How Much Do Patients Need to Know About a Potentially Risky Treatment?

A visiting researcher at NewYork-Presbyterian/Weill Cornell Medical Center was startled when he read the warning from the Food and Drug Administration about a product that had been used in spine surgeries at the esteemed Manhattan hospital.

The fluid, derived from umbilical cord blood, was not approved for such procedures, the agency cautioned, and its Idaho manufacturer had been cited for possible contamination problems and inadequate screening of donors, making the product potentially unsafe.

Yet before that advisory, about 40 patients at the hospital had received treatment with the fluid under the direction of Dr. Roger Härtl, a senior surgeon and professor at Weill Cornell, who is also a physician for the New York Giants. The surgeries were documented in a draft study that Härtl and others, including the visiting researcher, had intended to publish, tracking the fluid’s effectiveness in fusing delicate bones.

After seeing the FDA announcement, the researcher, Dr. Pravesh Gadjradj, approached Härtl and told him the fluid “is not yet proven to be safe,” according to a complaint filed with the hospital that was reviewed by The New York Times. The fluid fell under a booming area of treatment known as regenerative medicine, which is aimed at replacing or restoring damaged cells through gene and stem cell therapies.

In the complaint, Gadjradj said Härtl requested that he “delete” the research file on the project and “never bring up the topic again.” The researcher said he was concerned that Härtl had not gone on to inform the patients, according to the complaint, and instead “covered it up.”

The conversation cited in the complaint was in the spring of last year, Gadjradj said in an interview. In January, after months of worrying about the patients — and believing that they still had not been notified — Gadjradj lodged the complaint against his boss.

Still, he said, nothing came of sounding the alarm about his patient concerns. “Maybe all of these patients don’t have any adverse effects, but maybe they do,” he said. “We don’t know. That’s a terrible thing.” Because of privacy protections, Gadjradj said, he would not disclose the names of the patients or contact them himself.

FDA warning letters do not require that patients be notified about a product’s potential problems, posing an ethical dilemma for clinicians, according to medical ethics experts.

Even in the absence of a formal requirement, they said, there is often a moral obligation to inform patients, especially regarding new or untested treatments, but other considerations can get in the way.

“The safer thing, the more ethical thing, would be to tell everybody and give them whatever information you’ve got about what’s known about the risks,” said Hank Greely, a law professor at Stanford and director of its Center for Law and the Biosciences. But, he said, doctors and hospitals “are going to be reluctant to do that because they don’t want to look bad, don’t want to attract lawsuits and don’t want to make patients unhappy with them.”

Dozens of other medical centers, including prestigious institutions such as Duke University Health System and the George Washington University Hospital, also listed the fluid, known as BioBurst, on their hospital pricing records, according to data collected by the company Visible Charges. Umbilical cord blood products have been approved by the FDA to treat disorders that affect blood production.

A spokesperson for NewYork-Presbyterian would not comment on Gadjradj’s complaint. She said the hospital had stopped using BioBurst before the FDA issued its warning in February 2022, but she would not say whether patients had been told about receiving the fluid or, later, about its potential problems.

Härtl, who is the founder and director of the Weill Cornell Medicine Center for Comprehensive Spine Care, declined to be interviewed when reached by telephone. He later said in emails that he had used the fluid between 2019 and 2021 “as a bone grafting alternative” in minimally invasive spine surgeries. He did not directly address questions about what patients knew, but wrote that he “did not receive any patient complaints or see any unexpected adverse events, such as infections or revision surgeries, directly associated with the use of BioBurst Fluid.”

“My goal has always been to reduce the pain and suffering of patients by advancing the effectiveness of spine surgery” he said.

In the emails, Härtl also disputed “any implication that we used or studied” BioBurst in an “inappropriate manner,” and said that “all relevant data” remained on file and “any suggestion otherwise is not true.” A draft of the unpublished study, reviewed by the Times, said it had been approved by Weill Cornell’s institutional review board and had been “granted a waiver of consent.”

