email Dr Kerns
The great weight of the evidence before us is to the effect that certain types of medical experiments on human beings, when kept within reasonably well-defined bounds, conform to the ethics of the medical profession generally. The protagonists of the practice of human experimentation justify their views on the basis that such experiments yield results for the good of society that are unprocurable by other methods or means of study. All agree, however, that certain basic principles must be observed in order to satisfy moral, ethical and legal concepts:
1. The voluntary consent of the
human subject is absolutely essential.
This means that the person involved should have legal capacity
to give consent; should be so situated as to be able to exercise
free power of choice, without the intervention of any element
of force, fraud, deceit, duress, overreaching, or other ulterior
form of constraint or coercion, and should have sufficient knowledge
and comprehension of the elements of the subject matter involved
as to enable him to make an understanding and enlightened decision.
This latter element requires that before the acceptance of an
affirmative decision by the experimental subject there should
be made known to him the nature, duration, and purpose of the
experiment; the method and means by which it is to be conducted;
all inconveniences and hazards reasonably to be expected; and
the effects upon his health or person which may possibly come
from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random or unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problems under study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur, except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
10. During the course of the experiment
the scientist in charge must be prepared to terminate the experiment
at any stage if he has probable cause to believe, in the exercise
of the good faith, superior skill, and careful judgment required
of him that a continuation of the experiment is likely to result
in injury, disability, or death to the experimental subject.
from Trials of War Criminals Before the Nuremberg
Military Tribunals Under Control Council Law No 10 ,
Vol. II. Nuremberg, Germany, October 1946 - April 1949.
Guideline 1: Individual informed consent
For all biomedical research involving human subjects, the investigator must obtain the informed consent of the prospective subject or, in the case of an individual who is not capable of giving informed consent, the proxy consent of a properly authorized representative.
Guideline 2: Essential information for prospective research subjects
Before requesting an individual's
consent to participate in research, the investigator must provide
the individual with the following information, in language that
he or she is capable of understanding:
- that each individual is invited to participate as a subject
in research, and the aims and methods of the research;
- the expected duration of the subject's participation;
- the benefits that might reasonably be expected to result to
the subject or to others as an outcome of the research;
- any foreseeable risks or discomfort to the subject, associated
with participation in the research;
- any alternative procedures or courses of treatment that might
be as advantageous to the subject as the procedure or treatment
being tested;
- the extent to which confidentiality of records in which the
subject is identified will be maintained;
- the extent of the investigator's responsibility, if any, to
provide medical services to the subject;
- that therapy will be provided free of charge for specified types
of research-related injury;
- whether the subject or the subject's family or dependants will
be compensated for disability or death resulting from such injury;
and
- that the individual is free to refuse to participate and will
be free to withdraw from the research at any time without penalty
or loss of benefits to which he or she would otherwise be entitled.
Guideline 3: Obligations of investigators regarding informed consent
The investigator has a duty to:
- communicate to the prospective subject all the information necessary
for adequately informed consent;
- give the prospective subject full opportunity and encouragement
to ask questions;
- exclude the possibility of unjustified deception, undue influence
and intimidation;
- seek consent only after the prospective subject has adequate
knowledge of the relevant facts and of the consequences of participation,
and has had sufficient opportunity to consider whether to participate;
- as a general rule, obtain from each prospective subject a signed
form as evidence of informed consent; and
- renew the informed consent of each subject if there are material
changes in the conditions or procedures of the research.
Guideline 4: Inducement to participate
Subjects may be paid for inconvenience and time spent, and should be reimbursed for expenses incurred, in connection with their participation in research; they may also receive free medical services. However, the payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in the research against their better judgment ("undue inducement"). All payments, reimbursements and medical services to be provided to research subjects should be approved by an ethical review committee.
Guideline 5: Research involving children
Before undertaking research involving
children, the investigator must ensure that:
- children will not be involved in research that might equally
well be carried out with adults;
- the purpose of the research is to obtain knowledge relevant
to the health needs of children;
- a parent or legal guardian of each child has given proxy consent;
- the consent of each child has been obtained to the extent of
the child's capabilities;
- the child's refusal to participate in research must always be
respected unless according to the research protocol the child
would receive therapy for which there is no medically-acceptable
alternative;
- the risk presented by interventions not intended to benefit
the individual child-subject is low and commensurate with the
importance of the knowledge to be gained; and
- interventions that are intended to provide therapeutic benefit
are likely to be at least as advantageous to the individual child-subject
as any available alternative.
