As cancer care continues to evolve, oncology and the entire healthcare ecosystem are looking to targeted radiopharmaceuticals (TRPs) to address a range of oncology and even non-oncology indications. TRPs consist of a targeting molecule, linker, chelating agent and radionuclide. Together they can deliver DNA-damaging radiation to cells expressing molecular targets. TRPs can also serve as standalone or companion imaging agents to identify patients whose cells express actionable molecular targets and who would benefit from TRP therapies. Not surprisingly, we’ve seen several large TRP deals in recent months.

Several different healthcare provider (HCP) specialists and hospital staff across referring and treating institutions must collaborate to bring TRPs to patients. This figure shows the journey of TRP treatments and imaging agents and details how patients, products and resources play a role.
 

While TRPs are promising, there are still many barriers to successful commercialization. For example, despite its early success, about 70% of U.S. oncologists report challenges using the TRP therapy Pluvicto. Each phase of the TRP journey includes challenges, which we describe in detail below.
 

Institutional approval for a new radiopharmaceutical

For a site to offer TRPs, it must obtain a radioactive materials (RAM) license that requires the facility to have radiation safety procedures in place and a supervising authorized user (AU) on staff. An AU is typically a nuclear medicine physician or radiation oncologist with formal training in Nuclear Regulatory Commission (NRC) radiation handling.
 

The requirements for RAM licensing present the biggest regulatory hurdle that’s currently limiting the number of sites offering TRPs. In addition, if a TRP includes a radionuclide not under the site’s RAM license, the site must apply to extend the RAM license to include the new radionuclide. This can pose an additional commercialization barrier to introducing TRPs that use novel radionuclides.
 

“To administer a radiopharmaceutical, it’s essential to understand the applicable rules and regulations,” said Dr. Michael Yu, chief of nuclear medicine at Temple University Health System. “These may include federal, NRC or state guidelines, along with rules set by state-level departments of environmental protection. You’ll need a radiation safety officer to ensure these rules and regulations are followed as they evolve.”
 

TRPs must go through pharmacy and therapeutics (P&T) committee review and manufacturer onboarding. Typically, a nuclear medicine physician or radiation oncologist advocates for the addition of a new TRP, and the P&T committee discusses its clinical data, logistical factors and financial considerations.
 

Upon P&T committee approval, TRP manufacturers onboard sites, with the depth and duration of this training dictated by the site’s capabilities and experience in delivering TRPs. For example, a TRP with a novel radionuclide would require more onboarding than a TRP with a radionuclide with which the hospital is familiar. The process to approve and onboard a new TRP typically takes between one and four months.
 

Consultation and referrals for targeted radiopharmaceuticals

A patient’s TRP journey often begins by consulting an organ specialist or medical oncologist who writes a referral to a nuclear medicine physician or radiation oncologist for TRP imaging agents and TRP therapy treatment. With TRPs delivered only in select institutions, the referral is often external, and it marks a critical step in the TRP journey.

Referrals from organ specialists and medical oncologists to nuclear medicine or radiation oncology present three distinct challenges:

Recognizing TRP candidacy: The referring HCP must first correctly identify the patient as a candidate for a TRP. Novartis CEO Vas Narasimhan recently acknowledged that timely referrals from community-based HCPs are a key challenge to Pluvicto adoption. Referring HCPs must also provide patient education and support to combat the misunderstanding or fear of radiation therapy, or “radiophobia.”
 

Identifying a TRP referral destination: Referring HCPs who are not affiliated with a site that offers TRPs may find it difficult to identify TRP referral destinations. This challenge is especially noteworthy for HCPs practicing in rural areas far from facilities capable of delivering TRPs. Even with hospital locators available for TRPs, referring HCPs could still need a contact at the TRP administering center. Furthermore, referring HCPs may worry about losing visibility to their patient after the referral.
 

A lack of HCPs qualified to prescribe and administer TRPs: Nuclear medicine physicians and radiation oncologists qualify to prescribe and administer TRPs through their formal training, but these are not common specialties. There is a shortage of nuclear medicine physicians and the number of fellowship programs for nuclear medicine has been stagnant or decreasing.
 

Further, NRC-required training is onerous. Among other requirements, candidates must complete hundreds of hours of classroom and practical training overseen by a qualified preceptor.
 

Targeted radiopharmaceuticals imaging agents
 

To receive a TRP therapy, patients must test positive for an actionable target such as a prostate-specific membrane antigen or somatostatin receptor—via TRP imaging agents. This imaging process is a microcosm of the overall TRP process. First, staff select and order the TRP imaging agent to be used in the scan. They then submit prior authorization (PA). After PA is complete, staff typically order and schedule a PET scan and interpret its findings. The process is similar in other ways too:

• TRP imaging agents require careful product handling and radioactive waste disposal
• PA and patient scheduling can be particularly burdensome
• TRP imaging agents can be limited by PET scanner availability and capacity
• Smaller institutions may not have access to PET scanners and need to coordinate external referrals

A difference from TRP therapies is that the radionuclides used in TRP imaging agents typically have a much shorter half-life than TRP therapy radionuclides. This means patient scheduling, administration and imaging requires even greater coordination and urgency. Accordingly, TRP imaging agents are often manufactured through a decentralized approach to reduce transit time between manufacturing and administration.