The manufacturer, Burst Biologics, a small biotechnology company, had shipped the fluid to hospitals and clinics across the country, saying it could potentially stimulate bone regeneration. The draft study said the use of the product “showed promising results” when compared with existing literature on the subject.

The fluid belongs to a growing area of medicine that has drawn stepped-up attention from regulators. There are about 3,000 active investigational drug applications for cell and gene therapies, according to the FDA. Patients have clamored for the therapies to treat Parkinson’s disease, autism, arthritis, back pain and other conditions, but approval has been limited to certain cancers, disorders and immune conditions and includes fewer than three dozen products.

In 2021, as Härtl and the research team were compiling their findings, FDA investigators visited Burst’s laboratory in an office park near the Boise, Idaho, airport. An inspection found numerous problems, including significant breaches in sterile manufacturing and monitoring processes, as well as a failure to adequately screen donors for the Zika virus and other communicable pathogens, according to an inspection report.

The agency also said BioBurst Fluid and a similar product, BioBurst Rejuv, did not have proper approval.

The FDA ratcheted up scrutiny of the company and in February 2022 publicly posted the warning letter. The next month, Burst recalled vials of the two products, and its founder declared bankruptcy by year’s end; the company’s equipment was soon sold at auction. While recalls of the most seriously defective medical products can include a process for notifying patients, Burst’s did not rise to that level.

The founder, Christopher Jones, did not respond to requests for comment, but in correspondence with the FDA, which the Times obtained through a public records request, he defended his products as safe and accused the agency of being overzealous in its enforcement. “My business has been warned by FDA of alleged safety concerns with its products related to a regulatory scheme that does not apply to my business,” he wrote.

The FDA would not comment on the company or the use of the fluid at NewYork-Presbyterian/Weill Cornell Medical Center. But Carly Pflaum, an agency spokesperson, said in a written statement that as regenerative medicine companies make “unsubstantiated claims about the potential benefits” of unproven therapies, doctors and patients “may use these unapproved products with a false sense of security about their safety and efficacy” and are likely to underreport “adverse events.”

Five years ago, patients became seriously ill in Arizona, California, Florida and Texas with infections after receiving injections in their knees, shoulders or spines that contained stem cells from umbilical cord blood not associated with Burst. The FDA responded by pledging more inspections of the industry and warned about companies making unfounded claims.

Interviews as well as a review of government and corporate records by the Times found that Burst expanded its national footprint even as its own employees raised concerns to management and regulators as far back as 2017 about product safety, lab conditions and the skirting of regulatory requirements.

During that time, regulators did not take substantial action while the company was cultivating ties with doctors across the country, inviting some to visit Boise and meeting with others at medical conferences.

Among the doctors who learned about BioBurst Fluid at a medical conference: Härtl, according to a spokesperson for Weill Cornell Medicine, the hospital's academic partner.

In March, when Gadjradj called NewYork-Presbyterian’s compliance office to check on his complaint, he was told the hospital had created a committee and restructured how it screened the purchase of biologics — a class of drugs made from living organisms that included BioBurst.

Although it was unclear from the call when and why the committee was created, the compliance official told Gadjradj: “BioBurst Fluid didn’t get vetted in the same manner” as other products purchased after the committee was created, according to a recording of the conversation shared with the Times.

<b> Improving Lives </b>

After spending time in the U.S. Marine Corps, Jones, the Burst founder, became an entrepreneur and marketer. In 2010, he set up shop in Boise distributing medical implants used in spinal and orthopedic surgeries.

Within a few years, Jones had focused on the “cutting edge of biologics,” serving “hospitals and surgeons” and selling products under the name Burst Biologics, according to the company’s website. The company said it was committed to patient safety, employing scientists and medical directors with doctoral degrees to oversee the processing of products.

But in interviews with the Times, 11 former employees detailed serious problems that included subpar laboratory practices, a lack of training, inadequate safety protocols and a retaliatory work environment.

Several said they also had concerns about the regulatory status of two of the company’s main products, BioBurst Fluid and BioBurst Rejuv, both derived from umbilical cord blood and used in operating rooms and medical clinics.

