[{"id":"b-ac225-supply","kind":"bottleneck","name":"Actinium-225 supply","aka":[],"tldr":"There is barely enough of the radioactive metal actinium-225 in the world to treat a few hundred patients a year, even though several new cancer drugs need it. New ways of making it are being built, but they are not yet running at full scale.","summary":"Actinium-225's legacy supply comes from milking thorium-229 'cow' generators held at only four sites worldwide: Oak Ridge National Laboratory (US), the Joint Research Centre in Karlsruhe (Germany), the Institute for Physics and Power Engineering (Russia, irregular), and formerly SCK CEN (Belgium). Together they yield roughly 63 GBq (1.7 Ci) a year, which a 2025 review estimates is enough for only 100 to 200 patient treatments globally, against research and trial demand alone estimated at around 185 GBq (5 Ci) a year.\n\nThe scarcity has already stopped a clinical programme: in June 2024 Bristol Myers Squibb's RayzeBio paused new-patient enrolment in the phase 3 ACTION-1 trial of RYZ101 (225Ac-DOTATATE) specifically because it could not secure enough actinium-225, with the company citing a single global supplier for the trial. Every alpha-emitting PSMA and DOTATATE programme in development competes for the same small pool.\n\nThe fix is a shift from thorium-229 decay to direct production: accelerator irradiation of radium-226 or thorium-232 targets. The US DOE Isotope Program runs a tri-laboratory accelerator effort (Brookhaven, Los Alamos, Oak Ridge); commercial entrants are building cyclotron and electron-accelerator routes using radium-226 stocks. None of these has yet demonstrated tens of curies a year of GMP-grade material, which is the scale several late-stage alpha-emitter programmes will need if they reach approval.","asOf":"2026-09-22","links":[{"label":"Actinium-225/Bismuth-213 as potential leaders for targeted alpha therapy (2025 review)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12468084/"},{"label":"FiercePharma: BMS and RayzeBio halt radiotherapy trial enrollment after isotope runs scarce","url":"https://www.fiercepharma.com/pharma/bms-and-rayzebio-halt-radiotherapy-trial-enrollment-after-isotope-runs-scarce"},{"label":"DOE Isotope R&D and Production overview","url":"https://www.energy.gov/science/ip/isotope-rd-and-production-doe-ip"},{"label":"PanTera secures funding to scale actinium-225 production (company announcement, via Synapse)","url":"https://synapse.patsnap.com/article/pantera-secures-E282AC134m-to-boost-actinium-225-production"}],"tags":["alpha emitter","supply chain","actinium-225"],"related":["idea-reg-legacy-radium-recovery-ac225","idea-reg-alpha-emitter-portfolio","idea-reg-ac225-accelerator-pharmacopoeia","idea-reg-isotope-supply-observatory","b-rlt-trial-capacity","b-manufacturing-cell-therapy","ac-225"],"indications":[],"sections":[],"technologies":["actinium-225-supply","targeted-alpha-therapy","cyclotron-isotope-production","therapy-isotope-supply-chain"],"targets":[],"drugs":["ac225-psma","ryz101"],"companies":["rayzebio","bms","actinium-pharmaceuticals","terrapower-isotopes","orano-med","northstar-medical-radioisotopes","bayer"],"institutions":[],"pathways":[],"terms":[],"trials":["action-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"regulation-manufacturing","severity":"critical","metrics":[{"label":"Legacy thorium-229 generator supply, worldwide","value":"~63 GBq (1.7 Ci) per year across 4 sites","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12468084/"},{"label":"Patients that legacy supply can treat per year","value":"100–200 globally","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12468084/"},{"label":"Estimated annual demand from research and clinical trials alone","value":"~185 GBq (5 Ci)/year","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12468084/"},{"label":"RayzeBio (BMS) paused new enrolment in phase 3 ACTION-1 trial","value":"June 2024, cited as due to actinium-225 shortage","url":"https://www.fiercepharma.com/pharma/bms-and-rayzebio-halt-radiotherapy-trial-enrollment-after-isotope-runs-scarce"}],"causes":["Only four sites worldwide hold a usable thorium-229 stockpile, and one (Russia's IPPE) does not supply regularly.","Direct accelerator production of actinium-225 from radium-226 or thorium-232 is technically demanding and has not yet been demonstrated at industrial scale outside pilot facilities.","Radium-226 feedstock itself is scarce and its supply chain (legacy sealed sources, mining by-product) is not yet organised for pharmaceutical use.","Alpha-emitter production and purification require heavier shielding and faster processing than beta emitters because of short-lived, highly active daughter nuclides."],"currentEfforts":["US DOE Isotope Program tri-laboratory accelerator effort (Brookhaven National Laboratory, Los Alamos National Laboratory, Oak Ridge National Laboratory) producing actinium-225 by proton irradiation.","Commercial accelerator-route entrants (e.g. cyclotron irradiation of radium-226, announced by CNL/ITM-linked ventures from October 2024) aiming for GMP-grade supply.","Bayer's supply agreement with an accelerator-route producer to secure actinium-225 for its own clinical programmes from H2 2024.","BMS/RayzeBio advancing on-site accelerator production to de-risk its own trial supply after the ACTION-1 pause."],"successLooksLike":"Multiple independent, non-Th-229-dependent producers scaling to tens of curies a year of GMP-grade actinium-225, enough that a single supplier problem no longer stops a phase 3 trial."},{"id":"b-authorized-user-shortage","kind":"bottleneck","name":"Authorized user shortage for radionuclide therapy","aka":[],"tldr":"In the US, only specially trained doctors are legally allowed to give radioactive cancer treatments. Whether there are enough of these doctors to keep up with demand is genuinely disputed: regulators and physician groups have looked at the numbers and reached different conclusions.","summary":"Under US NRC rule 10 CFR 35.390, only a physician who has completed the required training and experience -- either full nuclear medicine/radiation oncology board certification, or an alternate pathway of about 700 hours (roughly four months) of structured training -- can become an 'Authorized User' (AU) and administer radionuclide therapies requiring a written directive. Since 2017-2018 the NRC's Advisory Committee on the Medical Uses of Isotopes (ACMUI) has repeatedly examined whether a future AU shortage will bottleneck access to radioligand therapy, prompted by the approval of 177Lu-DOTATATE and the shrinking pipeline of US-trained nuclear medicine physicians.