After early supply bottlenecks throttled its rollout, Novartis’ flagship radioligand therapy Pluvicto entered a rapid growth phase recently, driven by FDA approvals in earlier-stage prostate cancer and broader uptake in community settings. But a regulatory overhaul proposed by federal nuclear authorities now threatens to derail that momentum, potentially raising administrative hurdles that experts say could force clinics to rethink patient care while deterring others from adopting the therapy altogether.
The issue does not stem from Pluvicto or the treatment of radioligand therapy itself. Instead, it concerns how patients are managed following such treatment from a radiation safety perspective.
In August, the U.S. Nuclear Regulatory Commission (NRC) issued a draft regulatory guide, which governs the release of patients who have been administered radioactive materials, like Pluvicto. The guide, coded DG-8070, was meant to offer practical instructions to help treatment facilities comply with the actual radiation safety rules, which are undergoing their first major overhaul in decades under the Trump administration.
Instead, leading professional societies, clinical experts and pharmaceutical companies, including Novartis, warn that the draft guide contains rigid mathematical assumptions that could unintentionally add barriers to patient access, especially beyond major academic treatment centers.
Under DG-8070, a full course of Pluvicto would exceed the NRC’s threshold allowed for patient release. Without changes to its methodology, experts warn that clinics will have to either hold Pluvicto patients longer under enhanced radiation control protocols or rely on individualized calculations, which may be daunting for smaller practices.
“It’s not terrible, but it just creates a barrier,” Thomas Hope, M.D., vice chair of clinical operations and strategy in the department of radiology at the University of California, San Francisco told Fierce. “The question is: Is that barrier helping in a way? Is it creating extra safety? Are we fixing an underlying issue? Is there a massive exposure out there that we’re trying to address by changing these rules? I think that’s where the nuclear medicine community is saying: probably not.”
At the heart of the controversy is a shift in how the NRC proposes to measure radiation exposure. While the medical community largely supports the NRC’s effort to modernize its rules, two proposed changes have drawn fierce pushbacks, according to public comments submitted to the regulatory docket.
Rigid assumptions, unrealistic math
The NRC devised the patient release rule to ensure the safety of other individuals around the patients who have received radioactive materials. After being infused into the patient’s body, radioligand therapies can still temporarily emit low levels of radiation to the environment. High doses of radiation may lead to cancer as the body fails to repair the DNA damage caused by radiation.
Historically, radioactive materials have mainly been used in diagnostic scans, which have “trivially low” exposure to individuals, Pat Zanzonico, Ph.D., a medical physicist at Memorial Sloan Kettering Cancer Center and an expert in dosimetry for radiation therapies, explained to Fierce. In therapeutics, radioiodine treatment for thyroid disorders and Novartis’ Lutathera for neuroendocrine tumors represent relatively small populations. Pluvicto marks the first radiopharmaceutical use in a large indication, posing a more significant potential exposure to family members and others, he added.
Rather than a lump-sum concept of a general member of the public, the NRC recently introduced the term of a “caregiver,” a consenting person receiving specific radiation safety instructions who can be exposed to a higher radiation dose of up to 50 millisieverts (mSv), or 5 rem, per treatment regimen. Patients whose radioactive impact on a caregiver falls within that threshold can be safely released from the healthcare facility after treatment, per NRC rules.
That new limit would be tenfold the long-standing regulatory threshold, matching the annual legal limit for occupational radiation exposure. To put that into context, the average annual radiation dose per person in the U.S. is about 6.2 mSv, according to data from the National Council on Radiation Protection and Measurements cited by the U.S. Environmental Protection Agency.
Based on the exposure threshold, the NRC, in what Zanzonico called “a good faith effort,” calculated default releasable strengths for each radionuclide. For Lu-177, the radioactive material used in Pluvicto, the patient release threshold would be 41 GBq (1,100 mCi) of radioactivity.
In clinical practice, the recommended dosage of Pluvicto is 7.4 GBq (200 mCi) of radioactivity given every six weeks for six doses. As the Society of Nuclear Medicine & Molecular Imaging (SNMMI) pointed out in its comment on DG-8070, a full, six-administration course of Pluvicto reaches 44.4 GBq and therefore exceeds the default threshold.
By comparison, Novartis’ other Lu-177-based therapy, Lutathera, wouldn’t face the same problem. The drug is designed to give 7.4 GBq of radioactivity for a total of four doses.
Part of the problem, according to SNMMI’s comment, which Zanzonico helped draft, stems from a change in the NRC’s assumption around how long a caregiver spends with a radiopharmaceutical recipient.
Potential radiation absorption by a caregiver is derived from the radioactivity of a radionuclide based on multiple factors, such as the physical half-life and the energy carried by the radionuclide. One of them is called “occupancy factor,” which quantifies the fraction of time an individual is assumed to be at a 1-meter (about 3-feet) distance from the patient. Simply put, the more time a caregiver spends near a treated patient, the higher their cumulative radiation experience. To compensate for that extended exposure, the patient needs to clear lower emitted radiation levels before they can be discharged.