Guideline 6: Research involving
persons with mental or behavioural disorders
Before undertaking research involving individuals who by reason
of mental or behavioural disorders are not capable of giving adequately
informed consent, the investigator must ensure that:
- such persons will not be subjects of research that might equally
well be carried out on persons in full possession of their mental
faculties;
- the purpose of the research is to obtain knowledge relevant
to the particular health needs of persons with mental or behavioural
disorders;
- the consent of each subject has been obtained to the extent
of that subject's capabilities, and a prospective subject's refusal
to participate in non-clinical research is always respected;
- in the case of incompetent subjects, informed consent is obtained
from the legal guardian or other duly authorized person;
- the degree of risk attached to interventions that are not intended
to benefit the individual subject is low and commensurate with
the importance of the knowledge to be gained; and
- interventions that are intended to provide therapeutic benefit
are likely to be at least as advantageous to the individual subject
as any alternative.
Guideline 7: Research involving prisoners
Prisoners with serious illness or at risk of serious illness should not arbitrarily be denied access to investigational drugs, vaccines or other agents that show promise of therapeutic or preventive benefit.
Guideline 8: Research involving subjects in underdeveloped communities
Before undertaking research involving
subjects in underdeveloped communities, whether in developed or
developing countries, the investigator must ensure that:
- persons in underdeveloped communities will not ordinarily be
involved in research that could be carried out reasonably well
in developed communities;
- the research is responsive to the health needs and the priorities
of the community in which it is to be carried out:
- every effort will be made to secure the ethical imperative that
the consent of individual subjects be informed; and
- the proposals for the research have been reviewed and approved
by an ethical review committed that has among its members or consultants
persons who are thoroughly familiar with the customs and traditions
of the community.
Guideline 9: Informed consent in epidemiological studies
For several types of epidemiological research individual informed consent is either impracticable or inadvisable. In such cases the ethical review committee should determine whether it is ethically acceptable to proceed without individual informed consent and whether the investigator's plans to protect the safety and respect the privacy of research subjects and to maintain the confidentiality of the data are adequate.
Guideline 10: Equitable distribution of burdens and benefits
Individuals or communities to be invited to be subjects of research should be selected in such a way that the burdens and benefits of the research will be equitably distributed. Special justification is required for inviting vulnerable individuals and, if they are selected, the means of protecting their rights and welfare must be particularly strictly applied.
Guideline 11: Selection of pregnant or nursing (breastfeeding) women as research subjects
Pregnant or nursing women should in no circumstances be the subjects of non-clinical research unless the research carries no more than minimal risk to the fetus or nursing infant and the object of the research is to obtain new knowledge about pregnancy or lactation. As a general rule, pregnant or nursing women should not be subjects of any clinical trials except such trials as are designed to protect or advance the health of pregnant or nursing women or fetuses or nursing infants, and for which women who are not pregnant or nursing would not be suitable subjects.
Guideline 12: Safeguarding confidentiality
The investigator must establish secure safeguards of the confidentiality of research data. Subjects should be told of the limits to the investigators' ability to safeguard confidentiality and of the anticipated consequences of breaches of confidentiality.
Guideline 13: Right of subjects to compensation
Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability. In the case of death, their dependants are entitled to material compensation. The right to compensation may not be waived.
Guideline 14: Constitution and responsibilities of ethical review committees
All proposals to conduct research involving human subjects must be submitted for review and approval to one or more independent ethical and scientific review committees. The investigator must obtain such approval of the proposal to conduct research before the research is begun.
Guideline 15: Obligations of sponsoring and host countries
Externally sponsored research entails
two ethical obligations:
o An external sponsoring agency should submit the research protocol
to ethical and scientific review according to the standards of
the country of the sponsoring agency, and the ethical standards
applied should be no less exacting than they would be in the case
of research carried out in that country.
o After scientific and ethical approval in the country of the
sponsoring agency, the appropriate authorities of the host country,
including a national or local ethical review committee or its
equivalent, should satisfy themselves that the proposed research
meets their own ethical requirements.