\n\nThe evidence is contested. A 2019 JNM editorial estimated the existing board-certified US nuclear medicine physician workforce at around 1,200, with 50-60 new ABNM diplomates entering annually, and projected that meeting demand for 150,000-200,000 radionuclide therapy cycles a year (roughly 50,000 patients at four cycles each) would need about 150 dedicated theranostic centres -- a number the authors argued the existing and incoming workforce could support, so long as radiologists and radiation oncologists trained under the alternate pathway are counted. The NRC's own ACMUI subcommittee concluded in 2018-2019 that there was 'no objective data to confirm an authorized user shortage' and did not recommend creating a lower-training limited-scope AU pathway.\n\nWhatever the physician-supply numbers show nationally, the practical effect for patients is the same: AU status is concentrated in nuclear medicine, radiology and radiation oncology, not in the medical oncology clinics that manage most prostate cancer and neuroendocrine tumour patients, so referral to a licensed, AU-staffed centre remains an extra step in every patient's pathway.","asOf":"2026-09-22","links":[{"label":"JNM editorial: Delivering radionuclide therapies requires extensive training and competence","url":"https://jnm.snmjournals.org/content/60/1/1"},{"label":"NRC Advisory Committee on the Medical Uses of Isotopes, transcript on AU shortage evidence","url":"https://www.nrc.gov/docs/ML1907/ML19077A112.pdf"},{"label":"NRC: Authorized Individuals (10 CFR Part 35 training requirements)","url":"https://www.nrc.gov/materials/miau/med-use-toolkit/auth-individuals"},{"label":"SNMMI Theranostics Stakeholders Summit white paper (2025)","url":"https://snmmi.org/common/Uploaded%20files/News/Theranostics_Stakeholders_Summit_White_Paper_FINAL_6-2025.pdf"}],"tags":["workforce","regulation","authorized user"],"related":["b-nuclear-medicine-workforce","b-site-readiness-referral","lu-177"],"indications":[],"sections":[],"technologies":["radioligand-therapy","prrt","psma-pet"],"targets":[],"drugs":[],"companies":[],"institutions":["snmmi"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"people-culture","severity":"moderate","metrics":[{"label":"Training hours required for the 10 CFR 35.390 alternate Authorized User pathway","value":"700 hours (~4 months)","url":"https://jnm.snmjournals.org/content/60/1/1"},{"label":"Estimated US board-certified nuclear medicine physician workforce (2019)","value":"~1,200, plus 50–60 new ABNM diplomates/year","url":"https://jnm.snmjournals.org/content/60/1/1"},{"label":"Estimated dedicated theranostic centres needed for projected US radionuclide-therapy demand","value":"~150 centres for 150,000–200,000 cycles/year","url":"https://jnm.snmjournals.org/content/60/1/1"},{"label":"NRC ACMUI subcommittee finding on AU shortage evidence","value":"\"No objective data to confirm an authorized user shortage\" (2018–19)","url":"https://www.nrc.gov/docs/ML1907/ML19077A112.pdf"}],"causes":["Authorized User status requires either full nuclear medicine/radiation oncology board certification or a separate, lengthy alternate training pathway that most medical oncologists never complete.","The physicians who see most prostate cancer and neuroendocrine tumour patients (medical oncologists, urologists) are usually not the physicians licensed to administer the radioactive therapy itself.","Whether a genuine national AU shortage exists is disputed between professional societies and NRC advisory findings, which has slowed any policy resolution either way."],"currentEfforts":["NRC ongoing Federal Register outreach and stakeholder consultation (since 2018) on whether to create a limited-scope AU pathway specifically for radiopharmaceutical therapy.","SNMMI's 2025 Theranostics Stakeholders Summit naming workforce education and training as one of four priority focus areas for the field.","University of Alabama at Birmingham / SNMMI Nuclear Medicine Therapy Intensive, launched 2024, as a dedicated short-course training route for physicians and staff entering radioligand therapy."],"successLooksLike":"A data-driven, agreed assessment of AU supply versus projected radioligand-therapy demand, and, if a genuine gap is confirmed, a validated limited-scope training pathway that expands capacity without compromising radiation safety."},{"id":"b-rlt-trial-capacity","kind":"bottleneck","name":"Clinical trial capacity for radioligand therapy","aka":[],"tldr":"There are so many new radioactive cancer drugs now being tested that the trials themselves compete with each other, and with approved treatments, for the same scarce radioactive material, the same specially licensed hospital rooms, and the same trained staff. Sometimes a trial has to pause enrolling new patients simply because the isotope has run out.","summary":"Radioligand therapy's clinical pipeline has grown faster than the trial infrastructure needed to run it: industry analyses describe more than 200 lutetium-177-based radiopharmaceutical therapy trials of all phases in progress, including a large share of all active phase 3 radiopharmaceutical therapy trials underway worldwide. Because trial doses and commercial doses are drawn from the same limited isotope supply, a shortage hits trials directly: in June 2024, Bristol Myers Squibb's RayzeBio paused new-patient enrolment in the phase 3 ACTION-1 trial of RYZ101 (225Ac-DOTATATE) because it could not secure enough actinium-225, with a trial investigator noting there was only one Ac-225 supplier for the entire global study; patients already enrolled continued treatment while the company worked to bring on-site production online.