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Ethics of hepatitis C drug pitch questioned

EXETER, N.H. — They filed into the hotel conference room, faces pinched with worry, drawn by the prospect of an escape from hepatitis C.

It was a disease they never saw coming. They had gone to Exeter Hospital seeking treatment for other ailments, and wound up exposed to the hepatitis virus, allegedly by a technician now under federal indictment.

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On this August evening, the patients had the opportunity, promotional materials from an advocacy group promised, to learn about “new wonder drugs” with a “75 percent cure rate in clinical trials” from a Harvard Medical School instructor and liver disease researcher at Massachusetts General Hospital.

As he took the microphone, Dr. Raymond T. Chung offered an authoritative message of deliverance: “We want to get about the business of helping these folks undo what’s been done unto them.”

But the drug combination that Chung hoped would undo hepatitis C’s damage had not been approved by the Food and Drug Administration, remained in clinical trials, and would not be approved for study by the committee that oversees Mass. General research until a month after Chung’s presentation.

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Ethicists said in interviews that Chung’s comments appear to have breached ethics principles by potentially leaving his audience with outsize hope for drugs undergoing testing. Doing so, they said, was particularly striking at a moment when patients felt violated and vulnerable.

“I believe Dr. Chung is very well meaning, and it is possible that his study drug may be better than what is currently available,” said Dr. Brian O’Sullivan, director of the University of Massachusetts Medical School’s Bioethics Core. “But to sell it as such to a scared, desperate audience is not appropriate. He is misconstruing a promising but as yet unproven drug as a therapeutic alternative.”

Winslow Townson for The Boston Globe

Lawyer Domenic Paolini, left, and Dr. Raymond Chung spoke.

‘When you are doing research, you have to make sure that people understand it’s promising, that you’re making no guarantee of benefit.’

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Chung and hospital officials disputed the ethicists’ conclusions. In an interview, Chung said his comments reflected the promise of the drugs and his desire to make them available to patients who could benefit most — a presentation that, he said, conformed to ethical standards for clinical trials.

“We were very clear that this was a study,” Chung said in the telephone interview, “that this is a protocol and that patients would have to go through the next steps of private discussion and informed consent with a discussion of risks and benefits.

“That’s an absolute foundation of what we do with our clinical trials.”

For Jean Burke’s husband, who is among the infected and attended an earlier presentation by Chung in the summer, the doctor proved persuasive — so much so that her husband met privately with him and plans to enroll in the study, should it go forward.

“His reputation is nationally known. He’s a really excellent doctor and has been doing research on this for years,” said Burke, who said she and her husband understood Chung was talking about a drug trial. “He’s assured us that it’s probably going to be really successful.”

* * *

Human drug trials remain among the thorniest areas in medical ethics, poised between the need for scientific advancement and the mandate to protect patients. The revelation in the 1970s of the Tuskegee syphilis experiments, in which researchers deliberately withheld treatment from African-American men, spurred Congress to pass laws governing scientific trials.

A key area of oversight is recruitment, which can pose a hurdle for researchers. While patients stricken with life-ending illnesses, desperate for anything, sometimes seek out researchers and their trials, patients suffering diseases that do not pose an imminent threat may be less willing to submit to experimental interventions.

“Most people don’t want to be in research,” said George Annas, an ethics specialist at Boston University School of Public Health. “They want to be in treatment.”

Institutional review boards, composed of at least five members designated by the research institution, are charged with ensuring that researchers do not intentionally mislead patients about side effects and risks of an experimental drug. The review boards must also be on the lookout for well-meaning scientists who possess an exaggerated belief in their research and convey that to subjects — a phenomenon known as the therapeutic misconception.

“Researchers hope their drugs do well,” said Dr. Michael Grodin, a bioethicist at BU’s public health school. “There’s a bias on the investigator’s part. And that’s exactly why we want patients to know it’s research and not therapy.”