You have the right to
o Be treated with respect by all
persons connected with the research team.
o Be fully informed about
the purposes, nature, and methods of the research in which you
are participating,
all possible risks, inconveniences, hazards or discomforts of
any kind related to your health or well being that might result
from your participation in the trial,
any changes in knowledge about the vaccine being studied which
could materially affect your decision to continue participation
in the trial.
o Have all information relating to your participation in the trial,
including whether or not you are a volunteer in the trial, and
all records relating to your medical condition or serostatus,
kept fully confidential and released to no one except to persons
whom you explicitly, in writing, authorize to receive to it.
o Be reimbursed for transportation, meals and other out of pocket
expenses that result from your participation in the trial, as
well as to be given a small stipend for your time involvement
as described in the consent form.
o participate in support groups, counseling sessions and classes
designed for you and your family and/or partner.
o Be protected (to the fullest extent that the research team is
able to protect you) from all harms, physical, psychological,
social, economic and legal, which might result from your participation
in these trials.
o Have the research team be on your side and looking out for your
well-being.
o Be compensated for any accidental injuries which may result
from your participation in the trial (as described in the consent
form).
o Not be manipulated or coerced by anyone on the research team
into doing anything against what you consider to be in your own
best interests.
o Ask questions of the research team about anything regarding
any aspect of your participation in this research project.
o Quit your participation in the trial at any time you wish, for
any reason.
You have the responsibility to
o Keep your appointments with the
research team, to the best of your ability.
o Be fully truthful with the research team in your reports about
risk behaviors.
o Provide fully truthful responses to counselors' questions about
matters relating to your participation in the trial.
o Provide fully truthful responses on any tests or questionnaires
that are part of the research.
o Keep the research team apprised of any changes in the state
of your health.
o Keep the research team apprised of any changes in medications
you are taking.
o Keep the research team apprised of any drugs you are taking.
o Keep the research team apprised of any changes in your residence
or living situation, so they can communicate with you if they
need to.
o Not "unblind" yourself, i.e., to not secretly attempt
to learn whether you have received the candidate vaccine or the
placebo.
o Inform your counselor as soon as possible if you do inadvertently
become unblinded.
Signature of the investigator Date
Subject's statement:
The rights and responsibilities described above have been explained to me. I have had an opportunity to ask questions. I understand that future questions I may have about my rights or responsibilities as a subject can be answered by one of the investigators.
Signature of subject Date
This is a verbatim copy of a test supplied to me from an HIV vaccine research laboratory. It is used to assess subjects' comprehension of the information they have received.
Test of Understanding and Commitment [sic]
Instructions:
1. The pre-enrollment "test
of understanding and commitment" is to be administered to
all volunteers who meet all other inclusion and exclusion criteria
for this trial, prior to signing the informed consent and being
enrolled in the study. The test will be administered by protocol
nurse.
2. All volunteers must answer at least 90% (28 of 31) of the questions herein correctly before enrollment. The staff member administering the test may administer the test as few or as many times as necessary to allow the volunteer to successfully complete the test.
True or False Questions:
Interviewer reads to volunteer: Now, I would like to ask you some questions about your understanding of the HIV vaccine study which we have discussed with you and which you are considering joining. The purpose of these questions is to see what you know and think about this vaccine study. k First I will read you a series of statements. k As I read you each statement, you must tell me whether the statement is "True" or "False." Do you have any questions about what we are going to do?.... Can we start?
Interviewer Circles Volunteer's Response
1. AIDS is caused by a virus called HIV (Human Immunodeficiency Virus). T F
2. People who join this study will never again have to worry about catching HIV infection, no matter what they do. T F
3. Vaccines are a kind of medicine [sic] given to prevent infections. T F
4. The vaccine which is being tested in this study contains the HIV virus. T F
5. There is a very small chance that I could get HIV/AIDS from this vaccine. T F
6. This vaccine has been found to be safe for pregnant women; therefore, I may become pregnant during this study if I wish. (Women only) T F
7. If I enter this study, I may receive an inactive medication [sic] (placebo) and not the vaccine. T F
8. This study will require me to come to the vaccine center approximately 10 times during the next 8-9 months. Sometimes I may need to come in 2 days in a row. T F
9. I may develop a positive test for HIV/AIDS [sic] if I receive the vaccine, but this does not mean that I really have the virus that causes AIDS. T F
10. The vaccine could cause me to have mild fever, aches, pains and fatigue (tiredness). T F
11. This vaccine has already been
proved to be effective in preventing HIV-1 infection in humans.
