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Lawsuit filed re: ALLHAT Hypertension research death of human subject

Thu, 17 Jul 2003

The Bureau of National Affairs reports: "Just months after a groundbreaking blood pressure study made headlines across the nation, a principal investigator in the trial and his team have been sued in connection with the death of a 60-year-old participant." (Scheer v. Burke, Pa. Ct. complaint filed by attorney Alan Milltein on July 10).

The widow of Dr. R. Scott Scheer, a radiologist, sued Dr. James F. Burke, the principal investigator of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Clinical Trial (ALLHAT) at Lankenau Hospital in Wynnewood, Pa.

The suit alleges that the dangers of the trial were concealed to convince her husband to sign up. The suit further alleges that the researchers did not follow the study rules once he was enrolled, and that the vasodilator hydralazine, one of the other drugs used in the experiment, was misused and ultimately killed Scott Scheer.

The multi-site ALLHAT experiment involved 10,300 patients. It found strong evidence that low-cost, generic diuretics were more effective than expensive, brand-name calcium channel blockers and ACE inhibitors in lowering blood pressure and preventing heart attacks and strokes." It was hailed by the medical establishment as "one of the most important trials of antihypertensive therapy" in medical history.

But the experiment was the subject of a federal investigation by the Office of Human Research Protection (OHRP) which found that the IRB lacked sufficient information to justify its approval; that informed consent documents failed to describe the foreseeable risks--such as the risk of hydralazine-induced lupus; and that the potential benefits were overstated; misleading patients into becoming subjects.

The ALLHAT patient brochure stated: "if you agree with us [and participate in the ALLHAT trial], we promise to make every effort to safeguard your welfare and provide the best possible care for your high blood pressure and high cholesterol."

This is an example of how patients are being misled into believing that experimental treatment in the context of research is therapeutic and in their "best interest." In fact, within the research context, patients are randomized to treatments that may be against their best interest. In clinical practice, treatment is selected because it is intended to serve the individual patient's best interest.

This case is yet another example of systemic failure by the current research protection system—in particular, failure by the authorized IRBs who are responsible for ensuring that (a) human subjects are protected from harmful experiments, and (b) ensuring that the recruitment process and informed consent documents comply fully with federal regulations and full disclosure requirements. IRBs are empowered to evaluate the scientific and ethical justification of research prior to approval. IRBs are also responsible for monitoring adverse effects that may require a re-assessment of the risks.

It is unfortunate IRBs are taking their cue from the major stakeholders of the medical research community, and have not yet owned up to their responsibility and the significance of their failure—as documented by OHRP-- to protect research subjects. A culture of avoidance reigns even as an embarrassing cascade of public disclosures reveal that IRBs across the nation are failing to prevent research abuses at their institutions.

The most recent controversy surrounding two radical ARDSNetwork experiments that violated the ethical standards set forth in the Declaration of Helsinki: "The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods." [Article 29]

The ARDSNet investigators disregarded standard of care practice exposing 1,261 critically ill patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) to increased risk of death.

OHRP's investigation revealed systemic failure, and a research establishment that is out of control. See: OHRP July 3 letter of findings http://ohrp.osophs.dhhs.gov/detrm_letrs/YR03/jul03a.pdf ]

Of note: for well over a year, almost all AHRP Infomails have been blocked from the IRB Forum, a discussion group comprising about 3,000 gatekeepers of research involving human subjects. Members of the IRB Forum include professional IRB members from academic and commercial research review committees, public officials, and a few non-affiliated individuals. The Forum is supported by the University of Pennsylvania).

Most notably, the censored AHRP Infomails relate to research abuses, harm to human subjects, and federal investigations. Indeed, information about federal investigations and determinations--by OHRP and the FDA-- have rarely make it through the listserv for discussion. Indeed, there has been little if any discussion on the IRB Forum about the ARDSNetwork debacle--not about IRB approved consent failure to disclose the essential risks, or failure to obtain legally valid consent; not about research designs that increase risk of death for subjects, not about the ethics of withdrawing critically ill patients from best standard of individualized care and abruptly randomizing them to rarely used, experimental methods--independent of patient need; not about the failure to systematically monitor mortality rate during the trial-- to avoid preventable deaths.

