CHOC Found at Fault on Consent Procedures

A federal audit conducted in March found eight cases in which a research team at Children’s Hospital of Orange County failed to follow procedure in obtaining consent from patients or their families for experimental treatments, according to a report obtained by The Times.

In two of the cases, characterized by experts as the most serious, treatment started before consent forms were signed, and in one of those consent was obtained over the phone rather than in person.

In a third case, the audit found, the person involved appeared “incompetent to sign informed consent.”

The audit of 62 patients’ records was conducted by a multi-agency team that included the Children’s Cancer Group, the National Cancer Institute and the Office of Research Integrity, which fall under the National Institutes of Health, and the U.S. Food and Drug Administration.

Investigators reviewed government-supported medical research that was supervised by Dr. Mitchell Cairo, the oncologist known for attempting an experimental transplant last year to save baseball Hall of Famer Rod Carew’s daughter. And the final report on their findings, completed in late April, resulted in Cairo being suspended for six months as CHOC’s head investigator for the Children’s Cancer Group, a national research collaborative.

The audit report indicates that investigators found what they considered “only a few deficiencies” in the area of informed consent, but it noted that investigators had not focused on that area.

Children’s Hospital medical director Robert L. Manniello said he could not comment on specific cases reviewed by the audit. However, he said a special committee of the hospital’s Institutional Review Board is reviewing the entire consent process in an effort to improve it.

The committee is looking at all research performed at CHOC, not just those studies conducted as part of the Children’s Cancer Group, Manniello said. However, he would not comment on whether problems have been identified that go beyond the scope of the audit.

“The [board] is actively looking at the issues brought forth by the NCI/CCG special audit,” Manniello said. “They are looking at each individual record and looking at our entire process of informed consent, not only for CCG studies but for all research carried out at the institution.”

CHOC is where many of the county’s sickest children go, including those with terminal illnesses for whom experimental treatment might be the only hope.

Manniello said that according to procedures spelled out by the Institutional Review Board, “informed consent needs to be taken prior to the start of any” experimental therapy.

Cairo characterized the problems as “minor consent issues that come up in normal audits.”

In an interview Wednesday, he noted that the audit team did not feel that those issues needed further evaluation.

“We take very seriously providing informed consent to any patient going on a clinical research trial,” Cairo said.

The Times previously reported that a summary of the audit also cited cases in which ineligible patients were put on experimental treatments, and in which researchers failed to follow procedure in taking other patients off such treatments.

Cairo has characterized those findings as “not serious because they do not fall under anything that would be considered misconduct in research.” Allegations of research misconduct had prompted the audit but proved unfounded, according to the report.

In a written appeal of his suspension, Cairo said that the two cases involving ineligible patients occurred before he became the hospital’s top investigator for the research cooperative. He said that in most of the nine other cases, contrary to the audit’s findings, patients were taken off protocol within the group’s guidelines or standard treatment guidelines. He said most of them were removed because of their disease status, reactions to toxic therapy, or consultations with other medical experts.

Regarding the audit’s findings of problems with informed consent, the report obtained by The Times instructed the hospital to deal with informed consent findings through its Institutional Review Board, which under federal law is charged with protecting human subjects in research.

Bioethicists say that even a few deficiencies unearthed in a limited review of patient cases at the hospital, such as this one, could signal problems in that area.

Christopher Hook, a hematologist/oncologist and medical ethics expert at the Mayo Clinic in Rochester, Minn., called starting treatment before consent is obtained “a significant violation, not only of the doctrine of informed consent, but also of the federal regulations.”

“By all of the federal regulations and just by the basic principles of informed consent, that would be a violation of those principles,” said Hook, who also stressed that he could not address the specifics of the CHOC cases.

Placing a patient on treatment before consent is obtained is “problematic,” said Stephanie J. Bird, the Western Hemisphere editor for Science and Engineering Ethics.

“It’s not appropriate to start somebody on a study until you’re sure that they want to participate,” she said. “One of the problems with informed consent is the process is sometimes ‘I’ll tell you enough until you agree with me.’ But that isn’t the spirit of the activity. It’s really extremely important that this not indicate a flaunting of the process.”

Bird said she could not comment on the specifics of the Children’s Hospital case, but she said “eight [violations] out of 60-plus doesn’t seem like a horrendous number.”

They could be indicative of a larger problem, however.

“You want to make sure that those eight aren’t the tip of the iceberg,” Bird said.

Dr. Richard Mowery, chief of the National Cancer Institute’s clinical trials monitoring branch, said he also was concerned about the two cases in which patients were started on a chemotherapy regimen that became part of the study before they gave consent to be research subjects. He said that while that problem isn’t unusual at cancer research centers, the proper way is for patients and their families to be informed and consent obtained before the study begins.

He also expressed concern that in one of those two cases, researchers obtained a patient’s consent by phone, rather than in person.

“Obtaining a consent by telephone I personally think is not a very appropriate thing to do,” he said. “For a patient to be fully informed, they need to have a face-to-face discussion [with the practitioner].” The patient must be given a consent document and have a chance to answer questions before signing it.

In addition, the audit found that two consent forms were not signed by a physician, as required, and one of those also lacked a witness signature; one was signed, but otherwise incomplete; another was not dated; and another was not placed in the medical record, although a copy was located in the charts of the research group.

The federal watchdog agency for protecting human subjects in research is monitoring the situation at Children’s Hospital.

“We are in an inquiry phase on this matter,” said Tom Puglisi, director of the division of human subject protections for federal Office of Protection From Research Risks. “We have received preliminary information from the hospital. Additional information is expected. . . . Then we will determine if a formal investigation of human subjects protection at Children’s Hospital is warranted.”