The Brigham & Women’s Hospital has halted a controversial study that combined power morcellators with “containment bags” intended to capture tissue during minimally invasive gynecological surgery.
Launched earlier this summer, the study was designed to enroll 400 women to test dye leakage in several commercially available bags that have not been cleared by FDA for use with power morcellators.
The power morcellator cuts uterine tissue into small fragments that are then removed through small incisions. When it hits undetected uterine cancers, the device can spread the disease (The Cancer Letter, July 4).
“BWH is pausing the study while, together with our collaborators, we consider the FDA guidance,” Brigham officials said in a statement to The Cancer Letter.
Officials declined to answer questions about the number of patients that have been accrued to the study, which started earlier this year. A version of the consent form obtained by The Cancer Letter is dated May 2014.
In a safety communication issued Nov. 24, FDA declared power morcellators as contraindicated for removal of tissue containing fibroids in patients who are menopausal or post-menopausal, or in patients whose uterine tissue could be removed intact through the vagina or mini-laparotor.
A story on FDA’s guidance is available here.
On Nov. 20, prior to FDA’s restrictions on power morcellators, Brigham officials said in written response to questions from The Cancer Letter that the institution was conducting the study without an Investigational Device Exemption (The Cancer Letter, Nov. 21).
Officials at Brigham, a member institution of Partners HealthCare, a Harvard hospital network, said the study did not require the agency’s license allowing clinical testing of potentially high-risk devices.
By inference, this would mean that the Partners HealthCare IRB, which is separate from Dana-Farber Cancer Institute’s IRB, had concluded the study to be of “minimal risk,” and therefore did not see the need for an IDE submission.
When this reporter asked FDA officials to comment on the Brigham study during a press call, William Maisel, deputy director for science and chief scientist at the FDA Center for Devices and Radiological Health, said that the study should have been conducted only after an IDE has been approved.
“Whether or not we issued this warning, we believe that the investigational use of containment bags is a significant-risk device, and would require submission of an Investigational Device Exemption,” Maisel said at the press call Nov. 24.
“Clearly, there’s a difference of opinion between the Brigham and its decision-making system, and what the FDA has now declared,” said David Challoner, emeritus vice president for health affairs at the University of Florida.
Challoner chaired the Institute of Medicine committee tasked by FDA and Congress in 2009 to review the 510(k) process that clears Class II devices such as the power morcellator based on predicate devices.
“If I were them, I’d stop the study right away, until this gets clarified, or until they have an IDE,” Challoner said to The Cancer Letter.
Approving the investigational use of a significant-risk device without submitting an IDE could prompt an FDA review of the institution’s IRB.
“Brigham, by having approved their study, could bring FDA in to look at their whole IRB process,” said Bill Vodra, a former FDA associate chief counsel for drugs. “I don’t know if FDA will do that, but obviously there is a risk of that.”
Vodra helped draft many agency regulations still in use, including those implementing the Controlled Substances Act and FDA’s rules for Good Manufacturing Practices, Good Laboratory Practices, Good Clinical Practices, bioequivalency and the Orange Book.
“The penalty is the IRB may not do IRB activities anymore,” Vodra said to The Cancer Letter. “What the institution would have to do then is to reconstitute the IRB.
“FDA is not in the business of trying to shut down clinical research. Its goal is to make sure research is done ethically and safely,” said Vodra, a retired partner of Washington, D.C., law firm Arnold and Porter. “And so if FDA finds an IRB or an institution is sloppy in not instituting the proper ethical or safety standards, the remedy is to go in and get it straightened out.”
FDA: Bags Not “Panacea”
Rick Kaitz, a Boston real estate lawyer whose wife, Erica, died in December 2013 from leiomyosarcoma upstaged by power morcellation at Brigham, said the hospital should permanently stop the study (The Cancer Letter, Nov. 21).
“Pausing it is a good first step, but I think it should be preliminary to stopping it,” Kaitz said to The Cancer Letter. “That study doesn’t make sense. It’s playing a game of chance with women’s lives, and you’re not supposed to do that.
“Dye is not cancer cells. And a study without a significant number of women with malignancies won’t work. And what woman with a malignancy in her right mind would ever enroll for a study like that? It’s an absurd study, and the fact that it was ever IRB-approved was really troublesome.
“And, it was outrageous that the study was approved without talking to the physicians in the sarcoma center at Dana-Farber, Brigham’s sister institution.”
After Erica’s cancer diagnosis, she and Rick assembled a group of friends and supporters who have raised about $4 million for leiomyosarcoma research at Dana-Farber (The Cancer Letter, Nov. 21).
There is no guarantee that containment bags can prevent the spread of cancer via power morcellation, said FDA’s Maisel during the conference call.