* * *

For months, the news out of Exeter sounded a steady drumbeat of despair. In May, word came that four cases of hepatitis C — a disease that over time can attack the liver and can ultimately lead to death — had been linked to the hospital’s cardiac department. That was only the start.

The numbers climbed, federal investigators arrived, and on July 19, with at least 30 people having tested positive, prosecutors announced they had identified the source of the infections: a former technician at the hospital.

Prosecutors allege that 33-year-old David Kwiatkowski stole syringes of a powerful anesthetic called fentanyl from the cardiac catheterization lab, injected himself, and then returned the tainted needles, which were reused on patients. Kwiatkowski worked in seven other states before New Hampshire, raising the specter that he infected others — possibly hundreds across the country, according to prosecutors.

For the patients in Exeter, the revelations heaped a new health problem onto old ones. Many had underlying conditions that had brought them to Exeter Hospital. Some had primary care doctors affiliated with the hospital — a place from which they no longer wished to receive care.

That led some two dozen of them to the “Hepatitis C Patient Information Night” in the conference room at the Georgian-styled Exeter Inn.

The evening was billed by its attorney-organizer, Domenic Paolini, as a chance to learn about advances in hepatitis C treatment and to hear attorneys explain the legal landscape for medical malpractice in New Hampshire and possible settlement options.

Paolini organized the evening under the umbrella of the Patients Speak, a not-for-profit advocacy group that he formed with Elenore Casey Crane, a public relations consultant, after the outbreak. The group held an initial meeting in June, at which Chung also spoke, assuring patients that hepatitis C was not a death sentence and could be treated.

On this August evening, sandwiched between Paolini and another medical malpractice lawyer, Chung waited his turn to make a pitch — his latest foray in the fierce race to conquer hepatitis C, which affects an estimated 3.2 million people in the United States.

* * *

The standard treatment for hepatitis C for years has been weekly injections with interferon, a regimen that, on average, cures fewer than half of patients with the most common form of the virus and sometimes spawns flu-like side effects.

The terrain shifted dramatically last year when the FDA approved two new drugs, Vertex Pharmaceuticals’s telaprevir and Merck & Co.’s boceprevir, which, when taken in combination with interferon, increased cure rates to roughly 80 percent and 65 percent, respectively. Chung was an investigator for trials of both drugs.

Now, Chung is seeking to be at the forefront of the next frontier: identifying a combination of oral medications that would not require interferon.

“We are on the threshold of a treatment revolution,” Chung wrote in the New England Journal of Medicine in January.

But in late August, Bristol-Myers Squibb announced it was discontinuing development of an oral hepatitis C drug after nine patients in a clinical trial were hospitalized and one died. The FDA that month put a hold on trials of a drug in the same class being tested by Idenix Pharmaceuticals.

The oral combination that Chung hopes to test in Exeter is made by Gilead Sciences, according to Dr. Elizabeth Hohmann, director of Partners Human Research Committee, charged with overseeing Mass. General’s clinical trials. Chung, who said he does not have a financial stake in the research, said the combination had already been tested in phase one trials to establish safety, phase two trials to assess efficacy, and has entered phase three trials, often the last step before submission for FDA approval.

The Exeter patients, who would be in a phase 2 trial, represent a singular research opportunity because they contracted the disease in the same recent time span, potentially providing a window into how the infection plays out in its early stages — a vital piece of knowledge in tackling the disease.

At the Exeter Inn, Chung introduced that drug combination as a “strand of hope.”

“We were able to approach a company that was developing these newfangled drugs,” he told the audience. “And this isn’t just any set of compounds. This is a set of compounds that have already been in trials . . . that have demonstrated not just safety, but as well, effectiveness against hepatitis C. And effectiveness here means not only the clearance of virus during the administration of the medications but a permanent clearance.

“You can essentially equate that with a cure, a cure of the infection.” These drugs, he said, were accomplishing in as little as three months what an interferon-based regimen took six months or longer to achieve. The new drugs were doing so “in a manner that does not disrupt or interrupt quality of life to anywhere near the extent that interferon might,” Chung said.

