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Protecting children in clinical drug trials
Advocate argues new laws to reduce risk of harm
New federal laws aimed at encouraging drug companies to study how well their products work in children have had the unintended consequence of weakening already vague protections that prevent child research subjects from being exploited, a leading human subjects research advocate claims.
Passage of the Better Pharmaceuticals for Children Act (incorporated into the Food and Drug Administration Modernization Act [FDAMA]) in 1997 and the preceding Prescription Drug User Fee Act (PDUFA) in 1992 have created an environment in which children have become valuable research commodities, says Vera Hassner Sharav, MLS, president of The Alliance for Human Research Protection (AHRP), a nonprofit research advocacy organization based in New York City.
These laws, which provide financial incentives to pharmaceutical companies to perform research involving children, set in motion radical shifts in public policy away from protecting children by setting limits on permissible research risks to a policy aimed at broadening the inclusion of children in trials as test subjects, she notes.
In particular, FDAMA provides an additional six months of patent exclusivity for the manufacturer of pharmaceuticals that have undergone testing in children. Such an extension of patent rights can represent millions of dollars in profit.
In a recent report published in the American Journal of Bioethics,1 Hassner Sharav presents case studies detailing incidents in which children have been included in research projects that placed them at significant risk of harm without the potential for direct benefit to the child subject (in violation of federal human subjects research protections laws). In fact, in many instances, children are included as research subjects in trials that do not seem likely to yield scientifically valid information for any population.
"Children are being used in ever more speculative experiments, often in the absence of a therapeutic intent, but with a significant chance of harm and/or discomfort," Hassner Sharav tells Medical Ethics Advisor. "The Nuremberg Code provides the best standard for justifying research involving human subjects: 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.’"
The code also requires that human subjects give informed consent for participation — that they be informed of all the potential risks and benefits of participation in a given study and then consent to participate free of undue inducement or coercion.
"Children, however, are not capable of exercising the human right to informed consent. Therefore, they need additional protections to prevent their exploitation," she adds.
Institutional review boards (IRBs) and ethics committees, the bodies delegated with the primary task of protecting human subjects under U.S. law, have failed to protect child subjects in many well-documented research studies over the past decade, she argues. Thus, it is time for a national initiative to determine basic protections for child research subjects and a more universal oversight system to ensure the basic protections are enforced.
Animals have more rights
Under federal law, animals used as test subjects have more federal protections than human subjects, Hassner Sharav points out.
Under stipulations of the Animal Welfare Act of 1966, the well-being of research animals must be monitored by an independent veterinarian and documented and safeguarded by study researchers. These researchers must justify any pain inflicted on animal subjects and the U.S. Secretary of Agriculture must provide an annual report to Congress accounting for the outcome of every animal used in research.
However, no one maintains a record of the number or nature of clinical trials involving human subjects in this country, the number of human subjects involved or their disposition following research, Hassner Sharav notes.
While some may argue that humans have the ability to refuse to participate in trials that put them at risk of harm — where animals do not — this argument has less weight when the potential research subjects are children, she says.
Parents or guardians must consent to involve children as research subjects, because children are not able to give adequate informed consent themselves. Parents often do not understand the risks involved in research, and may themselves have conflicts of interest that prevent them from putting the interest of the individual child first.
Definition of minimal risk
Federal regulations adopted in 1983 preclude the inclusion of children in research involving "greater than minimal risk" unless the project poses a potential direct benefit to the child.
However, there are no strict definitions of "minimal risk" or "direct benefit" in the regulations and these terms have been open to wide interpretation, Hassner Sharav argues.
And under the regulations, children may be included in studies that present more than minimal risks to them, if the study will yield generalizable knowledge about the subject’s disorder or condition which is of vital importance. And if all of these standards are not met, inclusion of children still is permissible in studies that present significant risk to them if them if the investigator can demonstrate that the proposed project presents "an opportunity to understand, prevent, or alleviate a serious problem affecting the welfare of children."
These standards provide so much room for interpretation that individual IRBs have wide room for discretion in approving studies that pose considerable risks for children, Hassner Sharav says.
"As currently constituted, IRBs cannot claim to be independent," she argues. "IRBs are compromised by an inherent conflict of interest, and their decisions bear this out."
As examples, she cites a 1996 study approved by the IRB at the National Institute of Child and Human Development that approved an obesity experiment conducted on 100 obese and 92 normal-weight children ages 6 to 10. The experiment involving fasting, blood tests, X-rays, and a two-day overnight hospital stay during which the children were subjected to painful, invasive procedures. The procedures included insertion of an intravenous line for 18 hours; a battery of intensive measurements of metabolic rates; a two-hour hyperglycemic claim study involving a second IV line for two hours; blood sampling at five-minute intervals; a three-hour hyperinsulinemic clamp study for two hours with two IV lines; and infusion of glucose and insulin for two hours.
The IRB unanimously approved the study under the federal minimal-risk category justifying its decision by stating to an investigator from the federal Office of Human Research Protections (OHRP) that: "Several members of the committee explored the meaning of minimal risk and what a child might encounter in a visit to the doctor or while playing in traffic. It was felt that spending several hours in the clinical center in a clamp experiment would be safer than playing actively on sidewalks and streets."
The experiment was later suspended by the OHRP.
Defining a medical condition’
Under the current system and in the current climate, researchers also have been able to expand the definition of subjects’ medical conditions to include conditions the subjects are thought to be at risk for developing in the future.
This argument carries particular weight when the potential subjects are children because children could be considered to be at risk of developing almost any condition at some point in the future, Hassner Sharav notes.