Who, if not the federally authorized, professional IRB community should be discussing these issues?

~~~~~~~~~~~~~
Below two articles from BNA's Medical Research Law & Policy Report:

http://www.bna.com/products/health/mrlr.htm

July 16, 2003

ALLHAT Team Sued for Death of Subject;
Lack of Informed Consent, Negligence Cited

By M. Alexander Otto

Just months after a groundbreaking blood pressure study made headlines across the nation, a principal investigator in the trial and his team have been sued in connection with the death of a 60-year-old participant (Scheer v. Burke, Pa. Ct. Com. Pl., number not available, complaint filed 7/10/03). The widow of Dr. R. Scott Scheer July 10 sued Dr. James F. Burke, the principal investigator of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Clinical Trial (ALLHAT) at Lankenau Hospital in Wynnewood, Pa. Scheer died July 15, 2001, following three-and-one-half years in the trial. The 10,300-patient, nationwide ALLHAT grabbed headlines in December 2002 for providing strong evidence that low-cost, generic diuretics were more effective than expensive, brand-name calcium channel blockers and ACE inhibitors in lowering blood pressure and preventing heart attacks and strokes. A Dec. 14, 2002, Journal of the American Medical Association editorial declared ALLHAT "one of the most important trials of antihypertensive therapy" in medical history. But in her lawsuit, which was filed by attorney Alan C. Milstein, Beverly H. Scheer alleged the ALLHAT team at Lankenau concealed the dangers of the trial to convince her husband to sign up and did not follow the study rules once he was enrolled. Misuse of the vasodilator hydralazine, one of the other drugs used in the study, ultimately killed Scott Scheer, the suit alleged. Scheer was a consulting radiologist before he enrolled in ALLHAT.

Suit Follows OHRP Determination Letter

The federal Office for Human Research Protections found similar problems in a November 2002 determination letter to the hospital. Patients were not told of "any reasonably foreseeable risks and discomforts," including the risk of serious hydralazine side effects, OHRP said. Lankenau's institutional review board failed to update doses, informed consent forms, and eligibility requirements when other study centers made changes, and adverse events were not reported fast enough (1 MRLR 571, 12/4/02 ). In August 2002, Kristina Borror, director of the OHRP Division of Compliance Oversight, questioned how randomized subjects could be guaranteed the "best possible care," as the consent form Scheer signed promised, according to the complaint. Lankenau also promised potential subjects the study "would help people like you ... lead more productive and longer lives." JAMA reported that patients who got the calcium channel blocker had a 38 percent increase in heart failure compared to the diuretic group. Milstein, who practices with Sherman, Silverstein, Kohl, Rose & Podolsky in Pennsauken, N.J., told BNA he was aware of the determination letter when he filed, and that Beverly Scheer sought out his help. He plans no additional ALLHAT lawsuits are planned at present. OHRP told Lankenau it was satisfied with the hospital's corrective action plan in a January 2003 follow-up letter (2 MRLR 69, 1/15/03 ). Burke's attorney, Judy Mackarey, with Mackarey, Sunstein, Murphy & Davidson, Philadelphia, had no comment pending review of the complaint.

Drug-Induced Lupus.

Scheer developed soft tissue swelling (edema) during the trial, but Dr. Michael J. Duzy, the co-defendant who cared for Scheer, continued to increase the dose of the blinded drug--which turned out to be the calcium channel blocker, a known cause of edema--without investigating, the lawsuit alleged. He then prescribed hydralazine, another edema-causing drug, in response to a slight blood pressure increase in 1999. Lankenau's ALLHAT patients never were told of the risk of edema, which can cause permanent tissue damage, venous insufficiency, and death from blood clots or bleeding, according to the complaint. The swelling worsened and Scheer developed lupus--another side effect of hydralazine--in 2000, but was kept on the drug until days before his death in July 200. He also developed an abnormal electrocardiogram, muscle pain, and cataracts, all of which were likely caused by study drugs but either went unreported or uninvestigated in violation of ALLHAT protocols, the complaint alleged. Scheer should have been pulled from the trial when the lupus progressed to kidney damage, an ALLHAT endpoint, but he was not, the suit stated. The radiologist was killed by a blood clot in his lungs, "a consequence of drug induced lupus and end-stage rapidly progressing [kidney damage] brought on by the continued ingestion of hydralazine," the complaint explained. Scheer and other Lankenau patients were not told their blood pressure would be treated experimentally rather than according to medical standards that dictate starting patients on a diuretic and beta-blocker, the complaint said. Scheer rated his health as "very good," a 90 on a 100-point scale, just before entering the trial. The lawsuit seeks damages in excess of $50,000 on each of seven counts including wrongful death, lack of informed consent/battery, common law fraud/intentional misrepresentation, negligence on the part of the Lankenau IRB, and breach of fiduciary duty. In addition to Burke and Duzy, Lankenau Hospital, parent company Main Line Hospitals Inc., and the Main Line IRB are among the named defendants. Milstein understands the value of ALLHAT, but said researchers need to "do what you say you are going to do; give everyone care at least as good as the best standard care; and tell [subjects] what drugs are in the study, when they will be administered, and what the risks might be." The ALLHAT lawsuit and a separate complaint filed against Genentech Inc. are the latest in a string of suits Milstein has brought on behalf of patients injured in medical studies and their relatives (see related item in the News section ). He first won fame as a human subject plaintiff's attorney by representing the family of Jesse Gelsinger, an 18-year-old killed in a University of Pennsylvania gene therapy experiment in 1999. The school settled for an estimated $10 million.

