Pediatric research must balance two important social and ethical goals. First,
scientific progress that includes issues important to children will by necessity require that
children be involved in research. Second, because children cannot themselves consent to
participation in research and must depend on adults to protect their interests, it is
essential that the well-being of the individual child who participates in a research project
be protected. Although these two goals are compatible, they will at times conflict. Achieving
the appropriate balance between these two goals becomes the focus of discourse among those
who seek to do good research. Good research is ethical research, and both require
investigators who take seriously the importance of participant welfare, meaningful informed
consent, and respect for research participants. Current controversies in pediatric
research ethics: Proceedings introduction. D. S. Diekema, F.Bruder Stapleton. The Journal
of Pediatrics 2006: 149(1); S1-S2.
[Abstract]
I am giving a talk in London about the differences in research when children are involved.
One major aspect of these differences is that the ethical and regulatory requirements change.
I do not plan to talk about regulatory issues for two reasons.
First, the regulatory environment is quite diverse. At my hospital, which straddles the
border between the states of Kansas and Missouri, we have different legal requirements for
patients depending on which state they come from. How much more different is it when you
consider regulations in the international arena!
(Source:
www.idcide.com/citydata/mo/kansas-city.htm)
Second, a focus on just the regulations leads to a narrowly drawn perspective: what can I
get away with. Rather than thinking about your research from a narrow legalistic perspective,
I'd encourage you to think about what you are comfortable with. What type of research can you
do and still sleep well at night. The regulatory and legal constraints are important, of
course, because a small number of people have no conscience and sleep well at night after
doing terrible things during the day. These people cause all the problems for the rest of us.
Informed consent requirements were derived in response to Nazi medical experiments
Ethical research requires the full and free voluntary participation of your research
subjects. This principle was first elaborated in the Nuremberg code, a set of principles
developed in response to abusive medical experiments conducted by the Nazis at concentration
camps and prisons. There are other abusive medical experiments, such as the Tuskegee syphilis
study, that also raised our awareness of the importance of informed consent.
There is a nasty tendency in today's society to attack research that you do not like by
comparing it to the research done by the Nazis, and I want to discourage those sorts of
analogies. They are not helpful. But it also important to understand the abuses that led to
the first elaboration of principles of ethical research.
Eva Mozes-Kor tells the story of her family's experience
My thoughts were interrupted by the sound of the cattle car door as it opened.
"Schnell, schnell." The SS soldiers were ordering everybody out. As soon as we stepped
out onto the cement platform, my mother grabbed my sister and me by the hand, hoping
somehow to protect us. Everything was moving very fast. I suddenly realized that my
father and my two older sisters, Edit and Aliz, were gone. I never saw them again. I
think the whole thing took 10 minutes; they were lost in the crowd as Miriam and I
clutched my mother's hand. The SS soldiers walked by, shouting louder. Suddenly, they
stopped my mother and looked at my twin sister and me, because we dressed alike and
looked very much alike. "Are they twins?" one soldier asked my mother. My poor mother
was bewildered. What was this place? she must have thought. What was happening here?
What were the rules? What was a good answer and what was bad? She asked the SS soldier
if being a twin was good. The guard nodded his head. My mother said very hesitantly,
"Yes, they are." Without further explanation, the officer grabbed Miriam and me, and
another SS soldier grabbed my mother and pulled her in the opposite direction. We
screamed and pleaded as we were separated. I remember looking back and seeing my
mother's arm stretched in despair as she was being pulled away. I never even said
goodbye to her. I did not know that was the last time we would see our mother.
The Mengele Twins and Human Experimentation: A Personal Account. Mozes-Kor E. In:
Annas GJ and Grodin MA ed. The Nazi Doctors and the Nuremberg Code. 1992; Vol. New York
NY: Oxford University Press; 53-59.
It was the Spring of 1944. Eva and her twin sister were at Birkenau. Dr. Josef Mengele was
conducting medical research, and twins were highly prized for this research. No one told Eva
or Miriam what was going on, what was being done to them or what their ultimate fate would
be.
Eva was infected with a germ-she doesn't know which one-and developed a fever. She has put
in a hospital, but did not receive any care at all. Dr. Mengele and a team of doctors
reviewed Eva's fever chart but did not otherwise intervene. They gave her no medicine, no
food. She had to crawl by herself to a water faucet to drink.
Eva realized that she would never get out until she convinced these doctors that she no
longer had a fever. She manipulated the thermometers so that her fever gradually disappeared.
After three weeks, she was re-united with her sister.