The company had insisted that because the fluids required only minimal processing, they belonged to a product class that was not subject to heavy regulatory oversight or licensing requirements.

But in 2017, as regenerative medicine was gaining popularity, the FDA alerted companies to new guidelines and clarified the approval and licensing process, which would require more rigorous testing for efficacy and safety.

To give the companies a chance to gain their footing, the agency limited enforcement to significant safety threats. But Pflaum, the FDA spokesperson, said in the statement to the Times that the largely hands-off approach “did not excuse the violations of manufacturers or health care providers offering unapproved regenerative medicine products that have the potential to put patients at significant risk.”

At least seven former Burst employees — including a research director, Trillitye Paullin, and two lab technicians, Dylan Walker and Brecken Robb — said they suspected the fluids fell under the more stringent FDA standards. And multiple times, some of them said, they told their managers that the company should acknowledge that fact and apply for a biologics license.

In an email reviewed by the Times, Walker alerted the FDA in February 2018 about the employees’ regulatory concerns. Soon after, investigators visited the Boise lab, but they noted no significant problems, according to a review of FDA documents.

That December, the company’s correspondence indicates, it received a letter from the FDA saying that Burst appeared to be offering “stem cell” products to treat a variety of conditions. But it would be almost 2 1/2 years before the agency took significant action against the company.

In his 2018 email, Walker also expressed “grave concerns” about screening protocols for the Zika virus, because the company’s main supplier was an umbilical cord bank in Puerto Rico, where Zika was prevalent.

Around the same time, Paullin, Burst’s former head of research development, filed a complaint with the Occupational Safety and Health Administration about Zika exposure.

When she became pregnant, she said, she told top management that she would only handle material that had been deemed Zika-free. But after returning from a short leave for National Guard duty, Paullin said, she was informed by a co-worker that some placentas she had been handling had tested positive.

She quit her job within days and filed the OSHA complaint, one of three the agency said it received about Burst in 2017 and 2018. OSHA said it resolved the complaints without penalty, and told Paullin in a letter that the agency closed her case after determining that “the hazardous conditions no longer exist.” Her daughter was born healthy a few months later.

<b> ‘Just Another Customer’ </b>

How an unapproved medical product with serious manufacturing concerns made its way into the inventory of a respected New York medical institution remains unanswered. Spokespeople for both NewYork-Presbyterian and Weill Cornell Medicine would not explain how or when products are approved at the hospital, and would not comment on a recorded phone call between Gadjradj, the visiting researcher, and a compliance officer.

Hospitals tend to have a formal review process for products that will be used on patients. A committee often vets requests from doctors before the products are bought by the procurement department.

In interviews, doctors at several other hospitals said they also used Burst’s products and expressed surprise that the FDA had issued a warning about them.

Dr. Faheem A. Sandhu, a spine surgeon at MedStar Georgetown University Hospital, said he learned about BioBurst Fluid through a company sales representative around 2017, and that he had been led to believe the product was FDA-approved. “I was just another customer,” he said.

Sandhu said he had used the product on at least 50 patients, thought it worked well and hadn’t detected any problems. He recalled that for some patients, insurance covered Burst treatment, which typically cost thousands of dollars. But if he had been aware of the regulatory concerns, he said, he would not have used it and he does not believe it would have gotten through the hospital’s screening process. He said he would have notified patients had the FDA or the company recommended doing so.

Gadjradj had experience with clinical research on spine surgery but knew nothing about Burst when he arrived in New York for his two years as a postdoctoral research fellow at Weill Cornell.

He said he got off to a good start working for Härtl, but their standoff over the Burst research soured their relationship.

Gadjradj said it was the hospital’s lack of transparency with patients that was most troubling to him.

“They can’t ring the bell if something goes wrong,” said Gadjradj, who completed his tenure with Härtl at the end of June and returned home to the Netherlands with plans to finish a residency in neurosurgery. “We don’t know because we just discharged them like nothing happened.”

This article originally appeared in <a href="https://www.nytimes.com/2023/09/20/health/regenerative-medicine-risks-ethics.html">The New York Times</a>.