T F
12. If I experience a serious side-effect which is judged to be
due to the vaccine, I will receive care for that side-effect from
medical institutions sponsoring this study. T F
13. I will be asked to give a specimen of blood only one time during this study. T F
14. People who join this study might catch HIV anyway. T F
15. People who join this study will no longer need to use condoms when they have sex with new [sic] partners. T F
16. All information about my participation in this study is strictly [sic] confidential. T F
Multiple Choice Questions: (Circle as many answers as are correct for each question.)
Interviewer reads to volunteer: For the next 3 questions, I will read a series of statements. I want you to indicate which statements are correct. Do you have any questions?
19. HIV (the virus that causes AIDS) can be transmitted in the following ways:
a. Sharing of eating utensils with
someone who is already infected.
b. Having sex with someone who is already infected with HIV
c. Sharing a needle for injecting drugs with someone who is already
infected with HIV.
d. Hugging someone who is already infected with HIV.
e. Receiving a blood transfusion from a person who is infected
with HIV.
f. From a mother infected with HIV to her unborn baby.
20. Potential side-effects of participating in this study include:
a. Soreness in the arm at the site
of injection for a day or two after the injection.
b. Minor bleeding or bruising at the site where blood is taken
from arm.
c. The possibility of getting HIV/AIDS from this vaccine.
d. A brief period of lightheadedness or faint feeling after having
blood drawn.
e. A positive blood test for HIV/AIDS [sic].
21. Which of the following are true statements about this vaccine study?
a. This vaccine may provide protection from HIV/AIDS, so therefore, I should not be concerned with avoiding high risk behavior such as having sex with prostitutes or multiple partners.
b. My participation will require approximately 10 visits to the vaccine center during working hours. Some visits will be short, requiring less than 1 hour; however, some visits may require 2 or 3 hours of my time away from work, school or family.
c. I will be compensated for my time away from work, transportation to the vaccine center and meal expenses which result from my participation.
d. The vaccine being used in this study has been approved to be tested in humans by the FDA in Thailand and the United States.
Interviewer to volunteer: Thank you for taking this test with me. I would now like to go over the questions and your answers with you. This will be a chance for you to ask any questions you may still have about HIV/AIDS or this vaccine study.
Test of Understanding and Commitment [sic]
Phase I Safety and Immunogenicity Trial of [a candidate peptide vaccine].
Answer Key:
1. T
2. F
3. T
4. F
5. F
6. F
7. T
8. T
9. T
10. T
11. F
12. T
13. F
14. T
15. F
16. T
19.
a. Incorrect
b. Correct
c. Correct
d. Incorrect
e. Correct
f. Correct
20.
a. Correct
b. Correct
c. Incorrect
d. Correct
e. Correct
21
a. Incorrect
b. Correct
c. Correct
d. Correct
(Complete one form for each potential
harm to subjects and society in the study.
Attach these forms to the Form for requesting ethical review of
HIV vaccine trial.)
I. Type of candidate vaccine
II. The potential harm:
to individual physical
to society psycho-social
economic
III. Estimated seriousness of the suffering
miniscule
mild
moderate
serious
severe
comments:
IV. Estimated percent likelihood that this harm will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
Reasons for this estimate:
V. When is this harm likely to occur in a volunteer's life?
VI. What steps will you take to minimize the chances of this harm occurring?
VII. What remedies will you offer if this harm does occur?
VIII. What compensations will you make available to volunteers if the harm occurs?
IX. Assessing understanding
A. What method will you use to inform prospective volunteers of the nature, severity and likelihood of this harm?
B. What method will you use to assess
whether each prospective volunteer has understood the nature,
severity and likelihood of this harm?