\n\nSite-level capacity compounds the isotope constraint. A clinical-operations guide to radiopharmaceutical trials notes that qualifying a site can take several months longer than for a conventional drug trial, because sites need an active radioactive-materials licence, shielded rooms, dedicated patient toilets, imaging-camera qualification (dose calibrator checks, dummy deliveries), and pharmacy staff specifically trained to receive time-critical, non-reschedulable shipments; some radiopharmaceuticals also require ordering a month or more in advance, so a patient's slot can be blocked by another patient's ongoing treatment cycle. The same nuclear medicine departments that run these trials are also treating growing numbers of commercial Pluvicto and Lutathera patients, so trial and standard-of-care patients increasingly compete for the same limited administration slots at the same centres.\n\nBecause a no-show wastes a dose that can cost tens of thousands of dollars and cannot be re-used, site readiness guidance now stresses building slack into scheduling and engaging nuclear medicine leadership early, on top of the underlying isotope-supply constraint that no amount of site-level planning alone can fix.","asOf":"2026-09-22","links":[{"label":"FiercePharma: BMS and RayzeBio halt radiotherapy trial enrollment after isotope runs scarce","url":"https://www.fiercepharma.com/pharma/bms-and-rayzebio-halt-radiotherapy-trial-enrollment-after-isotope-runs-scarce"},{"label":"Preparing clinical sites for radiopharmaceutical trials (SCRS)","url":"https://myscrs.org/preparing-clinical-sites-radiopharmaceutical-trials/"},{"label":"Radioligand therapy manufacturing capacity: the CDMO and isotope-supply constraint (industry analysis)","url":"https://intuitionlabs.ai/articles/radioligand-therapy-manufacturing-capacity"}],"tags":["clinical trials","capacity","isotope supply"],"related":["b-ac225-supply","b-hot-lab-capacity","b-site-readiness-referral","lu-177","ac-225"],"indications":[],"sections":[],"technologies":["therapy-isotope-supply-chain","targeted-alpha-therapy","lu177-radioligand-therapy"],"targets":[],"drugs":["ryz101","pluvicto","lutathera"],"companies":["rayzebio","bms","novartis"],"institutions":[],"pathways":[],"terms":[],"trials":["action-1"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"trials","severity":"major","metrics":[{"label":"Lutetium-177 radiopharmaceutical therapy trials of all phases reported in progress (industry analysis)","value":">200","url":"https://intuitionlabs.ai/articles/radioligand-therapy-manufacturing-capacity"},{"label":"RayzeBio (BMS) paused new-patient enrolment in phase 3 ACTION-1 trial","value":"June 2024, cited cause: actinium-225 shortage, single global supplier","url":"https://www.fiercepharma.com/pharma/bms-and-rayzebio-halt-radiotherapy-trial-enrollment-after-isotope-runs-scarce"}],"causes":["Trial doses and commercial doses are drawn from the same constrained global isotope supply (particularly actinium-225 and, to a lesser extent, lutetium-177), so a supply shortfall hits both simultaneously.","Radiopharmaceutical trial sites typically take several months longer to qualify than conventional drug trial sites, because of radioactive-materials licensing, shielded-room construction, and imaging-equipment qualification requirements.","Nuclear medicine departments running trials are also treating a growing volume of approved standard-of-care patients, creating direct scheduling competition for the same hot labs and administration slots.","A missed or cancelled patient appointment wastes an individually manufactured, non-reschedulable dose that can cost tens of thousands of dollars, so scheduling slack has to be built in at a cost most conventional trials do not bear."],"currentEfforts":["BMS/RayzeBio advancing on-site accelerator-based actinium-225 production specifically to de-risk ACTION-1 and its wider RYZ101 programme after the 2024 enrolment pause.","Novartis and other sponsors building dedicated, multi-site radioligand therapy manufacturing capacity ahead of pivotal trial readouts, partly to protect trial as well as commercial supply.","Specialist clinical-operations guidance for radiopharmaceutical trial site readiness, recommending early engagement with nuclear medicine leadership and explicit resource-allocation planning between trial and standard-of-care caseloads."],"successLooksLike":"Isotope allocation and site capacity for clinical trials are planned and, where necessary, ring-fenced separately from commercial supply, so a manufacturing or feedstock shortage no longer forces a phase 3 trial to pause enrolment."},{"id":"b-cold-chain-logistics","kind":"bottleneck","name":"Cold chain and time-critical logistics","aka":[],"tldr":"Radioactive medicines keep losing strength from the moment they are made, so a doctor prescribes a specific amount to arrive at a specific time. If a flight is delayed, an airline refuses the cargo, or customs holds the package for even a few hours, the dose can decay below the amount a patient needs and has to be thrown away.","summary":"Because radioactive decay cannot be paused, every radiopharmaceutical shipment is ordered as an activity calibrated to a specific date and time, with the manufacturer dispensing extra margin so the prescribed activity still holds when the patient is dosed. For the shortest-lived isotopes the arithmetic is unforgiving: molybdenum-99, with a 66-hour half-life, loses about 22% of its activity to a single day's transport delay. A missed delivery window is not simply a late shipment -- the product is unusable and cannot be replaced from any stockpile.\n\nMost radiopharmaceutical shipments travel as Class 7 dangerous goods under IATA and national transport rules, on top of any temperature control (commonly 2-8°C) the specific product needs, and this dual compliance burden restricts which carriers and routes are available. Some major airlines refuse Class 7 cargo outright, individual pilots have refused loads once they see radioactive labelling, and flights that do accept it often cap the total transport index (radiation level) permitted per aircraft. A 2026 survey of six English-speaking Southern African Development Community countries found customs clearance delays of up to a day reported in South Africa, Zambia, Namibia, Tanzania and Mauritius, with reported order-to-delivery lead times ranging from a few days (regional generator shipments) to about a month for products sourced from further afield.