As an example, she cites a study by Pine and colleagues, published in 1997 in the Archives of General Psychiatry, which detailed a fenfluramine challenge experiment performed on 34 African-American and Hispanic boys, ages 6 to 11. The child subjects were drawn from a larger study involving 126 brothers who were deemed at risk of following in the footsteps of older brothers who were incarcerated juvenile delinquents.
The investigators stated that there was evidence of a correlation between reduced serotonin activity and aggressive behavior, and hypothesized that measuring the boys biochemical responses to fenfluramine, they would be able to replicate earlier findings and find a predictive biological marker predisposing the children to violence.
The children were required to follow a special diet for four days, fast for 18 hours prior to the challenge, and had an IV catheter inserted in their arm, which remained in place for more than five hours, during which time blood would be drawn.
The researchers were able to justify the risks and discomfort the children would bear by stating: "Research on the relationship between adverse rearing and serotonin may enhance understandings of the association between serotonin and aggression across development."
The parents of the subjects also were paid $125, and the children received $25 gift certificates to a toy store, Hassner Sharav notes.
The drug fenfluramine, she notes, carries the risk of neurotoxicity and heart valve damage.
Although federal regulations prohibit the use of children in research involving greater than minimal risk if there is no potential direct benefit to them, four prominent IRBs approved this admittedly nontherapeutic experiment.
More oversight warranted
These examples and others indicate that more comprehensive protections for children are needed, Hassner Sharav says. "IRBs are not protecting human subjects who have no voice in the research approval process; they are protecting their institution."
The Alliance for Human Research Protection has formulated 10 recommendations for improving research protections for children that include a National Review Board to oversee research involving children, and the establishment of a fund — supported by fees from drug and device manufacturers — to cover the cost of research oversight.
A National Review Board could serve in the capacity of a Supreme Court for research by rendering judgments about the appropriateness of specific studies to establish national standards for approval, Hassner Sharav notes.
"The board would be an independent body with one-third of its members nonscientists or not under the influence of industry," she says.
Individual institutions should also have specific child protection committees that function in conjunction with, but independently of, the institutional review boards.
"The majority of this committee’s members would be drawn from the community and then be vetted for absence of any conflict of interest," Hassner Sharav explains. "The protection afforded by an independent panel is to monitor, in person, the informed consent process, ensure that the risks are fully disclosed in the consent documents, that parents’ permission is reasonable, and to monitor the children’s assent and continued willingness to participate in research."
While Hassner Sharav raises some very compelling ethical points in her report, she doesn’t give appropriate equal weight to the need to test pharmaceuticals in children to determine their effectiveness and a safe dose, notes Howard Trachtman, MD, a pediatrician and clinical researcher at Schneider Children’s Hospital in New York City.
Patient advocacy groups, including advocacy groups for children, have driven much of the change in the drug evaluation and approval process that she finds so many faults with, he says. They have done so precisely because they felt that continuing to prescribe drugs for children in the clinical setting, which had previously largely been tested only in adults, was unethical.
"Vulnerable populations can be vulnerable in two ways," Trachtman notes. "One, you can abuse them and take advantage of them, and the other is that you can be overly protective of them."
He also takes issue with the contention that the potential for financial gain is the driving force behind the expansion of clinical research in children. "My sense, in reading [Hassner Shirav’s] article, was that she was putting all doctors into this group and that we were all doing this for the same reason, which is to make money," Trachtman notes. "That is not fair to everybody. There are clearly examples you see in the newspaper where investigators get rich off clinical trials in terms of supplementing their income, but I don’t think that is very relevant in pediatrics."
The profit motive in pharmaceutical research, while admittedly powerful, is less forceful in the pediatric community because fewer children are ill and pediatric physician investigators are not as sought after as their adult counterparts.
Most pediatric researchers primarily are motivated by the belief that they are doing whatever they can to find good treatments for their patients to find a cure for life-threatening conditions that affect children, Trachtman adds.
In his experience as an investigator, parents also are highly motivated to learn all that they can about a potential drug or treatment, and they are primarily concerned about its potential to benefit their child vs. the risks involved, he notes.
Children are vulnerable to abuse and exploitation in a number of settings — not just research — and improvements in enforcement of existing protections and oversight systems should be sufficient to protect them without depriving them of the benefits of participation in what could be a very helpful and empowering experience, says Trachtman.
Adding more layers to the oversight process would not have the results that Hassner Sharav and others desire, he states. The solution to improving protections for children, he notes, is in strengthening the quality and support for existing oversight structures.
"In industry-sponsored studies, they have quality assurance people who go out all the time to do site visits. In NIH [National Institutes of Health] studies, you have the data safety monitoring boards and you have good, quality people monitor them," Trachtman says. "The oversight responsibility is key. The investigator may not want to do it right; they may not do it in the right way. But the people who are empowered to do it, have to take their responsibility of oversight seriously."
Because research inherently involves experimenting on test subjects, it is easy to demonize human subjects research as being disrespectful and potentially damaging to human beings without seeing the essential benefits it can provide, he notes.
"The view that the research enterprise is this dark force is not fair," Trachtman says. "Most people that I see, they always want what is best for their kid. Well, where did that best drug come from? It had to come from somewhere; it didn’t pop out of the sky. The importance of ethical practice and all of the precautions are definitely justified. It is not reigning in some sort of criminal enterprise, but it is needed to make sure that a basically good enterprise is done right."
1. Sharav V. Children in clinical research: A conflict of moral values. Am J Bioethics 2003; 3(1):Infocus. Accessed on-line at: www.bioethics.net.