I. Type of vaccine
II. Research sponsor
Principal investigator
Funding source
III. Preliminary research
A. Laboratory research performed
Summary of results
B. Animal research
Summary of results
C. Phase I human trials
Summary of results
D. Phase II human trials
Summary of results
IV. Potential harms
A. To individual volunteers
i. Potential physical harms
(List each harm separately, and include the following)
a. Nature of harm
b. Estimated seriousness of suffering
miniscule
mild
moderate
serious
severe
comments:
c. Estimated degree of likelihood
that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When the harm might occur in volunteer's life
e. Steps sponsors will take to prevent this harm
f. Remedies if this harm does occur
g. Compensation to volunteer if the harm occurs
ii. Potential psycho-social
harms
(List each harm separately, and include the following)
a. Nature of harm
b. Estimated seriousness of suffering
miniscule
mild
moderate
serious
severe
comments:
c. Estimated degree of likelihood
that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When the harm might occur in volunteer's life
e. Steps sponsors will take to prevent this harm
f. Remedies if this harm does occur
g. Compensation to volunteer if the harm occurs
iii. Potential economic harms
(List each harm separately, and include the following)
a. Nature of harm
b. Estimated seriousness of suffering
miniscule
mild
moderate
serious
severe
comments:
c. Estimated degree of likelihood
that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When the harm might occur in volunteer's life
e. Steps sponsors will take to prevent this harm
f. Remedies if this harm does occur
g. Compensation to volunteer if the harm occurs
B. To society
i. Potential physical harms
(List each harm separately, and include the following)
a. Nature of harm
b. Estimated seriousness of suffering
miniscule
mild
moderate
serious
severe
comments:
c. Estimated degree of likelihood
that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When the harm might occur in society
e. Steps sponsors will take to prevent this harm
f. Remedies if this harm does occur
g. Compensation to society if the harm occurs
ii. Potential psycho-social
harms
(List each harm separately, and include the following)
a. Nature of harm
b. Estimated seriousness of suffering
miniscule
mild
moderate
serious
severe
comments:
c. Estimated degree of likelihood
that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When the harm might occur in society
e. Steps sponsors will take to prevent this harm
f. Remedies if this harm does occur
g. Compensation to society if the harm occurs
iii. Potential economic harms
(List each harm separately, and include the following)
a. Nature of harm
b. Estimated seriousness of suffering
miniscule
mild
moderate
serious
severe
comments:
c. Estimated degree of likelihood
that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When the harm might occur in society
e. Steps sponsors will take to prevent this harm
f. Remedies if this harm does occur
g. Compensation to society if the harm occurs
V. Potential benefits
A. To individual volunteers
i. Potential physical benefits
(List each benefit separately, and include the following)
a. Nature of benefit
b. Estimated importance of benefit
not very important
moderately important
very important
comments:
c. Estimated degree of likelihood that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When this benefit might occur in the volunteer's life
1) Reasons for this estimate
ii. Potential psycho-social
benefits
(List each benefit separately, and include the following)
a. Nature of benefit
b. Estimated importance of benefit
not very important
moderately important
very important
comments:
c. Estimated degree of likelihood that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When this benefit might occur in the volunteer's life
1) Reasons for this estimate
iii. Potential economic benefits
(List each benefit separately, and include the following)
a. Nature of benefit
b. Estimated importance of benefit
not very important
moderately important
very important
comments:
c. Estimated degree of likelihood that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When this benefit might occur in the volunteer's life
1) Reasons for this estimate
B. To society
i. Potential physical benefits
(List each benefit separately, and include the following)
a. Nature of benefit
b. Estimated importance of benefit
not very important
moderately important
very important
comments:
c. Estimated degree of likelihood that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When this benefit might occur in society
1) Reasons for this estimate
ii. Potential psycho-social
benefits
(List each benefit separately, and include the following)
a. Nature of benefit
b. Estimated importance of benefit
not very important
moderately important
very important
comments:
c. Estimated degree of likelihood that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When this benefit might occur in society
1) Reasons for this estimate
iii. Potential economic benefits
(List each benefit separately, and include the following)
a. Nature of benefit
b. Estimated importance of benefit
not very important
moderately important
very important
comments:
c. Estimated degree of likelihood that it will occur
extremely unlikely
not likely
fairly likely
very likely
completely unknown
1) Reasons for this estimate
d. When this benefit might occur in society
1) Reasons for this estimate
VI. Motivations to volunteer
(List each possible motivation
separately)
A. The motivation:
B. Is this motivation likely to be satisfied or not?
extremely unlikely
not likely
fairly likely
very likely
completely unknown
C. Reasons for this estimate
VII. Informed consent
Include a copy of the study's informed consent form.
VIII. Assessing comprehension
A. List the elements in the above sections which you consider important for prospective volunteers to know about
B. List the methods you will use to inform prospective volunteers of those elements
C. List the methods you will use to assess whether each of these elements has been understood by the prospective volunteers before asking for their consent