\n\nThe IAEA and ICAO have responded with a formal denial-and-delay-of-shipment reporting mechanism and national focal points to track and resolve recurring blockages, and IATA now requires shippers to hold specific Class 7 certification, but the underlying constraint -- a short, physics-set delivery window intersecting with an inconsistent, carrier-by-carrier and country-by-country regulatory patchwork -- has not been resolved.","asOf":"2026-09-22","links":[{"label":"INMM PATRAM 2010: Transport of radiopharmaceuticals, cradle to the patient","url":"https://resources.inmm.org/system/files/patram_proceedings/2010/233_Paper_TRANSPORT-OF-RADIOPHARMACEUTICALS,-CRADLE-TO-THE-P.pdf"},{"label":"Challenges in radiopharmaceutical importation across six SADC countries (2026)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13002445/"},{"label":"ICAO Assembly working paper on denial and delay of shipment of radioactive material","url":"https://www.icao.int/sites/default/files/Meetings/a42/Documents/WP/wp_439_en.pdf"},{"label":"Radiopharmaceutical supply chain structure (MedRaySintell)","url":"https://medraysintell.com/radiopharmaceutical-supply-chain-structure-7-7/"}],"tags":["logistics","Class 7","cold chain","half-life"],"related":["idea-reg-regional-radiopharmacy-hubs","b-mo99-supply","b-site-readiness-referral","mo-99"],"indications":[],"sections":[],"technologies":["therapy-isotope-supply-chain","radiopharmacy-network","pet-tracer-manufacturing"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"access-delivery","severity":"moderate","metrics":[{"label":"Activity lost to a one-day transport delay of molybdenum-99 (66-hour half-life)","value":"~22%","url":"https://resources.inmm.org/system/files/patram_proceedings/2010/233_Paper_TRANSPORT-OF-RADIOPHARMACEUTICALS,-CRADLE-TO-THE-P.pdf"},{"label":"Reported radiopharmaceutical order-to-delivery lead times across surveyed SADC countries","value":"range: a few days to ~1 month","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13002445/"},{"label":"Customs clearance delays reported for radiopharmaceutical imports","value":"up to ~1 day, in multiple surveyed countries","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13002445/"}],"causes":["Radioactive decay is continuous and irreversible, so there is no buffer stock to fall back on if a shipment is delayed anywhere in the chain.","Radiopharmaceuticals must simultaneously meet Class 7 radioactive-material transport rules and, for many products, refrigerated cold-chain requirements, a combination few carriers are equipped or willing to handle.","Some airlines and individual crews decline Class 7 cargo outright, narrowing available routes, and remaining carriers cap how much transport-index (radiation level) cargo they will carry per flight.","Customs procedures for radioactive material are inconsistently applied across countries, and staff at many border posts have limited familiarity with the specific documentation required."],"currentEfforts":["IAEA/ICAO joint denial-and-delay-of-shipment (DoS) reporting framework, with each IAEA member state encouraged to nominate a National Focal Point to resolve recurring blockages.","IATA Class 7 shipper certification requirements intended to standardise documentation and reduce carrier refusals.","Specialised radiopharma logistics providers building dedicated Class 7 lanes and direct routing to minimise transit hours for short-half-life products.","Customs staff education programmes proposed in regional supply-chain studies to reduce clearance delays for time-critical shipments."],"successLooksLike":"Harmonised customs treatment and reliable Class 7 carrier capacity worldwide, so that radioactive decay -- not paperwork, airline policy, or a border delay -- is the only factor limiting how far a dose can travel."},{"id":"b-dosimetry-standardisation","kind":"bottleneck","name":"Dosimetry standardisation for radioligand therapy","aka":[],"tldr":"Doctors give almost every patient the same fixed amount of radioactive drug, rather than measuring how much radiation each person's tumour and organs actually absorb and adjusting the dose. Personalising the dose might work better for some patients, but nobody has yet proven it clearly enough for it to become the standard of care.","summary":"177Lu-PSMA-617 (Pluvicto) is approved and almost always given at a fixed activity of 7.4 GBq every six weeks; the joint 2023 EANM/SNMMI procedure guideline confirms that patient-specific dosimetry is not mandatory for in-label use. Yet academic dosimetry studies show wide inter-patient variation: EANM Dosimetry Committee analyses report that the number of PRRT cycles needed to reach a preset kidney absorbed-dose limit ranges from 2 to 10 across patients, and the total activity required to hit that limit varies by a factor of roughly 1.5 for somatostatin-receptor therapy and by a factor of 3 for PSMA therapy.\n\nThe unresolved question is whether measuring and personalising that dose actually improves outcomes enough to justify the extra imaging burden. In its January 2025 reply to an EMA concept paper on clinical evaluation of therapeutic radiopharmaceuticals, EANM stated plainly that 'divergent opinion persists... the lack of sufficiently robust evidence demonstrating that personalizing administered activities based on dosimetry provides tangible benefits' means EANM does not hold a definitive position recommending dosimetry-guided over fixed-activity dosing. Methods themselves are only partly harmonised: the EANM Dosimetry Committee's 2022 recommendations for 177Lu-SSTR/PSMA dosimetry, and MIRD Pamphlet No. 26 for quantitative 177Lu SPECT, describe standard operating procedures, but implementation still varies by centre in imaging timepoints, segmentation method and software.