Prescribing and ordering targeted radiopharmaceuticals

Once a patient is deemed eligible for a TRP therapy, the nuclear medicine physician or radiation oncologist will write a prescription and work with office staff to submit documents for PA. The PA requirement is a hurdle for smaller medical offices in particular, as they have less staff available to help with documentation. PA denials may require appeals, further delaying TRP administration.

After a prescription is written and the PA process is complete, nuclear medicine nurses, technologists or office staff order the TRP therapy and schedule the patient for TRP administration. TRP therapies have a short half-life, so ordering, manufacturing and patient scheduling must be tightly coordinated. Further, using the manufacturer’s portal to schedule administration is often time consuming. As with cell therapies, there are multiple portals for different products, which increase administrative burden at the hospital.

Manufacturing targeted radiopharmaceuticals

TRP manufacturing can cause bottlenecks, as it requires more specialized facilities and materials compared to traditional small molecule and biologic manufacturing. Supply chain constraints can influence commercialization, as we saw with Pluvicto’s supply issues, as well as clinical trials, most recently experienced by RayzeBio.
 

Radionuclide sourcing is the main challenge. Starting materials for decay-based Lutetium-177 and Actinium-225 manufacturing processes are quite rare. Cyclotron manufacturing, while increasing in frequency, requires significant upfront capital investment. By contrast, some manufacturers such as Perspective Therapeutics are using Lead-212 and obtaining it through natural decay from Thorium-228, which has multiple global suppliers and is stable for two years.
 

“The easiest, safest and cheapest way to make an isotope is natural decay,” said Perspective Therapeutics CEO Thijs Spoor. “If you have something that turns into lead, what you’re looking for is natural decay.”
 

Manufacturers such as Perspective Therapeutics using Lead-212 in TRPs consider it a “Goldilocks” radionuclide with a strong anti-tumor effect and a cleaner decay chain than Actinium-225.
 

The manufacturing of the full TRP construct requires a critical decision: Should you centralize manufacturing to a small number of sites or decentralize manufacturing to a larger number of sites closer to the hospitals delivering TRPs? A centralized approach is often used with TRPs containing radionuclides with half-lives measured in days, while a decentralized approach is deployed for TRPs containing radionuclides with half-lives measured in hours. Further, there is a question about the value of redundancy within individual manufacturing facilities or across multiple facilities, as contamination­—via a spill of radioactive material or a similar event—could compromise production within an individual facility.
 

“I challenge you to find any modern distribution theory that says a single point of failure is actually the best way to build a supply chain,” Spoor said. “In the event of a spill, you must shut the facility down for 10 half-lives. So, if you have Actinium-225 with a 10-day half-life, multiplied by 10 half-lives, you’re shutting down for 100 days. That’s a major disruption.”
 

Distributing targeted radiopharmaceuticals

The distribution model for a TRP depends on its manufacturing model. Centralized manufacturing entails a more standardized distribution and sometimes involves engaging with specialty pharmacies. Decentralized manufacturing requires communicating with multiple courier services, which can increase logistical burdens for both hospitals and manufacturers. And the visibility of delivery issues may be delayed because key information, such as GPS tracking of the courier or weather and traffic information, is not necessarily integrated into hospital-facing portals. Errors in the distribution process—whether problems stemming from the manufacturer or a logistics issue at the hospital—can result in delayed or missed doses. The half-life of a product will also directly affect its distribution and storage characteristics.
 

Targeted radiopharma preparation, administration and follow up
 

Hospitals delivering TRPs need radioactive-safe “hot” labs to receive, test and prepare the TRP for administration. Once the product is ready for administration, it’s delivered to the patient by an accredited nuclear medicine physician or radiation oncologist in an isolated infusion room or space with a designated restroom. This standard is designed to help reduce radiation exposure to other patients or staff.
 

After administration, the nuclear medicine physician or radiation oncologist must educate the patient on radiopharmaceutical safety. This may include specifying limitations on contact with others, depending on the TRP radionuclide. Hospitals are also required to follow proper guidelines around disposing radioactive waste, which are often stipulated both by the TRP manufacturer and state and national governments.

To maximize TRP’s potential for patients and manufacturers, manufacturers need to solve these 10 specific challenges.

While TRP therapies and diagnostics have incredible clinical and commercial potential in oncology and other therapeutic areas, to fully realize that potential, manufacturers must comprehensively understand the TRP journey and prepare to address its challenges before and throughout commercialization.