Widely disparate perspectives are presented in an article in the Maryland Daily Record re: The Court of Appeals of Maryland decision (Gimes v Kennedy Krieger Institute, Aug 16, 2001). That 6-to-1 landmark decision severely criticized the practice of exposing healthy children to risks of harm in health related research. Children, we must bear in mind, are powerless to exercise that inviolable human right, the right to refuse to assume risks for research.

Will this decision undermine the legitimacy of research that puts healthy children at risk in clinical trials? AHRP believes it will, and that the decision will be sustained by other courts in other states.

Howard Fishman, member of AHRP's steering committee, focuses on the underlying conflicts of interest that influence the conduct of research:

"Federal funding and research funding by major pharmaceutical manufacturers determine the research agenda," Fishman said. "Major academic institutions have found themselves to be dependent on these funding streams."

"it's easy for institutional 'stakeholders' to succumb to the temptation to blur ethical rules."

"One sees repeatedly an effort to obfuscate facts and the use of rhetorical devices to justify otherwise unacceptable procedures," he added.

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http://www.mddailyrecord.com/cgi-bin/udt/im.print.story?client=dailyrecord&storyid=60140

Risk, research and the ripple effect

October 27, 2001
By JOE SURKIEWICZ,
Daily Record Legal Affairs Writer

Is a recent Court of Appeals opinion on the ethics of medical experimentation involving children in a Baltimore lead-paint abatement study "a landmark case" that will "change the face of medical research in America"?

Or, following a clarification issued by the top court two weeks ago, can the ruling be read as only a confirmation of existing federal ethical guidelines on medical studies on human subjects -- and, as a result, it's back to business as usual for medical research institutions?

[Photo: Lawyer Suzanne C. Shapiro stands with her client, 11-year-old Myron Higgins, in front of the Kennedy Krieger Institute in Baltimore. The Court of Appeals revived Higgins' lead-paint poisoning suit against the institute; whether the decision will have broader ramifications in Maryland, and beyond, remains an open question. ]

To find the answers means wading into the murky waters of research standards and ethical rules that guide federally funded studies using people -- increasingly, children  -- as subjects.

It also requires a look at the effect of the multibillion-dollar funding of medical research by the federal government and the pharmaceutical industry that some critics say shapes the landscape of human-subject research and tempts researchers to bend ethical rules.

The story began last summer, when the Court of Appeals revived two lawsuits brought by children lead poisoned in a study conducted by the prestigious Kennedy Krieger Institute, ä a ruling that sent shock waves through Maryland's medical research community.

It's easy to understand why: In addition to comparing the study to the Tuskegee experiments that withheld treatment to black men with syphilis and human experimentation by Nazis at Buchenwald, the state's top court held that children enrolled in non-therapeutic research studies cannot be exposed to "any" risk, even with their parent's approval.

That language, Kennedy Krieger argued, went beyond federal ethical guidelines and would shut down hundreds of ongoing and planned studies involving children. Yet the outrage was short-lived.

Officials at Kennedy Krieger and Johns Hopkins University expressed relief when the court earlier this month clarified that, by "any" risk, it meant "any articulable risk beyond the minimal kind of risk that is inherent in any endeavor," which officials said put Maryland back in line with existing federal ethical rules in a ruling denying Kennedy Krieger's motion for reconsideration of the August holding.

Still, some legal experts, pointing out there is little case law on human research, say the court's opinion could produce a ripple effect beyond Maryland, possibly to the detriment of society if clinical trials of drugs and vaccines for children are slowed or canceled.

"Without the studies, we'll never find out which drugs can help children," warned Susan Leviton, a University of Maryland law professor and children's advocate. "Children may not be able to participate in some studies, especially for vaccines. We do need trials. We need to know what helps these kids."

On the upswing

The Court of Appeals opinion is important because it addresses the minimal risk standard for children, which is applied more strictly than for adults, explained Ann M. Begley, an attorney with Kirkpatrick & Lockhart in Washington. Begley represents institutional review boards (IRBs) that oversee federally funded human clinical trials. "So the Maryland Court of Appeals decision can have an effect on studies in the future," said Begley.

The opinion may be used by plaintiffs' attorneys in other states, who will cite it for the proposition that "'more than minimal risk, no benefit to the child, that's the end,'" Begley said. "So it could definitely have an intense effect elsewhere."

