publication date: Nov. 21, 2014

As FDA Weighs its Options on Morcellation, Debate Erupts Over Harvard Device Study

Here is what we know: A surgical device used to perform about 100,000 hysterectomies and myomectomies every year in the U.S. has been shown to spread cells from undetected or missed uterine cancers—rapidly upstaging the disease.

And here is what we don’t know: What will FDA do about it?

The agency is under pressure to respond to the growing outcry from patient advocates, who want a ban on the device.

On the other side of the morcellation debate, major gynecologic organizations generally favor continued use of the minimally invasive device for hysterectomies and fibroid removal. And of course, some manufacturers want to keep selling power morcellators.

As FDA develops a strategy for balancing its legal authorities and moral imperatives, it has the following options:

• Ban, recall, or issue a warning on the risks of using the power morcellators for hysterectomies and myomectomies;

• Order device manufacturers to resubmit the power morcellator through the Class III high-risk device approval protocol;

• Put a black box label on the devices—FDA’s sternest warning for significant risk of serious or life-threatening adverse effects;

• Request more data via post-market surveillance studies, which can include registries and controlled trials.

Patient advocates, who propelled the controversy to the top of FDA’s must-do list, have the highest imaginable expectations from the regulatory agency. They are demanding fundamental change in the levels of evidence required for market clearance of a class of devices that include power morcellators.

Ultimately, they are looking to FDA to give meaning to the catastrophes that struck them by preventing harm from coming to others.

“It goes back to the Hippocratic Oath, ‘Do no harm.’ You’re dealing with entrenched economic interests that shouldn’t have gotten to where they are today,” said Rick Kaitz, a Boston real-estate attorney and a donor to Dana-Farber Cancer Institute, a Harvard-affiliated institution.

Kaitz’s wife, Erica, died Dec. 7, 2013, after she underwent power morcellation at Brigham & Women’s Hospital, a member institution of Partners HealthCare, a Harvard hospital network. It contributed to the upstaging of her fatal leiomyosarcoma.

After her cancer diagnosis, the Kaitzes assembled a group of friends and supporters who have raised about $4 million for leiomyosarcoma research at Dana-Farber.

For almost a year after his wife’s death, Kaitz worked behind the scenes to convince Harvard-affiliated institutions to ban power morcellation altogether. He has not spoken publicly with reporters on power morcellation before. A television news story by Boston’s ABC affiliate about Erica’s cancer, her post-diagnosis experience, and the couple’s efforts to fundraise for leiomyosarcoma is posted here.

Today, Kaitz is disappointed by Brigham’s launch of a prospective study focused on using power morcellators inside containment bags. The study is led by Jon Einarsson, the Brigham surgeon who performed the “open”—unbaggedversion of the procedure on Erica.

“I’ve given Brigham, privately, the opportunity to do the right thing about 10 different times and 10 different ways,” Kaitz said to The Cancer Letter. “I told them last June in a written exchange—including to the associate general counsel and chairman at Partners HealthCare, amongst others—that I would not go public, and I would not sue if Partners instituted a permanent ban on power morcellation.”

Kaitz said the health care system considered his request “for a while” and declined to institute a permanent ban.

A total of 400 patients will be enrolled in Brigham’s study across several Partners institutions.

“This is a prospective study to evaluate the feasibility and safety of electromechanical morcellation within a containment system (bag) during laparoscopic myomectomy or hysterectomy,” Brigham officials said in a statement to The Cancer Letter. “There are no study sponsors. The study coordination is done internally at BWH, and there is no industrial support for this study.” The study’s investigators declined to speak with this reporter.

By going public, Kaitz joins Amy Reed and Hooman Noorchashm, two former Harvard physicians, who led an international campaign that put power morcellation on FDA’s must-do list.

There is no deadline for FDA to act.

