read anywhere, particular in Thai language. However, I have heard this project for
a long time.”
APPENDIX V
The example of informed consent in the research study
Ref: Charles EH. Drug Development 2nd CRC Press 1990: 172-3.
CONSENT TO PARTICIPATE IN A STUDY
We invite you (your child……………………)to participate in a study of
…………………We hope to learn………………You were (Your child was) selected
for this study because…………………………...
Investigational Procedures
If you choose (agree to permit your child) to participate in this study. We will
……………………….
Risks and Benefits
Research studies often involve some risks. The risks of this study
are…………… In addition. It is possible in any experiment harmful effects, which are
not now known could occur. Of course, we will take every precaution to watch for
and prevent any harmful side effect. If you are pregnant, we want you to tell us and
we will not include you in experiment, because to do so might be harmful to your
unborn baby: we also want you to avoid getting pregnant during this study, and expect
you to use and effective method of birth control. If you should become pregnant in
spite of all precautions, please contact immediately the investigator whose phone
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number is listed below and he/she will discuss with you the choices available for your
consideration. If you (your child) participate(s) in this study you (your child) may
experience ……………… We do not guarantee or promise, however, that you (your
child) will receive any of these benefits.
Alternative Treatments
Often, the treatment for your (child’s) condition would be ……….. However,
in order to test the effectiveness of our experimental treatment, we must necessarily
withhold (delay) customary treatments. If the experimental treatment is not effectively
improving your (child’s) condition, we will treat you (your child) with ………………
(Customary treatment). Other alternative participating in this experiment include
………… or simply a decision not to participate.
Privacy of Records
Any information that we learn about you (your child) that can be individually
traced to you (your child) will be use responsibly and will be protected against release
to unauthorized people. In addition to the numbers of the health care staff who usually
have access to your (child’s) file, you (your child) records are likely to be show to
…………… (e.g., FDA and employees of the sponsor). If you sign this form, you
have given us permission to release information to those other people. The results of
this study may be published in the medical literature, but no publication will contain
any information that will identify you (your child)
Payment
You (your child) will (will not) receive ……………….. dollars (any payment)
for participating in and completing this study. In the event you (your child) suffer(s)
physical injury resulting from the research procedures, no financial compensation for
such things as lost wages, discomfort is available, but medical treatment that is not
covered by your insurance will be provided free of charge. If you have any questions
concerning financial compensation for injuries caused by the experiment, you should
talk to ……………… at ………………
Conclusion
Neither your decision not to (allow your child to) participate in this study, nor
your decision to stop and withdraw from the study after having agreed to participate
will hurt your future care at this hospital. Of course, we will tell you anything we
learn during the study that may help decide whether or not to continue participating.
You are making a decision whether or not you (your child) will participate in
this study. If you sign this form, you have agreed that you (your child) will participate
based upon reading and understanding this form. If you have any questions about the
study, please ask ………………… before signing.
If you have any questions regarding research subjects’ rights, please contact
..……………… Chairman of the ……………… at……………… You will receive
an unsigned copy of this form to keep. …………………
Witness…………………………………..
Signature………………………
Member of Research Team……………
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Signature of Parent or Guardian……………..
Date…………………..
NOTE: The same version of the consent form should not be used for both adults and
children. The bracketed reference to children should be omitted from adult forms. The
brackets and preceding language should be omitted if the study is confined to
children.
APPENDIX VI
Deciding to Enter an HIV/AIDS Drug Trial
Ref: AIDS Treatment Resources 6th New York 1990
1. About the trial
a. What is the name of this trial? What kind of trial is it? Phase I? Phase II?
Phase III? Double-blind design? Open label? Placebo?
b. What type of drug is being tested? Antiretroviral? Immunomodulator?
Antineoplastic? Treatment or prophylaxis for a specific opportunistic infection
or illness?
c. How often must the drug be taken? How will the drug be given in this trial?
Orally? Intravenously? Other?
d. If the participant is a child, will this affect how often the drug is taken? Will
any physical restrains be used (for instance, in the case of intravenous drugs)?
How long will the drug’s effectiveness be monitored in children?
e. Must the drug be taken in the hospital or at a test site, or can I take the drug at
home?
f. Do I need to be in the hospital to be in this trial? For how long?
g. How often must I visit the test site? What will happen on these visits? How
long will each visit take?
h. Is the trial being conducted at any other locations? Is there a location easier for
me to get to? Is there a site that may meet my particular needs (for instance,
Spanish-speaking counselors, or childcare)?
i. What if I have to miss a visit or forget to take the drug?
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2.
3.
4.
5.
6.
j. When can I start in the trial? How long will the trial last?
k. Do I have to do any special activities while I am at home? Do I have to write
down these activities?
About the drug
a. What other drugs are being used today for my problems? How does the trial
drug compare in safety and success? What is the evidence that this substance
can be helpful in treating my problem?
b. Has this drug been used before? For what conditions? What were the results?