Moreover, the opinion came at a time when clinical trials on children, who previously were routinely left out of pharmaceutical research, are on an upswing.

Food and Drug Administration-filed pediatric studies increased 250 percent between 1990 and 2000, with the number of child research subjects rising from fewer than 1,000 in 1990 to 18,000 scheduled for trials next year.

The story so far ...

Kennedy Krieger Institute's study, funded in part by the federal Environmental Protection Agency, was designed to evaluate the cost-effectiveness of different lead-paint abatement methods in preventing lead poisoning in young children. More than 100 families in Baltimore "¥ä many of whom lived in economically deprived and minority neighborhoods "¥ä participated in the research effort.

Among them were Myron Higgins and Ericka Grimes. Both suffered elevated blood lead levels and, according to their attorneys, suffer irreversible brain damage.

They sued, but the Circuit Court for Baltimore City granted summary judgment for Kennedy Krieger, finding the researchers had no duty to warn of potential harm to the children.

In August, the top court reinstated the cases, finding the research relationship could create duties to the children, which Kennedy Krieger may have breached by not fully informing their parents of the inherent dangers of potential blood lead poisoning.

But the court did not stop there. In dicta, six of the seven judges agreed that, in Maryland, parents cannot consent to a child's participation in non-therapeutic research that carries "any" risk of harm to the child.

Kennedy Krieger asked the court to reconsider. The court declined. But in ruling on the motion this month, it "clarified" its statement about risk, saying it meant "any articulable risk beyond the minimal kind of risk that is inherent in any endeavor." Whether the Kennedy Krieger study involved such a risk was one of the issues to be determined at trial, the appeals court held.

The increase is driven by a 1997 law passed by Congress that gives drug manufacturers a six-month extension on patents if they agree to test drugs on children -- legislation scheduled to sunset in January, but likely to be extended. On Oct. 11, the House Energy and Commerce Committee approved legislation that would allow drug companies to continue receiving six-month extensions on patent life by a vote of 41-6, with Democrats on the committee complaining that the law has produced windfall profits for some drug companies.

The law is controversial because of huge profits pharmaceutical manufacturers can earn by delaying generic competition in exchange for pediatric testing. The New York Times reported earlier this year that the manufacturer of blockbuster drugs such as Claritin, an allergy medicine, and the anti-depressant Prozac earned hundreds of millions of dollars in additional profits because of patent extensions.

"We're having an increase in studies and an increase in roadblocks to those studies," Begley noted. "We're telling major drug companies to test on children, but there's a risk. They'll have some difficulty if an institutional review board looks at the Kennedy Krieger study, especially if it involves healthy children, and won't approve it."

Comfort from clarification

Yet Richard Turman, director of federal relations at the Association of American Universities in Washington, said he doubted the opinion will have any effect nationwide. "I know the case was watched closely at campuses across the country," said Turman, whose organization represents Hopkins on Capitol Hill and filed an amicus brief in support of Kennedy Krieger in its motion for reconsideration. "But I'm not aware of any concern since the clarification."

Dr. Gary Goldstein, president of Kennedy Krieger, said the October clarification by the court removed any roadblocks to clinical trials involving children as long as federal guidelines are followed. He estimated "several hundred" such trials are under way in Maryland, with about a third categorized as non-therapeutic (meaning the study is not designed to treat the child-subjects).

"Essentially, legal experts here and at Johns Hopkins say they don't feel any limitations beyond the federal requirements were put on and that there is no change," Goldstein said in an interview. "Whether there was more than a minimal risk [to the plaintiffs in the two suits filed against Kennedy Krieger] will come out at trial. I don't think the court made any change. But they stirred up controversy."

At a hearing earlier this week in Annapolis to consider whether additional legal immunity should be extended by the General Assembly to research institutions (a briefing scheduled after the August opinion, but before the October clarification), Assistant Attorney General Jack Schwartz said no new laws are needed.

"Do we need immediate legislative action? No," said Schwartz, the director of Health Policy Development in the attorney general's office, when briefing the House Appropriations Health and Human Resources Subcommittee on Tuesday.

Goldstein, who also spoke at the briefing, agreed. "I don't think there's any implication [from the Court of Appeals opinions] to the research climate in Maryland," he said. "Everyone at Johns Hopkins feels the same way."