\n\nAlpha emitters add a further layer of difficulty: EANM's same 2025 submission flags that actinium-225's limited imaging potential on current nuclear-medicine cameras means image-based dosimetry approaches developed for beta emitters do not simply transfer across, and new strategies or technology are still needed.","asOf":"2026-09-22","links":[{"label":"EANM Dosimetry Committee recommendations for 177Lu-labelled SSTR/PSMA ligands (2022)","url":"https://link.springer.com/article/10.1007/s00259-022-05727-7"},{"label":"Joint EANM/SNMMI procedure guideline for 177Lu-PSMA-RLT (2023)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10317889/"},{"label":"EANM reply to EMA consultation on clinical evaluation of therapeutic radiopharmaceuticals (Jan 2025)","url":"https://eanm.org/wp-content/uploads/2025/02/EANM-Reply-to-the-public-consultation-on-the-European-Medicines-Agency-Concept-paper-on-clinical-evaluation-of-therapeutic-radiopharmaceuticals-in-oncology.pdf"}],"tags":["dosimetry","standardisation","guideline"],"related":["idea-net-dosimetry-prrt","idea-total-body-pet-dosimetry","b-dose-optimisation","lu-177","ac-225"],"indications":[],"sections":[],"technologies":["radioligand-dosimetry","in-vivo-dosimetry","quantitative-imaging-biomarkers","prrt"],"targets":[],"drugs":["pluvicto","lutathera"],"companies":[],"institutions":["eanm","snmmi","ema"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"data-knowledge","severity":"moderate","metrics":[{"label":"Number of PRRT cycles needed to reach a preset kidney dose limit, across patients","value":"range 2–10 cycles","url":"https://link.springer.com/article/10.1007/s00259-022-05727-7"},{"label":"Variation in total activity needed to reach a preset absorbed-dose limit","value":"~1.5-fold (SSTR therapy), ~3-fold (PSMA therapy)","url":"https://link.springer.com/article/10.1007/s00259-022-05727-7"},{"label":"177Lu-PSMA-617 approved regimen: fixed activity per cycle","value":"7.4 GBq (200 mCi) every 6 weeks (±1 week), dosimetry not mandatory in-label","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10317889/"}],"causes":["No large randomised trial has yet shown that dosimetry-guided individualised dosing improves survival or reduces toxicity compared with fixed-activity dosing.","Dosimetry protocols (imaging timepoints, organ/tumour segmentation, software) are not fully harmonised across centres, so results are not always directly comparable.","Multiple SPECT/CT imaging sessions over days add patient burden and resource use that many centres cannot absorb for every patient.","Alpha emitters such as actinium-225 are difficult to image directly with current nuclear medicine cameras, so beta-emitter dosimetry methods do not transfer straightforwardly."],"currentEfforts":["EANM Dosimetry Committee recommendations (2022) for harmonised dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands.","Joint EANM/MIRD Pamphlet No. 26 on quantitative 177Lu SPECT methodology for dosimetry.","EANM's proposal, in its 2025 EMA consultation reply, for a unified pan-European database to pool dosimetric data across centres and generate the evidence base still missing.","EANM guidance document specifically for dosimetry in first-in-human and early-phase clinical trials of new radioligands."],"successLooksLike":"A trial-validated, low-burden dosimetry protocol shown to improve outcomes or reduce toxicity versus fixed dosing, harmonised across centres and reimbursed as standard practice where it adds value."},{"id":"b-enriched-target-material","kind":"bottleneck","name":"Enriched target material for therapeutic isotopes","aka":[],"tldr":"Making the pure form of lutetium-177 used in cancer drugs like Pluvicto requires starting from a rare, heavily purified metal called ytterbium-176. Almost all of the world's supply of that starting material has come from one country, which is a risky place for the whole medicine to depend on.","summary":"No-carrier-added lutetium-177 (177Lu), the form used in Pluvicto and Lutathera, is made by neutron-irradiating a target of ytterbium enriched to above 96-99% in the stable isotope ytterbium-176, then chemically separating the trace lutetium-177 produced. Only about one in 5,000 atoms in the irradiated target ends up as lutetium-177, and producing the same activity by this route needs roughly a thousand times more enriched starting material than the alternative (but lower-purity) carrier-added route using enriched lutetium-176. There is no accelerator-based alternative: no-carrier-added Lu-177 can only be made by neutron irradiation of Yb-176.\n\nThe enrichment step itself -- separating Yb-176 from the other six stable ytterbium isotopes -- has historically been dominated by Russian electromagnetic separators (calutrons), described by the EU's Economic and Social Committee as 100% European dependence on Russia for this specific material. The US Department of Energy's Oak Ridge National Laboratory restarted its own electromagnetic separation in the early 2020s but as of 2022 could only offer 'research quantities' not available for commercial resale, and Western capacity has generally atrophied because the customer base for any single enriched isotope is small and capital costs are high.\n\nThe same underlying problem -- a handful of highly specialised, low-throughput separation facilities feeding a fast-growing radioligand therapy market -- applies to other enriched targets in the pipeline (enriched molybdenum-100 for cyclotron-based Mo-99/Tc-99m, enriched gadolinium for astatine-211 routes), making enriched stable-isotope supply a structural constraint on the whole field, not just on lutetium-177.","asOf":"2026-09-22","links":[{"label":"Challenges and future options for the production of lutetium-177 (EJNMMI, 2021)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8241800/"},{"label":"One country's isotope, everyone's cancer drug (Problem Genome brief on Yb-176 dependence)","url":"https://www.problemgenome.com/briefs/health-yb176-enriched-isotope-single-country-supply"},{"label":"DOE Isotope R&D and Production, FY2025 budget request (stable isotope enrichment priorities)","url":"https://www.energy.gov/sites/default/files/2024-03/FY2025-PresidentsRequest-IRP.pdf"}],"tags":["supply chain","ytterbium-176","lutetium-177","enrichment"],"related":["idea-reg-yb176-enrichment-capacity","b-mo99-supply","b-ac225-supply","tc-99m","mo-99","lu-177","at-211"],"indications":[],"sections":[],"technologies":["therapy-isotope-supply-chain","research-reactor-isotope-production","lu177-radioligand-therapy"],"targets":[],"drugs":["pluvicto","lutathera","itm-11"],"companies":["novartis","itm","ntp-radioisotopes","curium"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"regulation-manufacturing","severity":"major","metrics":[{"label":"Fraction