By M. Alexander Otto

Copyright © 2003 by The Bureau of National Affairs, Inc., Washington D.C.

http://www.bna.com/products/health/mrlr.htm
BNA's Medical Research Law & Policy Report
Volume 2, July 16, 2003
Human Subject Protection
OHRP OKs ARDSnet Trial With Conditions;
Researchers Working to Resume Enrollment
By M. Alexander Otto

A controversial, multi-site acute respiratory distress syndrome (ARDS) trial can resume, but only after informed consent forms are rewritten to provide more information and institutional review boards re-review the study in light of additional information, the Department of Health and Human Services Office for Human Research Protections said July 3 in a letter to three of the several universities involved in the project.

The trial compares liberal versus conservative fluid replacement in patients with the often-fatal lung condition. The National Institutes of Health, which is funding the experiment, halted the trial in July 2002 after a five-member review panel concluded ARDSnet, a consortium of pulmonary and critical care specialists at 24 hospitals in the United States, used an invalid control and inadequate patient protections in an earlier trial comparing ventilator tidal volumes (1 MRLR 428, 10/2/02).

About 400 patients were enrolled at the time with another 600 planned. The 19 study centers and 40 affiliated hospitals participating in the trial expect to resume enrollment in about a month, the time investigators say they will need to address OHRP's concerns, said Dr. Herbert P. Wiedemann, chairman of the Cleveland Clinic's Department of Pulmonary and Critical Care Medicine and study chair of the fluid replacement trial.

OHRP said July 3 that ARDSnet researchers did not give IRBs enough information in both the fluid replacement and ventilator trials. Among the cited deficiencies, investigators never explained how or why they chose to compare two experimental treatments, instead of an experimental procedure against a standard one. They also did not inform board members about standard treatments used in the their own hospitals, the letter said.

Patients were not told they would be randomized to experimental treatments and could die as a result, nor were they told they could choose alternative, standard-of-care therapy, OHRP said. The fluid replacement trial must be re-reviewed and consent forms reworked in light of such findings, the office said. A team of eight consultants helped OHRP reach its conclusions, according to the letter. OHRP Seeks Bioethicist Help. OHRP acknowledged that, until the ARDSnet studies, there was no universally applied standard ventilator tidal-volume setting for acute lung injury and ARDS patients. Decisions were made based on best clinical judgment. The office twice in its letter asked the scientific and bioethics communities for help in determining how ethically to compare treatments when no true standard exists, commenting that "the interests of future human subjects would be served best by further discussion" of the issue. The office said one approach might be to rely on local standards if universal standards are lacking.

Patient advocate Vera Sharav, founder of the Alliance for Human Research Protection, said the July 3 letter vindicated her concerns. "You cannot bypass standard of care and expose patients to two experimental treatments when the risk is death," she told BNA.

A better way would be to compare an experimental group against patients whose ARDS treatments are customized to their individual needs, as is usually the case. Patients fared worse when plucked from individualized care and randomly assigned tidal volumes in the ARDSnet trial that studied tidal volumes, she said, adding that the group's work remains "a scandal."

However, Wiedemann said ARDSnet investigators read an entirely different message into OHRP's letter. By allowing the fluid management trial to resume, the office said it is permissible to compare two experimental treatments within the range of those used when a standard approach is lacking, the Cleveland Clinic researcher said.

OHRP "has ruled the trial does not violate federal law. This is huge, in our view, and a major validation of our approach. The design of our trial was not faulted, and the trial can resume with the exact same design we started with," he said. In the April 3 issue of The New England Journal of Medicine, two ARDSnet researchers criticized OHRP for its pursuit of their work, claiming the office had no authority to question the scientific merits of any study, only its adherence to federal study safety rules (2 MRLR 340, 5/7/03). OHRP had questioned whether comparing experimental treatments had value in a December 2002 determination letter demanding to review ARDSnet patient records. By M. Alexander Otto

Copyright 2003, The Bureau of National Affairs, Inc., Washington, D.C.

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