The NRC’s existing guide is based on an occupancy factor of 0.25, which means that an individual spends a quarter, or six hours, of a day within 1 m from the patient. However, the draft guide now changes the occupancy factor to 1, which “essentially assumes that a caregiver never leaves the patient’s side,” Novartis noted in its public comment.
To Zanzonico, Hope and many others who have weighed in on DG-8070, the new assumption is unrealistic and shouldn’t be used to dictate practice.
Further constraining patient release limits, the NRC proposes evaluating allowable public exposure on a per-administration regimen basis. Rather than assessing one infusion at a time under the current standard, medical centers would be required to calculate the cumulative radiation emitted across a patient’s entire treatment course.
The rationale behind a per-full-treatment calculation is that radiation dose is cumulative, and a caregiver’s total exposure isn’t isolated to a single infusion, an industry expert told Fierce. Similarly, current federal regulations set occupational whole-body radiation exposure limits over the span of one year.
Yet, these updates together create a paradox. Even though the NRC draft guide raises the allowable exposure bar for caregivers, the assumption of increased duration of contact and the combination of all infusions of a multi-dose regimen will likely push Pluvicto patients over the release limit. The result, experts fear, is new administrative burdens for healthcare providers and a barrier for patient access.
Unintended consequences
Most Pluvicto recipients are treated as outpatient, according to Hope and the industry expert. Today, UCSF no longer measures Pluvicto’s radiation emission after noticing that the first few patients were all below the NCR’s limit. Patients are quickly discharged following discussions about radiation safety, including urine contamination and sleeping arrangements.
If implemented in its current form, the new guide would force clinics to temporarily hold the patient or hospitalize them.
“In practice, many nuclear medicine departments, community hospitals, and freestanding theranostics centers do not have appropriate space to hold a radioactive patient for prolonged periods,” the American Association of Physicists in Medicine (AAPM) commented on DG-8070. “If inpatient admission is required solely to satisfy a release calculation, the patient may occupy a bed needed for someone who has a clinical need for hospitalization.”
Similarly, the American College of Radiology, representing over 40,000 radiologic professionals, wrote in its comment letter (PDF) that the proposed change “would result in a major patient access barrier as most healthcare facilities do not have the capacity to hold nuclear medicine patients who do not need inpatient care,” pointing out such “medically unnecessary hospitalization” would likely not be covered by insurance.
“From my perspective, I wish all the small places went away because I get more business,” Hope said. “But that’s not the goal of the field. We need to get people access to these therapies.”
Experts view NRC’s proposed math not as a warranted safeguard but as a technical fumble. The NRC also acknowledges in its draft guide that its calculations use “highly conservative assumptions.”
“Regulators in general tend to opt for conservatism,” Zanzonico said. “That’s not an unreasonable approach. But I don’t think there’s any data demonstrable [of] increased risk to family members […] Suddenly we’re finding an increased risk of cancer or other adverse effects—I don’t think there’s any such data at all.”
To compensate for the conservative approach, the NRC’s proposal would add what Zanzonico called “an escape hatch.”
Under DG-8070, treating facilities that exceed default release thresholds can still offer outpatient treatment if they perform individualized calculations that justify patient release by tinkering with exposure variables like the occupancy factor.
According to Zanzonico, the justification is not a high bar. A treatment center, called a “licensee” because they must obtain a special license to administer radioactive material, can instruct the caregiver to not be within 1 m of the patient for more than six hours a day to bring the occupancy factor back to 0.25 without any in-depth justifications, he suggested.
Even so, the actual execution takes more than just a few verbal instructions.
“It does require operational discipline,” the industry expert told Fierce. “The site would need a defined process, appropriate calculations, documentation, radiation safety review, and clear patient and caregiver instructions.”
“The one wrinkle is that, increasingly, these treatments are being administered not at academic medical centers where there’s extensive technical and physics support,” Zanzonico said. “Not that the physics is that sophisticated, but some people, as soon as they start seeing equations and Greek symbols, it gets a little daunting.”
“The point is,” Zanzonico said, “if this is what’s going to happen anyway, why not just from the outset recognize that reality, that an occupancy factor of 1 is unrealistic?”
Calculating exposure based on the full treatment has its own flaws.
It “creates practical difficulties for licensees and patients alike, particularly because the number of planned administrations in a regimen may be uncertain at the outset and may change as treatment progresses, the administered dose may change over the treatment course, and there may be a change in caregiving arrangements between administrations,” Eli Lilly said in its comment letter for DG-8070. The obesity and diabetes pharma giant entered radiopharmaceuticals recently and beefed up its stake in the field through a series of acquisitions.
Both Zanzonico and Hope also pointed to similar potential logistical problems under the per-regimen approach. Patients may be hosted by different caregivers and receive treatment at different facilities throughout their course of treatment.