of irradiated ytterbium-176 target atoms converted to lutetium-177","value":"~1 in 5,000","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8241800/"},{"label":"Extra enriched target material needed for the no-carrier-added (Yb-176) route vs the carrier-added (Lu-176) route, for equivalent activity","value":"~1,000-fold more","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8241800/"},{"label":"EU dependence on Russia for enriched ytterbium-176 supply","value":"100% (EU Economic and Social Committee statement)","url":"https://www.problemgenome.com/briefs/health-yb176-enriched-isotope-single-country-supply"}],"causes":["There is no feasible accelerator- or proton-based production route for lutetium-177: only neutron irradiation works, which locks the process to a small number of high-flux research reactors and to whichever enriched target is available to them.","Enrichment of ytterbium-176 requires electromagnetic separators (calutrons), gas centrifuges, or laser separation -- all capital-intensive, low-throughput technologies with very few operators worldwide.","The customer base for any single enriched stable isotope is small, so for decades it was cheaper to buy Russian material than to build competing Western capacity, and that Western capacity atrophied.","Chemical recovery and recycling of the expensive enriched ytterbium target after irradiation is technically demanding, so yields and reuse rates limit how far existing enriched stock can be stretched."],"currentEfforts":["US DOE Isotope Program restarting electromagnetic isotope separation and building the Stable Isotope Production Facility at Oak Ridge National Laboratory, initially for other isotopes (e.g. xenon-129) with stable-isotope enrichment as a stated strategic priority including ytterbium-176.","EU SAMIRA action plan and Euratom research calls specifically funding alternative, non-Russian ytterbium-176 production routes.","Radiopharmaceutical manufacturers (Novartis, ITM, others) reported to be pursuing multiple, geographically diversified Yb-176 supply agreements to reduce single-country exposure."],"successLooksLike":"At least two commercially viable, non-Russian sources of pharmaceutical-grade enriched ytterbium-176 (or an alternative no-carrier-added Lu-177 production route), so that lutetium-177 supply is not exposed to a single country's export policy."},{"id":"b-hot-lab-capacity","kind":"bottleneck","name":"Hot lab and shielded treatment room capacity","aka":[],"tldr":"Even where the radioactive medicine itself is available, giving it to a patient needs a specially shielded room, lead-lined equipment, and a toilet that can hold radioactive waste safely. Most hospitals only have one or two of these set up, which limits how many patients they can treat each week.","summary":"Administering a radioligand therapy such as 177Lu-PSMA-617 or 177Lu-DOTATATE requires a licensed 'hot lab': shielded space for receiving and dispensing the dose, a dose calibrator, syringe shields and pumps, and a decay-storage area for waste and used consumables. A 2021 German capacity analysis estimated the country's nationwide nuclear-medicine therapy bed capacity at around 234,000 treatment-days a year with a reserve of only about 19,000 bed-days (roughly 63 beds), concluding that Lu-177-PSMA therapy could reach that capacity limit in some federal states even before newer indications or additional radiopharmaceuticals are added.\n\nBuilding a hot lab is expensive and slow: the Netherlands' national innovation ecosystem review describes hot labs costing in the order of millions of euros and taking multiple years to set up, and notes that because they are often designed around a specific radiopharmaceutical, they may not flex to accommodate other products. Some centres, particularly urology clinics starting smaller programmes, have instead converted an existing procedure room into a part-time hot lab (used on designated days each month) with reinforced cabinetry, a second 'hot trash' bin, and a syringe pump and shield -- a lower-cost model that suits a modest caseload but does not scale to high volume.\n\nManufacturers have partly addressed the manufacturing side of this bottleneck (Novartis added a fourth global production site after Pluvicto's 2022-23 shortage and reports network capacity exceeding 250,000 doses a year), but the administration side -- shielded rooms, decay-tank capacity, and trained staff at the point of care -- has not scaled at the same pace, so treatment slots rather than drug supply are increasingly the limiting step at busy centres.","asOf":"2026-09-22","links":[{"label":"PSMA radioligand therapy could pose infrastructural challenges for nuclear medicine (German bed-capacity calculation)","url":"https://pubmed.ncbi.nlm.nih.gov/33530110/"},{"label":"How one urology clinic set up a hot lab for a radioligand therapy programme (UroToday)","url":"https://www.urotoday.com/video-lectures/practical-aspects-of-operationalizing-lutetium-177-177lu-psma-617-in-the-urology-clinic/video/3623-how-one-urology-clinic-successfully-sets-up-a-hot-lab-for-radioligand-therapy-program-william-oresick.html"},{"label":"The Dutch innovation ecosystem for nuclear medicine (hot lab cost and scarcity)","url":"https://nvng.nl/wp-content/uploads/FAST-rapportage-medische-isotopen_def.pdf"},{"label":"Radiopharmaceutical supply chain under pressure: can infrastructure keep up with demand?","url":"https://www.scienceandmedicinegroup.com/resource/radiopharmaceutical-supply-chain-under-pressure-can-infrastructure-keep-up-with-demand/"}],"tags":["infrastructure","hot lab","capacity"],"related":["b-site-readiness-referral","b-nuclear-medicine-workforce","b-radioactive-waste-regulation","lu-177"],"indications":[],"sections":[],"technologies":["radiopharmaceutical-gmp-release","radiopharmacy-network","nuclear-medicine-hardware","lu177-radioligand-therapy"],"targets":[],"drugs":["pluvicto","lutathera"],"companies":["novartis","itm"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"access-delivery","severity":"major","metrics":[{"label":"German nationwide nuclear-medicine therapy bed reserve for Lu-177-PSMA-RLT","value":"~19,000 of 234,000 bed-days/year (≈63 