InfoMail for March 25, 2002

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News Stories on Human ResearchProtection and
Commentary by Vera Hassner Sharav

March 25, 2002

Federal Agency Does Not Adequately Enforce Federal Standards of Ethics andSafety.

FYI

The Boston Globe takes a critical look at the federalOffice of Human Research Protections (OHRP) and at its director, Dr. Greg Koski.The Globe reports that millions of people are subjects in 70,000 clinical trialsconducted at 3,000 institutions, but the agency has not been an adequateenforcer of federal ethics and safety standards.

OHRP “opened investigations in response to only 1percent of reports in 2001 from hospitals and universities that an unanticipated”adverse event” or death had occurred as a result of a research experiment.”

On Jan. 10, 2001 an Associated Press article described thedeath of a healthy nurse, Elaine Holden-Able, who was a research subject at CaseWestern University. Ms. Holden-Able died in April, probably as a result of anoverdose of a dietary supplement. AP reported that the University had notreported the death to OHRP for several months.

We examined OHRP’s subsequent letter of findings (Nov30, 2001), and noted in our Jan. 10 Infomail that Ms. Holden-Able’s death wasnot even mentioned in OHRP’s letter. For text of letter, please click on URL: http://ohrp.osophs.dhhs.gov/detrm_letrs/nov01f.pdf 

The Globe reports that although contradictions about thecircumstances of Ms. Holden-Abel’s death remain, OHRP has never interviewedhospital workers, who had denied making any mistake. "The agency reviewedand mostly accepted the hospital’s internal report, imposed no penalty, andclosed the case.”

We agree with Senator Edward Kennedy who noted: ”conflictof interest threatens the basic integrity of the system.”

We also agree with Sen. Kennedy that a single, independentagency should be authorized to provide oversight and enforcement of federalstandards to protect human subjects from undue harm.

We don’t agree that the FDA–which is currently under theundue influence of the pharmaceutical industry-could provide the much neededdependable oversight. A better choice would the Office of the Inspector General.

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http://www.boston.com/dailyglobe2/084/nation/System_for_protecting_humans_in_research_faulted+.shtml

System for protecting humans in research faulted

By Michael Kranish, Globe Staff, 3/25/2002

WASHINGTON – At 8:32 a.m. on April 4, 2001, ElaineHolden-Able, a healthy retired nurse, consumed a glass of orange juice that hadbeen mixed with a dietary supplement for the sake of medical research. TheAlzheimer’s experiment, financed by the tobacco industry, wound up killing herin what was called a ”tragic human error.”

The case seemed tailor-made for review by a little-knownfederal agency with the weighty title of the Office for Human ResearchProtections. But the agency, headed by a former top Boston hospital official,didn’t learn of the death until four months later. No official from the agencytraveled to Cleveland to interview hospital workers, who had denied making anymistake. The agency reviewed and mostly accepted the hospital’s internal report,imposed no penalty, and closed the case.

Even this modest inquiry was unusual.

The agency opened investigations in response to only 1percent of reports in 2001 from hospitals and universities that an unanticipated”adverse event” or death had occurred as a result of a research experiment.

Moreover, of the 100 cases the agency did examine lastyear, it conducted on-site visits in only four instances, according to agencyofficials. And its overtaxed staff believes many institutions are failing toreport such incidents at all.

As Congress is poised to consider the biggest overhaul ofmedical research laws in 28 years, the agency’s director, Dr. Greg Koski, saidin an interview that the system of protecting humans in medical research is in”critical” condition.

”It’s like a nuclear reactor,” said Koski, who wasdirector of human research affairs at Boston-based Partners HealthCare until heleft to head the newly reorganized federal agency in December 2000. ”Actionsneed to be taken to prevent the system from melting down.”

The agency’s problems are largely due to outdatedregulations that don’t protect participants equally in various types of medicalexperiments. The agency also has just 47 employees – including only fiveinvestigators – who rely mostly on reports from overburdened voluntary panels atuniversities and hospitals. And it is trying to keep up at a time when humanexperimentation has proliferated, with a doubling of the federal research budgetin the past five years.

The bottom line is that, today, a private researcher mustreport to the government about experiments on cats and dogs, but not necessarilyon human beings. ”That is not an acceptable situation,” Koski said.

Millions of Americans participate in an estimated 70,000clinical trials conducted by industry- and government-sponsored researchers eachyear. The reporting and investigative system is so strained that Koski said itwould take 10 years to fix it ”to my liking.” While Koski stressed that mosthuman medical experiments are safe, he said a series of highly publicized deathsat some of the nation’s most prestigious institutions have highlighted the needfor major reforms.

Koski said he is sure that some of the nation’s 3,000institutions involved in medical research are under-reporting information aboutunexpected adverse events to the government. From 1990 to August 2000, theagency that was the forerunner to the one Koski leads received just 386 reportsof adverse events. But 158 of those came from a single institution, the StateUniversity of New York at Buffalo, which now says it was ”overzealous” inreporting incidental problems.