Upon my return, Miriam told me that during the first 2 weeks of my
hospitalization, someone had stayed with her continually. She was not told of my
condition, but it was clear that had I died in the hospital, Miriam would have been
taken immediately to Mengele's lab to be killed
In very cold and cruel terms, Miriam would have been a matched control subject. Her
healthy organs at autopsy would be compared to Eva's disease ravaged organs.
The public's response to the horrors of stories like this led to the development of the
Nuremberg Code. The ideas behind the Nuremberg Code have been refined over time, but it is
valuable to read these original principles. Here are the ten principles.
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, over-reaching, 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 reasonable 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 and 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 problem
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 seemed 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 judgement required of him, that a
continuation of the experiment is likely to result in injury, disability, or death to
the experimental subject.
The desire to insure that research participation is truly voluntary has led to a huge
framework for the production and review of the informed consent process.
There are several notable areas where the need for informed consent can SOMETIMES
be waived. It is a bit dangerous to summarize these areas with just a few bullet points
because each of these areas could probably demand its own three hour training class.
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Quality assurance programs,
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Publicly available records,
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Anonymous patient records,
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Retrospective chart reviews,
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Emergency situations where consent is impractical.
The rules are different in the United States and in Europe, but in general you need to
consider the degree of risk in the research and the practical barriers that obtaining
informed consent might raise. The barriers imposed by obtaining informed consent need to be
more than just an inconvenience to the researcher before you can waive the informed consent
requirement.
There are other areas where informed consent has sometimes been waived. For example, there
have been many studies in which intercessory prayer has been studied in a double blind
randomized trial. In most of these studies, subjects were not asked for their consent prior
to randomization so as to avoid selection bias.
Informed consent is impossible in children
The whole issue of informed consent gets tossed out the window when it comes to research
involving children. Children do not have the maturity and intellectual capability to make an
informed decision to participate. There is a vigorous debate in the research community about
what this implies, and some have taken the position that non-therapeutic research (research
that does not benefit the patient) is always unethical in children.
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Nontherapeutic research with children: the Ramsey versus McCormick debate. A. R.
Jonsen. J Pediatr 2006: 149(1 Suppl); S12-4.
[Medline]
[Full text]
[PDF]
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Children in clinical research: a conflict of moral values. Vera Hassner Sharav.
American Journal of Bioethics 2003: 3(1); W12-W59.
[PDF]
There is also vigorous debate about the definition of non-therapeutic research
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Phase I research and the meaning of direct benefit. L. Ross. J Pediatr 2006: 149(1
Suppl); S20-4.
[Medline]
[Full text]
[PDF] (Ethics, Children)
Among those who believe that non-therapeutic research in children can be ethical, the
conditions under which the research can be considered ethical center on three carefully
defined terms:
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minimal risk,
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permission, and
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assent.
Minimal risk. I could not find a European (e.g., EMEA) definition of minimal risk.
The U.S. Code of Federal Regulations (45CFR46.102) defines minimal risk as "the
probability and magnitude of harm or discomfort anticipated in the research are not greater
in and of themselves than those ordinarily encountered in daily life or during the
performance of routine physical or psychological examinations or tests." Note that there
are two dimensions, probability and magnitude. If either dimension is too large, then the
research is not minimal risk. Research is possible if the risk is greater than minimal risk,
but extra safeguards are needed. The U.S. regulations use some rather convoluted language
here, such as "minor increase over minimal risk."
Permission. Most research involving children will obtain permission from the
child's parent or legal guardian prior to the research. Just like informed consent can
sometimes be waived, the need for parental permission can also sometimes be waived. The
criteria for waiver examine the practicality of getting permission as well as the degree of
risk. Sometimes permission is called "proxy consent" but you need to be careful how you use
this term.
Assent. Although children do not have the intellectual capacity to provide informed
consent, you should still seek their assent before starting the research. Assent should be an
active agreement rather than a passive failure to raise an objection. When you should seek
assent and the type of assent that you get depends on the age and intellectual development of
the child. There is no hard and fast rule, but many sources have suggested that children at
the age of seven have sufficient capacity to be able to offer assent. The process of seeking
assent, of course, should be more detailed and involved for a teenager than a seven year old.
Keep in mind that some pediatric diseases can cause developmental delays.
A nice review of the issues associated with assent can be found in
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A developmental approach to child assent for nontherapeutic research. V. A. Miller,
R. M. Nelson. J Pediatr 2006: 149(1 Suppl); S25-30.
[Medline]
[Full text]
[PDF]
Please note that many of the controversies involving minimal risk, permission, and assent
are irrelevant if your pharmacovigilance efforts involve the use of existing databases. There
are indeed privacy risks for these types of studies, but no need for you to seek permission
or assent, unless you are the one developing the database yourself.