beds)","url":"https://pubmed.ncbi.nlm.nih.gov/33530110/"},{"label":"Novartis global radioligand therapy manufacturing network capacity target","value":">250,000 doses/year (company figure)","url":"https://www.scienceandmedicinegroup.com/resource/radiopharmaceutical-supply-chain-under-pressure-can-infrastructure-keep-up-with-demand/"}],"causes":["Hot labs cost in the order of millions of euros and take years to build, and are often engineered around one specific radiopharmaceutical rather than being flexible to new agents.","Shielded patient rooms and dedicated 'hot' toilets with radioactive-waste decay tanks are a fixed physical constraint at most hospitals, typically only two or three per site.","Nuclear-medicine bed and hot-lab capacity was planned around historic diagnostic and legacy-therapy caseloads, not the scale of demand created by PSMA- and SSTR-directed radioligand therapy.","Manufacturing capacity for the drug product itself has been scaled up faster than administration-site infrastructure, shifting the binding constraint downstream to the point of care."],"currentEfforts":["Novartis operating four global manufacturing sites for Pluvicto/Lutathera after the 2023 shortage, reporting combined capacity above 250,000 doses/year.","Community urology and oncology clinics converting existing procedure rooms into part-time hot labs (reinforced cabinetry, dedicated syringe shields/pumps, extra decay storage) as a lower-capital entry model.","Hospitals building dedicated 'theranostics wings' with multiple shielded rooms as radioligand therapy caseloads grow."],"successLooksLike":"Shielded room, decay-tank, and trained-staff capacity at treatment sites scale ahead of dose-manufacturing capacity, so an available dose is never wasted because there is nowhere and no one to give it to."},{"id":"b-manufacturing-cell-therapy","kind":"bottleneck","name":"Manufacturing cost and time for living and radioactive medicines","aka":[],"tldr":"Cell therapies take weeks to make for one patient and cost hundreds of thousands of dollars. Isotopes run short.","summary":"Autologous CAR-T, TIL and TCR-T are one-batch-per-patient manufacturing: leukapheresis, shipping, transduction, expansion, release testing and return take several weeks, during which some patients progress or die, a proportion of products fail specification, and list prices run to several hundred thousand dollars before hospital costs. Only a small fraction of eligible patients receive approved CAR-T because of slot availability, referral and cost. Radioligand therapy has a different supply problem: lutetium-177 depends on a handful of reactors and enrichment sources, and actinium-225 for alpha therapy has been limited to a few curies a year worldwide from thorium-229 stocks, with accelerator and thorium-based production only now scaling. ADCs and bispecifics have complex biologics supply chains with a small number of contract manufacturers. In vivo CAR generation, allogeneic products, point-of-care and automated manufacturing, and new isotope production routes are the technical answers.","asOf":"2026-09-08","links":[{"label":"Hernandez, Prasad & Gellad, Total costs of chimeric antigen receptor T-cell immunotherapy (JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.0977"},{"label":"Maude et al., Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia (ELIANA, NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1709866"},{"label":"US Department of Energy Isotope Program","url":"https://www.isotopes.gov/"}],"tags":[],"related":["radiopharma-roadmap","idea-reg-legacy-radium-recovery-ac225","idea-reg-ac225-accelerator-pharmacopoeia","idea-reg-yb176-enrichment-capacity","idea-reg-medical-isotope-reactor-reserve","idea-reg-alpha-emitter-portfolio","idea-reg-regional-radiopharmacy-hubs","idea-reg-isotope-supply-observatory","lu-177","ac-225"],"indications":["dlbcl","prostate","neuroendocrine"],"sections":[],"technologies":["radioligand-therapy","targeted-alpha-therapy"],"targets":[],"drugs":["pluvicto","lutathera","ac225-psma"],"companies":["novartis","terrapower-isotopes","orano-med","itm","curium"],"institutions":[],"pathways":[],"terms":["alpha-vs-beta","dosimetry","theranostics"],"trials":["vision"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"regulation-manufacturing","severity":"major","metrics":[{"label":"Estimated total cost of CAR-T therapy including list price and management of adverse events (2018 US analysis)","value":"Up to ~US$500,000 per patient","source":"Hernandez, Prasad & Gellad, JAMA Oncology 2018","url":"https://doi.org/10.1001/jamaoncol.2018.0977"},{"label":"Patients in ELIANA for whom tisagenlecleucel could not be manufactured","value":"7 of 92 enrolled","source":"Maude et al., NEJM 2018","url":"https://doi.org/10.1056/NEJMoa1709866"},{"label":"Historic global actinium-225 supply from thorium-229 stockpiles","value":"~63 GBq (1.7 Ci) per year","source":"Robertson et al., Current Radiopharmaceuticals 2018","url":"https://doi.org/10.2174/1874471011666180416161908"}],"causes":["Autologous products are bespoke batches with no economies of scale.","Viral vector and GMP capacity are limited and expensive.","Actinium-225 has historically come only from decay of legacy thorium-229 held by a few government laboratories.","Lutetium-177 production depends on reactor time and enriched target material from few suppliers.","Release testing, cold-chain logistics and hospital accreditation add weeks and cost that no design optimisation removes."],"currentEfforts":["Umoja, Interius and Orna are developing in vivo CAR-T that programmes T cells inside the patient, removing manufacturing entirely.","Allogene, Caribou, Sana and Fate build off-the-shelf allogeneic CAR-T and CAR-NK products from healthy donor or iPSC sources.","Novartis' T-Charge and point-of-care manufacturing programmes at academic centres cut vein-to-vein time to days.","The US Department of Energy Isotope Program is producing accelerator-based actinium-225, and TerraPower Isotopes and Orano Med are scaling thorium-derived and accelerator-based supply.","ITM and Curium have expanded non-carrier-added lutetium-177 production, and Novartis has built dedicated radioligand plants.","Automated closed-system cell manufacturing platforms (for example, Miltenyi CliniMACS Prodigy and Lonza Cocoon) reduce labour and cleanroom needs."],"successLooksLike":"A CAR-T or equivalent cell therapy is available within a week of decision at a cost comparable to a course of biologic therapy, the majority of eligible patients actually receive it, and isotope supply is no longer the limiting factor for any approved radioligand."