One legal expert, however, warned that if the General Assembly were to increase immunity for researchers, the Court of Appeals opinion could backfire and work against the interests of children enrolled in non-therapeutic studies.

"Sadly, if this does create a legislative push for immunity, ironically this opinion could result in more harm to children by virtue of research institutions being able to operate with immunity," said Michele E. Gilman, a law professor at the University of Baltimore and head of UB Law's community development clinic. "They're going to spin gold out of straw."

An attorney involved in the litigation, speaking on condition of anonymity, said researchers not involved in the Kennedy Krieger case may not understand the "nuances" of the opinion. "It really is back to the federal regulations," the attorney said. "But others may view it as a dramatic new rule, leaving them open and exposed. I hope not. But there are researchers out there who may back away from doing research.

"But most people in the Maryland research community know that things are better [following the October clarification]," the attorney added. "So maybe we shouldn't be worried about perceptions down the road."

Landmark Decision

While many expressed concerns over possible repercussions from the Court of Appeals rulings, one expert on child welfare issues praised them, saying, "They will change the face of medical research in America."

"It's a landmark decision," said Howard Fishman, a member of the steering committee of the Alliance for Human Research Protection, a self-funded advocacy group concerned with protecting the rights of human research participants and the director of continuing medical education at Harvard Medical School. "Much to my relief, the court has intervened with a broad and sweeping statement of ethical requirements."

Fishman, a former Montgomery County resident who lives in Philadelphia, said child advocates in other states "undoubtedly" will use the opinion to petition their own courts for additional safeguards on behalf of children and disabled adults.

He also praised Congress' extension of patents in exchange for validating appropriate dosages of drugs for use on children.

"But Congress didn't deal with the ethical issues of testing the drugs on healthy children," said Fishman, who explained that initial drug trials often are performed on healthy children before moving on to test a drug's efficacy on sick children. "It's generally believed that medical science is an unalloyed boon to mankind, and we tend not to be skeptical of medical research."

Yet history shows that science is "ethically neutral" and gives "little consideration" to the application of new knowledge, noted Fishman, the lead author of the only amicus brief submitted on behalf of the plaintiffs on Kennedy Krieger's motion for reconsideration.

"That's the reason for international ethical codes and the establishment of Independent monitoring agencies such as IRBs," Fishman continued. "It is essential that the autonomy of IRBs be maintained. But the IRB system, as it is currently structured, co-opts IRB members and undermines the ethical safeguards."

That's an issue the Court of Appeals addressed head-on, Fishman said: "The Johns Hopkins IRB became accomplices to the researchers with the intent of circumventing ethical standards."

For a fuller understanding of the ethical debates over human-subject research, Fishman suggested following the "money trail."

"Federal funding and research funding by major pharmaceutical manufacturers determine the research agenda," Fishman said. "Major academic institutions have found themselves to be dependent on these funding streams.

Particularly in this era of deconstructionism [a term Fishman defined as the perceived right to reinterpret the author's original intent], moral relativism and muticulturalism," he said, "it's easy for institutional stakeholders to succumb to the temptation to blur ethical rules."

"One sees repeatedly an effort to obfuscate facts and the use of rhetorical devices to justify otherwise unacceptable procedures," he added.

An example: "Kennedy Krieger seems to suggest the risks to medical research are analogous to the everyday risks of life," Fishman said. "These kinds of statements raise our concern that research institutions view ethical safeguards as inconveniences that should be circumvented."

Fishman praised the Court of Appeals for another aspect of its August opinion. "A related concern expressed by the court is the need to provide protection -- specifically for the poor and less educated who bear most of the research burden,'" Fishman said, quoting the opinion. "Research harms are visited disproportionately on poor and minority children."

Fishman also pointed to an "inherent and natural" tension between the needs of science and the protection of the public.

"Over time, we've established the primacy of the rights and inviolability of the individual," he said. "Probably the greatest deficiency is the absence of an answer to one question: äwhen should the value of advancing medical knowledge take primacy over the protection of citizen-subjects?"

The dilemma, he said, can be resolved -- but at a cost.

"The bottom-line answer is that clearly medical research will slow down as a result of this opinion," Fishman said. "That's the price we'll pay."

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