(Source: www.idcide.com/citydata/mo/kansas-city.htm)
StATS: Ethical concerns about research in children (October 17, 2006).
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!
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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.
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.
There is also vigorous debate about the definition of non-therapeutic research
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:
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
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:
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
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.
Outside resources:
This page was written by Steve Simon while working at Children's Mercy Hospital. Although I do not hold the copyright for this material, I am reproducing it here as a service, as it is no longer available on the Children's Mercy Hospital website. Need more information? I have a page with general help resources. You can also browse for pages similar to this one at Category: Children in research.