Reed and Noorchashm demand nothing less than a ban, and a complete overhaul of the 510(k) regulation, the FDA process that put power morcellators on the market. Together, these two couples lend human faces to a 2011 Institute of Medicine committee report that recommended a revamp of the clearance process (The Cancer Letter, July 4).

“I hope you can bring yourself and the FDA to do justice,” Noorchashm wrote in an email to Peter Lurie, acting associate commissioner for policy and planning at FDA. “Leaving these devices in gynecological operating rooms will leave open the door to defiant or under-informed gynecologists morcellating other trusting women with occult or missed cancer somewhere in the U.S. and abroad.

“Recall these devices, Dr. Lurie.”

Brigham’s study is approved through a separate Institutional Review Board from Dana-Farber’s, said George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber and a professor of medicine at Harvard Medical School.

“I’m a fan of regulatory science. I’m not a negative person, so I would have to say that our gynecology colleagues at the Brigham and Women’s Hospital hopefully have a good rationale for what they’re doing,” said Demetri, who was involved in treating Erica Kaitz, and whose research is partially financed by the couple’s fundraising. “I think that the patients who would conceivably be study participants in this—it would be an interesting consent process. It would be interesting to know what doctors tell patients in such a consent process.

“As we all know, a consent form is a form; consenting patients to a clinical investigation is a process. I’ve served on our IRB for about 24 years and I love it, and I take informed consent extremely seriously.

“I’m not going to shirk from saying it’s terrible when we get one of these patients who had morcellation. And then, the question is, ‘Well, gee whiz, did she understand the risks prior to the procedure? Would she have possibly died from an open procedure? And so, although it was an undiagnosed disease, it may be less difficult if she doesn’t look back with any regret?’

“I think this is where I do trust our regulators to look out for the safety of our patients.”

A May 2014 version of the patient consent form for the Brigham study can be downloaded here. Further details on the study, its investigators, and their patents are available on page 2.

A conversation with Demetri appears here.

 

The Debate and the Data

FDA’s pending decision on power morcellators follows this timeline of events:

• Oct. 17, 2013: Amy Reed, formerly an anesthesiologist at Beth Israel Deaconness Medical Center, underwent power morcellation performed at Brigham & Women’s Hospital. Reed and her husband, Hooman Noorchashm, linked her disseminated leiomyosarcoma to the device’s spinning blades, and launched a high-profile campaign. The couple’s Change.org petition has over 86,500 signatures to date (The Cancer Letter, July 4). Erica Kaitz died nearly two months after Reed received her diagnosis.

• April 17, 2014: FDA issued an advisory discouraging the use of power morcellation, stating that one in 350 women who undergo hysterectomy or myomectomy for fibroids have an unsuspected uterine sarcoma.

• July 10-11: Several members of an FDA advisory panel expressed low confidence in power morcellation as a treatment for uterine fibroids. No vote was taken, and no formal consensus was reached on either an outright ban or issuance of warning labels (The Cancer Letter, July 25).

• July 22: JAMA published a retrospective study of 36,470 women who underwent power morcellation from 2006 to 2012. The study found that one in 368 women undergoing hysterectomies have an undetected uterine cancer that could be spread by a power morcellator.

• July 31: Johnson & Johnson subsidiary Ethicon withdrew its power morcellators from the market, a few months after it suspended global sales of the devices. J&J’s morcellators accounted for about 75 percent of the market (The Cancer Letter, Aug. 1).

As the controversy developed, Brigham banned all open, unbagged morcellation procedures for gynecologic surgery (The Cancer Letter, July 4). Several hospitals and health systems stopped using power morcellators altogether, and some insurance companies—including Harvard Pilgrim, AmeriHealth, UPMC Health Plan, and Blue Cross Blue Shield in Massachusetts and Pennsylvania (Highmark)—have ended payments for the procedure.