Were there any risks with taking the drug?
c. What are the immediate side effects of this drug? What are the long-term
effects of my using this drug? Are any of the above effects permanent?
d. If I have any side effects, how will be helped to deal with them? Whom can I
call?
e. How will taking the drug affect my day-to-day activities? Are there things I
can not do during the trial? Will I be able to continue working? Exercising?
Having sex?
f. Is this drug available outside this trial? If so, where and how could I get it?
Financial concerns
a. Do I need to have my own doctor to get into this trial? If I cannot afford my
own doctor, will the trial provide one?
b. Do I need to have my own doctor to get into this trial?
c. Do I have to pay for laboratory tests or any other costs?
d. If I experience side effects requiring emergency treatment, which hospital can
I go to and who pays for the treatment?
e. Will I be given any money for participating in the trial?
f. Will I be given any carfare for traveling to and from any visits?
g. If I am caring for a child, is child care available?
Laboratory tests
a. What tests will be given before I start? Will I be given the results of these
tests?
b. What tests will be given during the trial? How often? Will I be given the
results of these tests?
c. How often will the researchers tell me how I am doing while I am in the trial?
Describe all the risks and benefits of my participating in the trial?
Medical history
a. What do the researchers need to know about my medical condition to see how
the drug may affect my health?
b. If I am a person with a medical problem, including hemophilia, how will the
drug affect my specific condition?
Foods, special diets, and other considerations
a. If the drug is a pill or capsule, should I take it on an empty stomach? With
food? Which foods?
b. Are there any special foods that I need to eat while in this trial? If I am already
on a special diet, may I continue? Can I take vitamins?
c. Are there any foods or other substances that I shouldn’t have while taking this
drug? Can I take any over-the-counter (non-prescription) drugs? Aspirin? Non
aspirin pain killers (such as Tylenol or other forms of acetaminophen)? Cold
tablets? Cough syrup?
d. Can I use prescription drugs while I am in this trial? Can I use other
experimental drugs? Can I take drugs against HIV? Can I take
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immunomodulators? Can I take prophylaxis or treatment for opportunistic
infections, cancers, or any other illnesses I may get?
e. What type of contraceptives can I use? Are oral contraceptives permitted? Will
my use of contraceptives be monitored? Are pregnant women allowed in the
trial?
7. Informed consent
a. Is this trial confidential? Will anyone outside the trial know about my health
condition without my permission?
b. How will information about me be coded to protect my privacy?
c. Do the consent papers that I am signing describe all the risks and benefits of
my participating in the trial?
d. What written information will be given about the trial and the drug?
e. How often will the institutional review board (IRB) review the trial for any
changes?
f. How will I be informed of those changes? If this trial changes significantly, or
if I’m put into another trial, will I receive an updated informed consent form to
sign?
8. Leaving the trial/end of the trial
a. If my condition gets worse I am on the drug, will I be taken out of the trial? If
I am in a placebo group, can I get the drug if my condition gets worse during
the trial?
b. If I develop health problems as a result of being in the trial, will treatment be
available to me even if I have the trial before it is over?
c. If the trial was successful, can I take the drug once the trial is over? Will the
sponsors of the drug supply it to me free until it is marketed and available to
the public? If the drug worked for me, can I continue to take the drug even if
the trial was declared a failure? How is the success of this trial defined by the
protocol?
d. How will decisions about stopping the trial be made? How is failure defined in
the protocol?
e. Will my health continue to be checked after I stop taking the drug? For how
long and under what conditions? Will this be done even if I decide to leave the
trial before it is over? Even if the entire trial is stopped early by the
researchers?
f. Will there be long-term follow-up on how I am doing? Will this be done even
if I have the trial before it is over? Even if the entire trial is stopped early by
the researchers?
g. How can I find out the results of the trial?
h. Will I be able to participate in future trials of this drug? Will I receive the
results or future trials using this drug?
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APPENDIX VII
The example of medical accidental report of health care professionals
Ref: สุรพล สุวรรณกูล, สมหวัง ด่านวิเชียร, สมสิ ทธิ์ ต้นศุภสวัสดิ์กุล บทที่ 21: บุคลากรทางการแพทย์กบั การ
ติดเชื้อเอชไอวี หน้า 439-40.
Medical Accidental Report
Name:……………………………….
Surname:………………………
Workplace/Ward:…………..……….
Telephone number:……………
Occupational status;
( ) Physician supervisor
( ) Nurse
( ) Medical student
( ) Physician
( ) Practical nurse
( ) Nurse student
( ) Laboratory person
( ) Hospital workers
( ) Others;………..
Date of accident:…………………
Time:………………..
Place of accident:………………...
Type of work during accidental take place:………………..
Type of accident:
- Penetration from the needle-stick contaminated with blood (e.g. hand, finger,
arm etc.): …………………………..
- Cutting from blade contaminated with blood (e.g. hand, finger, arm
etc.):………………………………..
- Others: ……………………………..
Blood of the patient get into ( ) eye ( ) mouth ( ) nose other …………….
Secretion of the patient get into ( ) eye ( ) mouth ( ) nose other…………….