“That’s way over the top,” said Arthur Caplan, head of the division of medical ethics at NYU Langone Medical Center. “When you are doing research, you have to make sure that people understand it’s promising, that you’re making no guarantee of benefit. That’s getting very close to guaranteeing a benefit. That language is irresponsible.”

* * *

Five ethicists and researchers who reviewed Chung’s comments at the Globe’s request said they appeared to violate ethical standards requiring that researchers convey a balanced message about clinical trials to possible research subjects.

“It’s inappropriate, and I would argue unethical, to approach people about a research study that hasn’t been approved and to say the potential benefits outweigh the risks,” Grodin said.

“That was definitely overselling,” O’Sullivan said. “There needed to be, ‘We hope there will be fewer side effects. We hope it will be more effective, but we don’t know that.’ ”

Chung made little mention of side effects. After prompting by an audience member’s question, he said, “The important point to make about this combination therapy is that it has been very well tolerated . . . and we believe that the side effect profile described in those [earlier] trials will be something we will be able to manage effectively in this group of patients.”

Hohmann said Chung’s comments were not “hyperbolic.”

“I think it’s enthusiastic but justified based on these drugs, which are really looking very good,” she said.

Chung, too, defended his comments. “This is not a hard sell. This is simply a restatement of facts in an informational setting.”

Indeed, he said, he felt it was his responsibility to alert the patients to the drug combination’s promise so they could, if they wished, access it before approval, which he said could come as early as next year.

He also noted that the evening’s promotional materials — which called the combination he hopes to test “wonder drugs” — were the work of the Patients Speak; neither he nor Mass. General officials reviewed the materials.

The FDA, which enforces laws governing clinical research trials, declined to comment on Chung’s presentation. But agency spokeswoman Michelle Bolek pointed to laws that bar investigators from representing “in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.”

Some ethicists questioned Chung’s timing, saying he should have held off on taking names and contact information of interested patients until he had secured approval from the Partners Human Research Committee. That panel did not approve Chung’s study until a month after the Exeter presentation.

FDA guidelines note that institutional review boards — widely known by the acronym IRB — should review the “methods and material that investigators propose to use to recruit subjects.”

“In his capacity as an educator and a doctor, he may want to educate people broadly about what’s going on in hepatitis C and how there is a sea change afoot in hepatitis C drug treatment options,” said Dr. Timothy Lahey, cochairman of the Dartmouth-Hitchcock Medical Center Ethics Committee.

“But he would have to be very careful not to actively recruit anyone to a specific study without IRB approval or to overstate the expected potency of an experimental regimen.”

And taking names, some ethicists said, clearly constituted recruitment.

“If you are taking names so you can contact them, that’s recruiting,” said Lisa Bero, a University of California, San Francisco specialist in clinical trial ethics.

Chung and Hohmann disagreed. “This is simply collecting names and contact information for when [the study] is ready to rock,” Hohmann said.

She compared Chung’s presentation to notices about upcoming trials placed by researchers and institutions on the Internet. Those are permitted, under FDA guidelines, so long as they are restricted to basic information, such as the study’s title, purpose, protocol, eligibility criteria, and study site.

Chung said he notified Hohmann before the meeting in Exeter and advised her that he planned to discuss the upcoming trial.

Some ethicists said Chung’s recruitment methods reflected real-world pressures and demands on researchers.

“I have a little sympathy,” Annas said. “It’s hard to recruit people for a study. The key thing is, did he tell people clearly that this is research?”

At root, Chung said, “I was responding to what I perceived and I felt was a very strong, intense need for information on behalf of an aggrieved group of patients who were confused and had nowhere to turn.”

For Jean Burke and her 61-year-old husband, whose work days have been marked by fatigue and other symptoms they attribute to hepatitis C, Chung offered an infusion of good news.

“It was very exciting for us to hear because we are in such a bad situation,” Jean Burke said.

Sarah Schweitzer
can be reached at
schweitzer@globe.com.
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