Reed’s and Noorchashm’s advocacy has drawn the attention of several lawmakers, including Sens. Kirsten Gillibrand (D-N.Y.), Elizabeth Warren (D-Mass.), Bob Casey (D-Penn.), Charles Schumer (D-N.Y.), and Rand Paul (R-Ky.) who issued statements on power morcellation and wrote letters to FDA Commissioner Margaret Hamburg. Their statements can be downloaded here.

The power morcellator is categorized as a Class II moderate-risk device, which is cleared—not approved—through the 510(k) process, which applies to new devices that are based on comparability to predicate devices already in use. Only Class III high-risk devices require an FDA premarket approval application.

Risk estimates for the dissemination of undetected sarcomas via power morcellation range from one in 350, according to the April 17 FDA advisory, to one in 7,450, according to gynecology researchers.

The American Congress of Obstetricians and Gynecologists and the American Association of Gynecologic Laparoscopists argue that the risk is minimal, because the incidence of uterine cancers—especially leiomyosarcoma, one of the most aggressive forms—is very low.

Using this logic, power morcellation benefits the majority of women. Unlike open abdominal procedures that generally remove uterine tissue intact, it can be used to preserve fertility, prevent large scars, and avoid or shorten hospital stays.

However, for patients with undiagnosed cancers who underwent morcellation, the data tell a sad story, Dana-Farber’s Demetri said.

“[Patients] who had morcellation did worse,” Demetri said to The Cancer Letter. “Their disease came back faster. I think the data are quite remarkably consistent. The last few years of publications—now several different independent publications—are honing in on what I would consider to be a believable truth.

“But, you know, at some point, you have to use common sense, and I’m comfortable with the data saying, ‘It does worsen outcomes.’ That’s a key point.

“If there is a cogent argument about why this is such an important procedure and tool for this group of doctors and some specifiable type of patients, I would like to understand that.

“And I think the public would want to understand that—in words that we can all understand. If there is a rational, understandable argument for why the risk-benefit would tilt in certain patients, let’s define who those patients are.”

 

FDA’s Tool Chest

Few FDA-watchers expect to see the agency ban the power morcellator.

The agency has the capacity to accomplish the same practical results via other strategies, they say.

“There is a regulatory tool that FDA has called ‘a banned device,’ which they have only used once in the history of FDA—for synthetic hair implantation,” said Bill Vodra, a former FDA associate chief counsel for drugs.

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 authority to ban devices basically turns out to be a very cumbersome tool. It was one of those things that was written into the statute in 1976, and Congress said, ‘What a great thing!’” Vodra said to The Cancer Letter. “But the process for imposing a ban is fairly elaborate, and FDA has learned that the resources to do that are expensive, compared to simply putting out a warning from the commissioner to tell America not to use this.

“Every product liability and malpractice lawyer in the United States picks this warning up in a minute, and any doctor that uses it after that is exposing himself to all kinds of risks.” Vodra is a retired partner of the Washington, D.C., law firm Arnold and Porter.

“So for FDA, a warning is one of those tools they can use that’s not in the statute, but it can modify behavior dramatically fast in that regard. There are other courses of action besides the law to get things done.”

In the past, FDA’s press releases have demonstrated the capacity to destroy markets for products overnight, Vodra said.

“FDA has demanded a recall that pulled a product from the market,” he said. “The recall did not legally prohibit reentry, but it left no customers who would touch the product.

“They have also ordered a product to go through the PMA Class III process, and never had the product do so, thereby preventing it from being marketed.

“In short, the ultimate effect is whether physicians, hospitals with internal risk committees, and liability insurers elect to abandon a product or practice, rather than run risks of financial exposure to handle the product or perform the practice.

“The effect can be produced by a product ban, a recall, a requirement for preclearance, or a press release.”

In addition to a black box warning, some panel members at the FDA devices advisory hearing recommended the withdrawal of the power morcellator’s Class II status, and for any future iterations of the device to be submitted through the Class III process, which requires pre-market testing (The Cancer Letter, July 25).

FDA may also elect to put a black box label on the power morcellator, as well as require post-market surveillance.