“I’m not saying that’s a common scenario, but those are the kind of practical considerations I think that may make it more straightforward to specify the dose limits on a per-administration rather than administration-regimen basis for a multi-fraction regimen,” Zanzonico said.
The NRC defines administration regimen as “the full course of a radiopharmaceutical […] as intended by the authorized user.”
For Pluvicto, Hope hypothesized that a facility could theoretically get around the rule by first prescribing five doses and then count the sixth dose, which would push the exposure above the releasable limit under DG-8070, as a new course.
In Novartis’ phase 3 PSMAfore trial for Pluvicto conducted in patients with metastatic castration-resistant prostate cancer who had not received a prior chemotherapy, 63% of patients received the full six doses.
“I’m sure there’s ways around this,” Hope said. “But then, why are we doing this in the first place?”
Threatening a $5B trajectory
Concerns over treatment barriers could lead to slower uptake, putting a damper on Novartis’ effort to expand Pluvicto into a $5 billion blockbuster at peak sales.
Holding patients longer “shifts radiation exposure from members of the public to facility personnel and creates staffing, room-control, security, and operational burdens,” the AAPM observed. “For some sites, the practical response may be not to offer the therapy at all.”
At UCSF, Hope said a small team of radiation safety specialists can perform individualized release analyses, and he expects the process to take less than 30 minutes per patient once the team gains experience. Zanzonico also called it “almost a trivial thing to do” at large academic centers.
The problem, again, comes down to the community setting, where treatment centers don’t always have a team of dedicated nuclear medicine physicians.
Hope pointed to Novartis’ Lutathera, the first FDA-approved radioligand therapy. An intravenous infusion of amino acids is given alongside Lutathera to protect the kidneys from radiation damage. That extra step has prevented many sites in the U.S. from offering Lutathera, he said. About 440 U.S. sites offer Lutathera, roughly half the number treating with Pluvicto, according to Novartis.
“This NRC guideline is not as big of a barrier as that,” Hope said. “But there is clear evidence that barriers do prevent adoption.”
“If you can get smaller centers, maybe they only do a tenth of the therapies that we’re doing, but they can offer it much more conveniently to the patient, which is great,” Hope said. “That’s the margin that could be punished by these rules.”
The reality is, collectively, that these community sites are no longer the margin but the mainstay for Pluvicto.
With nearly 900 sites in the U.S. now offering Pluvicto, more than half of the drug’s doses are delivered in what Novartis would deem as community, Michael Gwinner, Ph.D., VP and senior general manager of radioligand therapy at Novartis, said during a panel in Washington, D.C., on Sept. 16.
Citing continued site expansion and earlier-line approval by the FDA, Novartis reported a 38% sales jump for Pluvicto in the U.S. year over year in the second quarter, reaching $493 million.
The good news is, DG-8070 remains a draft guide, and the NRC’s Advisory Committee on the Medical Uses of Isotopes (ACMUI) has echoed those concerns.
After an Aug. 17 meeting, the subcommittee tasked to review the patient release guide also recognized that an occupancy factor of 1 would increase the need for patient-specific calculation, “which can be prohibitively complex for many licensees,” according to a committee report (PDF).
The committee recommends, among other things, that the NRC adopt more realistic occupancy factors, such as 0.67, which would assume the patient has close contact with the caregiver throughout the day without sleeping together. The committee also recommends that the NRC maintain a per-release radiation dose limit or use the term “expected administration regimen,” along with further guidance to address various scenarios.
According to Zanzonico, who previously served on ACMUI, the NRC has historically been responsive to feedback from practitioners.
The NRC declined to comment on the guide as it has not been finalized.
“The agency carefully considers all public comments, as well as input from the Advisory Committee on the Medical Uses of Isotopes, before finalizing any guidance,” an NRC public affairs officer told Fierce.
If the guide goes through unchanged, Hope expects that sites that are already offering Pluvicto would likely choose to adapt, while new sites may be more reluctant to get on board. Even though Novartis would develop solutions to make individualized analysis easier, “any barrier does slow down the adoption,” he said.
If that turns out to be the case, the rule would be more of a temporary speed bump for Novartis than a roadblock. Highlighting Pluvicto’s expansive footprint of more than 880 U.S. treatment sites, Novartis CEO Vas Narasimhan recently noted that a major focus for the company is now “getting additional depth” in those existing sites.
Zanzonico remains hopeful that “the tail will not wag the dog”—that the proposed NRC rule would not dictate clinical care because radioligand therapies like Pluvicto are effective. Still, he acknowledges that standalone facilities and community hospitals could face real challenges.
That optimism, however, doesn’t lessen the urgency to revise DG-8070, Zanzonico argues.
“It’s simply a matter of how easily, how quickly, how cost-effectively these therapies can be implemented,” he said. “It would be easier, more cost-effect, if the regulations were formulated in such a way that did not require additional technical or physics support.”