”The numbers are just ludicrous,” said University ofMaryland professor Adil Shamoo, a member of a government advisory board on humanresearch protections.

By contrast, pharmaceutical companies investigating newdrugs have been far more likely to provide reports of ”adverse events” to theFood and Drug Administration. The FDA received 241,000 such reports between 1987and 2001, according to CenterWatch, a Boston group that monitors clinicaltrials. While the FDA has jurisdiction over twice as much research and has abroader definition of adverse events, the disparity between the number ofreports received by the agencies remains striking.

Congress enacted landmark legislation 28 years ago calledthe National Research Act, which was aimed at protecting humans in medicalresearch. The law was passed following reports of government involvement inexperiments that wound up killing subjects who could have survived with propercare, including black men in a syphilis study.

Senator Edward M. Kennedy, who chaired those hearings,said in an interview that he now wants to enact the biggest overhaul of humanresearch protections since he shepherded the National Research Act throughCongress in 1974. Kennedy hopes to enact legislation that may centralize thegovernment’s oversight of human research, possibly by moving Koski’s agency intothe FDA. Kennedy also wants to make changes that would require more training inmedical ethics and restrict most researchers from having financial stakes in theoutcome of their experiments.

When researchers can stand to gain personally, Kennedyargued, ”The conflict of interest threatens the basic integrity of thesystem.”

Last year, in addition to the little-publicized death ofHolden-Able, a healthy volunteer at Johns Hopkins University in Baltimore diedduring an asthma trial. When Koski’s agency froze federal research funding toJohns Hopkins, the university blasted the government for going too far. But anexternal review commissioned by the university concluded that its system ofreviewing experiments was ”grossly inadequate.”

The external review of the Johns Hopkins case underscoredthe biggest issue facing Congress: whether the system of volunteer,self-policing ”Institutional Review Boards” at universities and hospitals canadequately protect human volunteers in medical research. The Johns Hopkinsreview board never fully discussed the asthma experiment as intended under thelaw, the review found.

Kennedy views these boards as a major problem, saying theyare ”overworked and underfunded.”

Holden-Able, whose case has received far less attentionthan the one at Johns Hopkins, died after receiving an overdose of what isusually a harmless dietary supplement, investigators concluded.

A Case Western University researcher, working from a $1million grant provided by the tobacco industry to study whether cigarettesmoking slowed the onset of Alzheimer’s, had money left over for a relatedexperiment. The researcher wanted to know how the supplement, methionine, wasconverted by the body.

According to documents received in a Freedom ofInformation Act request, Holden-Able signed a form that said, ”I understandthat the risks of my participation in this study are minor.”

She took the mix of orange juice and methionine, and hadher blood drawn. Within hours, she became demented and seriously ill, governmentofficials said.

Case Western informed the federal agency of the illness,but did not report her demise until Aug. 8. She died May 6.

An investigation by Case Western’s review board concludedthat Holden-Able died as a result of an overdose of methionine. It was a”tragic human error,” said Eric Cottington, Case Western’s associate vicepresident for research.

Although the hospital worker who administered the dosedenied the charge to the school, federal officials did not see the need totravel to Cleveland or interview the hospital workers to resolve the conflictingaccounts. Case Western issued a press release saying it had satisfied thegovernment’s concerns, and the file was closed.

Koski, asked about the matter, said there was no reason togo to Cleveland even though it was one of only two deaths reviewed last year byhis agency. He said the matter was ”thoroughly investigated” by Case Westernand reviewed by his agency.

He said he was satisfied because his review noted some”deficiencies” in Case Western’s review board and the hospital agreed tomeasure dietary supplements more carefully. There was no systemic problem atCase, unlike at Johns Hopkins, he said.

”The goal here is not to punish,” Koski said. ”Thesystem is not expected to be punitive. The goal is to make sure the systemworks.”

As it happens, the person who appointed Koski to his postdoes think punishment is a good idea. Donna Shalala, who was secretary of healthand human services in the Clinton administration, said she proposed that thegovernment levy fines in the most serious cases: a $250,000 penalty onresearchers and $1 million on institutions. But she said universities andhospitals fought the idea so strongly that it died.

”The health care system has always held itself to adifferent set of rules,” said Shalala, now president of the University ofMiami.

The idea of major new regulation is not welcome news formany of the nation’s medical schools.

Dr. Jordan Cohen, president of the Association of AmericanMedical Colleges, agrees that major changes are needed to protect humans inresearch. Indeed, he said, conflicts of interests are ”essentiallyubiquitous.”

But Cohen said the solution is to let medical schoolsvoluntarily adopt tougher rules, including accreditation of review board membersand a ban on most conflicts.

Still, Cohen said the schools do want something fromCongress: new funding to help pay for better review boards.

Michael Kranish can be reached by e-mail at kranish@globe.com.

This story ran on page A1 of the Boston Globe on3/25/2002.
© Copyright 2002 Globe Newspaper Company.

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