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Status of patient:
( ) Positive in HIV antibody test ( ) Waiting for the result of HIV antibody test
( ) Intravascular Drug User (I.D.U)
( ) Prostitute
( ) Homosexual, Bisexual
( ) Other: …………………
Witnesses:
1) Name……………….
Surname…………………….
Workplace/Ward: ……………….…….
Telephone number:……………
2) Name……………….
Surname…………………….
Workplace/Ward:……………………...
Telephone number:……………
Exposure signature ……………………….
APPENDIX VIII
Questions from the audiences after presentation
Thida Chanyachukul (Mahidol U): If we want to perform the clinical trials about
the HIV in children, who can sign the informed consent?
Answer: I think their parent. But normally, the children can not permit to sign the
consent by themselves. In Thailand, the children age below 18 can not do anything
such as marriage because the law is not permitted.
Rodjana Chunhabundit (Mahidol U): What is the different between randomizeplacebo control and standard therapy?
Answer: Placebo means the synthetic compound that try to mimic your interested
compound not only general appearance but also taste and smell and it will not have
any effect when using. In case of the study for anti-HIV drug, if you use placebo as a
control. It will make the volunteers worse than normal situation, which is unethical
due to the human’s right that all volunteers must received the maximize benefit and
no harm. Therefore, the standard therapy such as the use of AZT in the control group
must be used instead of placebo and it must be use in all of the study of lethal disease
like cancer as well. Even though the standard therapy is not make the best benefit to
the volunteers in control group but it can hold their condition not too bad than they
will be. So, their human’s right can be maintain.
Dr. Maria Kartalou (MIT): Can drug abuse persons sign the informed consent?
Answer: I think they can. But they must be in the normal condition like normal
people. For example they must be stop using the drug injection for a certain time until
the action of drug inactive. In addition the investigator in the trial team must check
and screen these persons again before permit them to submit the consent form.
Dr. Suvit Loprasert (CRI): Is 3R use in Thailand?
Answer: Yes. I do not know when but for Mahidol University, it was used for more
than 5 years. And we have “Animal Research Meeting” for everybody about the use
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of animal every year, which was done by the “International Animal Research Center”’
Salaya province, Nakornprathom.
Dr. Suvit Loprasert (CRI): Do you write the report if you use them in the research?
Answer: No, but we have the form to write. For example how many animals do you
want? What are the purposes in using them? Who will care for them?
Phanit Ratasuk (AIT/CRI/MU): Can 3R use in the pharmaceutical company? Is it
necessary to use?
Answer: Yes, it can. I think anything that involves in the use of animal is better to
follow 3R even though in Thailand don’t have the law to force the company.
Therefore, it isn’t necessary but it’s good to follow.
Dr. Suvit Loprasert (CRI): If HCPs exposed to the patient’s blood, can they ask the
patient to do HIV testing?
Answer: Yes, they can because they right to know but the patient also has right to
protect himself or herself if they don’t want to. But in Thailand, if this situation
occurs and the patient doesn’t agree to test, the HCP will play a trick and get the
blood for testing without the consent, which are illegal and unethical. As I knew, in
Siriraj hospital the patients always obey the physician so, they will do everything if
the physician told them.
Dr. Suvit Loprasert (CRI): As you are a nurse, can you know the HIV status of the
patient?
Answer: Yes. Normally, I can see the HIV status of the patients, if they already had,
in the nurse’s note. And it’s easy to see because the whole form is written by blue pen
but for the HIV status, if positive, it will write in red. Very significant different.
Dr. Suvit Loprasert (CRI): Do you think can we request the government to test HIV
in all patients?
Answer: Yes we can. But it is impossible to do due to the human rights and the
important is the budget since the cost for HIV testing is rather high.
Dr. Suvit Loprasert (CRI): Is it important to know the HIV status of the patient?
Answer: For me I think “No”. Because I was trained to use the “Universal
precautions” technique and I must remind myself that all of the patients have the
possibility to infect by some disease at that time, not only for HIV. So, I must protect
myself all times.
Dr. Suvit Loprasert (CRI): Do you think is it good to tell the patient that you are
HIV-positive?
Answer: Yes because they will know how to avoid the risk or increase more infection.
They can prepare themselves in the right way because if they are in healthy status they
can prolong their life. But it may be two-shape sword as well.
Dr. Suvit Loprasert (CRI): Can the patient ask for HIV testing?
Answer: Yes they can.
Dr. Suvit Loprasert (CRI): If those patients do not want to hear their HIV test’s
result, can their parents listen instead?
Answer: I think “No”. It is very secret and important to the patients. So, the physician
must tell directly to the blood’s owner and the physician will teach them what will
they do after this time.
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Biomedical research
Alternatives
Alternatives methods
Ethics
Ethics
Animal experimentation
- restraint and handling
- identification
- drug administration
- anesthesia
- surgical technique
- specimen collection
- autopsy procedure
- euthanasia
Information resources
- research
- education
- publication
- audiovisual aids
- computer
Lab animal care & management
- genetic
- health & environment
- animal production
- transportation
Quality assessment
- genetic monitoring
- health monitoring
- environmental monitoring
Figure 2 The relationship between ethic and biomedical research
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