“There are some in the clinical community who believe that the use of bags can reduce the spread of tissue within the abdominal cavity, and particularly, reduce the spread of cancerous tissue within the abdominal cavity,” Maisel said.
“This issue was discussed at [an FDA advisory committee hearing] that was held in July. One of the important factors for people to understand is that, with use of a bag, it’s not a guarantee that there will not be the spread of cancer. So the use of a bag is not a panacea.
“It also potentially can create other adverse events related to the reduced visibility in the abdominal cavity, injury to organs et cetera. The agency at this time is not either recommending or discouraging the use of the bag. We view that as an important issue that individual physicians, within their skill and understanding, should decide for themselves.
“That being said, the use of a bag does make inherent sense, and so, for those that do have the ability and skill for using it, it does seem like a reasonable idea.”
The study in question is led by Jon Einarsson, a Brigham surgeon who performed the “open”—unbagged—version of the procedure on Erica. Einarsson and another investigator, James Greenberg, have applied for or own patents on containment bags that are intended for use with power morcellators (The Cancer Letter, Nov. 21).
“I think if the science can be proven, in a non-risky and effective manner, then I’m for safe medical procedures,” Kaitz said. “To date, anything that I’ve seen about containment systems is premature and exceedingly risky, and really just a crapshoot.
“And you shouldn’t be taking a crapshoot with women’s lives.”
Kaitz said Brigham doctors had mischaracterized the risk his wife was facing when she underwent power morcellation, two years before Einarsson’s study was launched.
“They gave us numbers—one out of 10,000—that they knew to be wrong,” Kaitz said. “The Seidman, Muto article was published in November 2012. It says right in that article that multiple parties at Brigham said that the number they are quoting for the risk are nine times lower than the real risk.
“These are their own people who are saying that in 2012. Most, if not all of that data was in, I’m sure, by June 2012 when Erica was operated on.”
After Erica’s disease was upstaged, Brigham officials declined Kaitz’s demand for an outright ban on power morcellation at Harvard-affiliated institutions.
“Erica and I went through more medical stuff in the last two years than most people go through in their lifetimes, and I want to emphasize that the vast majority of physicians, nurses, and technicians were caring, sensitive and thoughtful,” Kaitz said. “That’s different from the system.
“The work system is incredibly insular, and arrogant. The reality is, they think that non-doctors don’t have a right to an opinion on anything that has to do with medicine. Well, guess what, they’re wrong.
“The minimally invasive surgeons have proven to be incapable of self-regulation. It has to do with the fact that doctors don’t want to step on other doctors’ toes. And for oncologists and the oncologic gynecological surgeons to say, ‘This procedure needs to be stopped,’ would be stepping on the toes and the livelihood of the minimally invasive gynecological surgeons.”
Vodra: The Risk of Patient Lawsuits
It’s not publicly known how many patients were enrolled in the Brigham study.
Vodra said that patients who have enrolled in the study, regardless of injury, could file lawsuits against Brigham for not conveying that the investigational use of containment bags with power morcellators carry significant risk.
“If any one of the subjects already treated in the study is injured in any respect, they can go back and sue on the grounds that they would not have participated in the study had they known it was a high-risk study, not a minimal-risk study,” Vodra said.
“In theory, even the patients who weren’t injured might sue for what we would call invasion of privacy. You have to consent to be touched.
“I can see a clever lawyer trying to make an argument on the fact that a doctor used a misleading consent form to perform an operation on a woman without telling her what the real risks were. Now, what the damages would be, I don’t know.
“There might be some sort of punitive damage or compensatory damage—I don’t know what the injury was other than a loss of control and autonomy, and invasion of privacy.”
Brigham’s first priority would be to resolve the dispute with FDA, Vodra said.
“It’s not a matter of looking at liabilities. As a major research hospital, you do not want to have FDA unhappy with you,” Vodra said. “It’s not what you want.
“If you’re hoping to send studies to FDA, in order to support applications for you or your contract with industry, and FDA says, ‘We can’t accept research from an institution that doesn’t have ethical standards,’ that’s going to dry up your research contract within minutes.
“What you would do is say, ‘OK, we’ll submit this as an IDE.’ And if FDA says, ‘We won’t allow that study to be done,’ then you say, ‘OK, we stop the study.’
“There is no sponsor in this study. Why would the hospital fight for anybody to continue doing the study if they are doing it?
“It’s not in their interest to fight FDA on the matter.”
Kaitz, who continues to raise funds for research at Dana-Farber, said he understands why patients and their families would seek recourse.
“It’s unfortunate that the medical system requires you to consider various alternatives that you would never ever want to consider in order to try and influence institutional change,” he said.
An interview with Amy Reed, formerly an anesthesiologist at Beth Israel Deaconess Medical Center, and Hooman Noorchashm, formerly a cardiothoracic surgeon at Brigham & Women’s Hospital.