Financial payments can sometimes undermine informed consent
When a person volunteers to participate in research, they are offering a gift to the
researchers. They usually suffer some level of inconvenience. Sometimes they endure painful
procedures like venipuncture. In some cases, they take on additional risk in order to
participate. It seems only natural to offer financial compensation in return for their
sacrifices. But you need to be careful that any financial payment does not become so large as
to become an undue influence. This influence could lead people to discount the risks of the
research and to hide potential disqualifying information from the researchers. To better
understand the controversies behind these issues, you should recognize the distinctions among
four different types of financial payments:
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Reimbursement payments, which cover direct expenditures such as transportation
costs and time lost from work,
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Compensation payments, which cover indirect expenses such as the inconvenience of
not being able to sleep late on a Saturday morning,
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Appreciation payments, which represent an effort to offer thanks to the research
participants.
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Incentive payments, which represent an effort to encourage enrollment in the
research study.
Financial compensation in a pediatric study is controversial and there are those who argue
that ANY payments in a pediatric research study are unethical. In children, there are two
problems. First, even a small amount of money may seem large to a child and cloud their
judgment. For some children, the amount of money they receive in exchange for participating
in a research study might be more money at one time than they have ever had before. Second,
money that is given to the parent may potentially encourage the parent to exploit their
children. Very few parents would do something that would benefit them at the expense of their
children. Indeed, almost every parent will make significant sacrifices on behalf of their
children and would be horrified at even the thought of doing anything against the interests
of their children. Sadly, though, there are enough parents who don't have their children's
best interests at heart that you need to be careful.
Discussion of what level is appropriate for these four types of payments appears in an
Institute of Medicine report, Ethical Conduct of Research Involving Children (available at
www.nap.edu/catalog/10958.html) and is
summarized in
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Appropriate compensation of pediatric research participants: thoughts from an Institute
of Medicine committee report. B. W. Ramsey. J Pediatr 2006: 149(1 Suppl); S15-9.
[Medline]
[Full text]
[PDF]
Incentive payments raise the most concerns and the committee strongly discouraged their
use. Incentives intended to overcome recruitment problems for painful and risky procedures
are especially to be avoided. Appreciation payments are acceptable if they are
"age-appropriate and of nominal monetary value."
There is little controversy, according to the IOM report, on reimbursement payments or
compensation payments, as long as they are not unrealistically large. You can offer to buy
someone lunch, but not lunch at a five star restaurant, for example. Defining what is
unrealistic for indirect expenses is tricky and depends a lot on the economic circumstances
of the child and parents. Bonnie Ramsey, the author of the above article shares two
interesting anecdotes.
The first described a teenager who visited a clinic with multiple research studies open
for volunteers who announced "Tell me all the studies going on and exactly how much each
pays!" Clearly there is a problem with undue financial influence in this situation.
The second involved a discussion of a particular research project between Dr. Ramsey and a
teenager with Cystic Fibrosis as well as that teenager's parents.
The family had faced a recent job loss by the father and change in employment by
the mother. They lived a significant distance from the medical center. I began
discussions regarding the study rationale, risks versus benefits, and study procedures
but had not addressed the issue of compensation for participation. Compensation was
clearly defined in the consent form, which the parents had not yet read. The adolescent
expressed significant interest, but the parents were reluctant and claimed "lack of
time" and a "long trip over the mountains." Going against my usual policy to not
emphasize compensation, I noted that we would cover the costs of gas for the trip and
compensate them for their time. The parents' faces lit up and both stated that they had
always wanted to have both of their children with CF participate in research
trials but were too proud and embarrassed to admit that they could not afford the money
for gas.
Dr. Ramsey makes an important point here, that compensation to remove barriers is
certainly reasonable and goes on to suggest that other things beyond money (such as
scheduling appointments at times convenient to the family rather than at times convenient to
the researcher) might be worth considering.
Another important issue is the timing and distribution of payments in a longitudinal
study. Certain studies have an increasing scale of compensation over time that reflects the
real value of getting full information across the time spectrum on as many patients as
possible. This can include a "balloon payment" at the end of the study, a large sum paid only
to patients that complete all of the required visits. In general, the use of an increasing
scale or a balloon payment is not consistent with reimbursement or compensation. These
payments can sometimes be coercive, because a patient may be reluctant to withdraw from the
study early when faced with the loss of a substantial portion of the financial compensation.
Again it is worth noting with data collected by someone else (a frequent source of
information in pharmacovigilance trials) that you do not have to worry about any compensation
issues.
Other resources:
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Psychological screening of children for participation in nontherapeutic invasive
research. McCarthy AM, Richman LC, Hoffman RP, Rubenstein L. Arch Pediatr Adolesc Med
2001: 155(11); 1197-203.
[Medline] [Abstract]
[Full text]
[PDF]