“FDA can say, ‘based on the best available information, it is very risky to use this device in this way…’ and also say, ‘We want better data to quantify the risk,’” Vodra said. “Don’t underestimate the potency of a black box. They intensify the duty of care that a doctor must exhibit in order to avoid malpractice exposure.

“Many oncologic agents carry black boxes—which may explain why most GPs and internists don’t use them in their practices, but refer patients to oncologists.”

 

Post-Market Surveillance Possible

If FDA chooses to allow the power morcellator to remain as-is on the market, it would need to conduct post-market surveillance, 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.

“FDA does have the capacity, which they have not used very often with 510(k) devices, to add that they want some kind of post-market surveillance or monitoring to take place,” Challoner said to The Cancer Letter. “They could be considering allowing the morcellator to stay on the market, but under the condition that the manufacturer set in place a post-market surveillance monitoring system.

“That exists for a lot of other devices—some 510(k), some with other kinds of clearances to the market.”

Creating a registry is one post-market strategy to collect data.

“Now who would do it?” Challoner said. “FDA can require the manufacturer to establish and maintain a registry through the physicians that use that product.

“In other cases, the establishment of a registry has come through specialty providers, in many cases. So exactly how [Johnson & Johnson]—assuming they would even want to get back into the business—and Karl Storz [a German-based company that continues to make power morcellators] would establish and require a physician who purchases and uses their morcellator to report all cases to them, I don’t know exactly what the details of that would be.”

Establishing a registry would mean encompassing 100 percent of the patients in whom the device is used, Vodra said.

“Registries are useful when you may wish to contact every patient after an extended period of time, such as implant wearers,” Vodra said. “They seem less useful for a surgical or diagnostic tool that is not implanted, and where long-term follow-up or notification is foreseen.”

“It is expensive to create and to maintain; and it may not yield any better data than a focused post-market surveillance study on 2,000 to 5,000 patients at a select number of hospitals. FDA can get a group of institutions to enroll in a registry, or go to Boston, New York or California where there are major hospitals and say, ‘We want to follow the next 2,000 patients that are treated, put them in a study, and follow those patients for a period of time.’”

A registry may work for power morcellation patients, if the adverse effects surface rapidly, Vodra said.

“If the gestation period for cancers disseminated by the power morcellator is a couple of weeks, it’s very quick and easy to do that study,” he said. “What FDA would need, if it decides to do this, is a large enough denominator that an incidence rate can be obtained.

“If there is a conflict among the data that has been developed since FDA issued its advisory, FDA might well say, ‘Gee, we are now stepping back. We’re not sure that we got the right numbers here.’

What would FDA need to say to justify asking for a post-market study focused on assessing the risk of disseminating malignant tissue?

“If the decision is to collect more data, then what FDA would require is to say, ‘Yes, we know a qualitative risk of injury, but we don’t know if it’s one in 10,000 or one in 500. And we need the data to answer that question,’” Vodra said.

Registries or studies would expose large numbers of patients to potential harm, said Challoner.

“Given what we’ve discovered so far about the incidence of the tumor dissemination, it’s going to put a lot of people at risk,” Challoner said. “There are ways to take care of fibroids without this risk, that we discovered is being introduced by morcellation, and that Hooman Noorchashm has widely disseminated.

“With the Hippocratic Oath in mind, until we have a means of preoperatively determining the presence or absence of a sarcoma vs. a fibroid, the morcellator has no place in clinical use for this purpose.

“So what we probably ought to do, in my point of view, is put it off until our geniuses—as they are doing with other kinds of tumors—find a way of preoperatively detecting the genetic abnormalities in a uterine sarcoma, and with a simple blood test.

“We’re not there yet, and if companies who are currently manufacturing morcellators are going to be impatient about it, I think we ought to sit on this technology until such time as we actually have that kind of preoperative determination of the risk vs. no risk.”

 

Next Page: The Debate Over Brigham’s Containment Bag Study

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