},{"id":"b-mo99-supply","kind":"bottleneck","name":"Molybdenum-99 supply","aka":[],"tldr":"Most of the world's everyday nuclear medicine scans depend on a radioactive metal, molybdenum-99, made in a handful of ageing research reactors. When one of them breaks down, hospitals thousands of miles away run short of scans within days because the material decays so fast it cannot be stockpiled.","summary":"Technetium-99m, used in roughly two-thirds of all nuclear medicine procedures worldwide, is generated on-site from its parent, molybdenum-99 (Mo-99, half-life 66 hours). Around 95% of global Mo-99 supply comes from a small set of research reactors, several of them from the 1950s-60s: BR2 (Belgium, commissioned 1961), SAFARI-1 (South Africa, 1965), LVR-15 (Czechia, 1957), MARIA (Poland, 1974), HFR (Netherlands, 1961) and OPAL (Australia, 2006, the newest of the group). These reactors were not built for continuous isotope production, so unplanned outages are common; the HFR was shut down in October 2024 for an unscheduled structural repair, compounding scheduled maintenance elsewhere and tightening Tc-99m availability in Europe and North America.\n\nBecause Mo-99 and its daughter Tc-99m decay too quickly to stockpile, the whole chain -- irradiation, chemical processing, generator manufacture, air freight, and hospital elution -- has to run on a near-continuous, just-in-time schedule with almost no buffer. The United States, which consumes more than half of global Tc-99m demand, has historically produced none of the Mo-99 it uses, importing all of it from these ageing overseas reactors.\n\nThe response has been diversification rather than a single fix: new LEU-target and cyclotron-based domestic production efforts in the US and Canada, a CMS reimbursement add-on to reward non-highly-enriched-uranium production, and a slow build-out of newer reactors and accelerator routes to replace the 1960s fleet as it eventually retires.","asOf":"2026-09-22","links":[{"label":"OECD-NEA: Current trends in the supply and utilisation of medical radioisotopes (Oct 2025)","url":"https://www.oecd-nea.org/upload/docs/application/pdf/2025-10/7743_medical_radioisotopes_supply_rev.pdf"},{"label":"McGuireWoods: Radiopharmaceutical industry update, CY2025 HOPPS rule and Mo-99 add-on payment","url":"https://www.mcguirewoods.com/client-resources/alerts/2025/4/radiopharmaceutical-industry-update-q4-q1-2024-2025/"},{"label":"INMM PATRAM 2010: Transport of radiopharmaceuticals, cradle to the patient","url":"https://resources.inmm.org/system/files/patram_proceedings/2010/233_Paper_TRANSPORT-OF-RADIOPHARMACEUTICALS,-CRADLE-TO-THE-P.pdf"}],"tags":["supply chain","molybdenum-99","technetium-99m","reactor infrastructure"],"related":["idea-reg-medical-isotope-reactor-reserve","idea-reg-isotope-supply-observatory","b-cold-chain-logistics","tc-99m","mo-99"],"indications":[],"sections":[],"technologies":["research-reactor-isotope-production","therapy-isotope-supply-chain","radionuclide-generators-kits"],"targets":[],"drugs":[],"companies":["northstar-medical-radioisotopes","shine-technologies","curium","ntp-radioisotopes","ire","ansto","nordion"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"regulation-manufacturing","severity":"major","metrics":[{"label":"Share of global Mo-99 supply from six ageing research reactors","value":"~95%","url":"https://www.oecd-nea.org/upload/docs/application/pdf/2025-10/7743_medical_radioisotopes_supply_rev.pdf"},{"label":"Oldest Mo-99-producing reactor still in service (LVR-15, Czechia)","value":"commissioned 1957","url":"https://www.oecd-nea.org/upload/docs/application/pdf/2025-10/7743_medical_radioisotopes_supply_rev.pdf"},{"label":"HFR (Netherlands) unplanned shutdown","value":"October 2024, structural repair","url":"https://www.oecd-nea.org/upload/docs/application/pdf/2025-10/7743_medical_radioisotopes_supply_rev.pdf"},{"label":"CMS add-on payment for Tc-99m from domestically produced (non-HEU) Mo-99","value":"$10 per dose, effective 1 January 2026","url":"https://www.mcguirewoods.com/client-resources/alerts/2025/4/radiopharmaceutical-industry-update-q4-q1-2024-2025/"},{"label":"Activity lost to a one-day transport delay of Mo-99 (66-hour half-life)","value":"~22%","url":"https://resources.inmm.org/system/files/patram_proceedings/2010/233_Paper_TRANSPORT-OF-RADIOPHARMACEUTICALS,-CRADLE-TO-THE-P.pdf"}],"causes":["Global Mo-99 production is concentrated in a small number of research reactors originally built for other purposes and now decades past their design life.","The isotope's 66-hour half-life means there is no meaningful stockpile; any outage propagates into a shortage within days.","Historic reliance on highly enriched uranium (HEU) targets created conversion costs and regulatory complexity when moving to low-enriched uranium (LEU).","Low economic return on Mo-99 production relative to its public-health importance has discouraged reactor operators from investing in dedicated new capacity."],"currentEfforts":["NorthStar Medical Radioisotopes and SHINE Technologies scaling non-uranium (accelerator- and fusion-based) domestic US Mo-99 production.","Canada's Darlington Nuclear Generating Station (CANDU) beginning Mo-99, Lu-177 and Y-90 production runs from 2025.","CMS's CY2025/2026 rule adding a $10-per-dose payment for Tc-99m derived from domestically produced, non-HEU Mo-99.","Private US test reactors (e.g. Oklo's Groves Isotope Test Reactor, first criticality August 2026) aiming to prove domestic medical-isotope production pathways."],"successLooksLike":"Mo-99 production diversified across enough LEU and non-reactor routes, in enough countries, that a single reactor's unplanned outage no longer causes a multi-country Tc-99m shortage."},{"id":"b-nuclear-medicine-workforce","kind":"bottleneck","name":"Nuclear medicine technologist and physicist workforce","aka":[],"tldr":"Radioactive cancer treatments need specially trained technologists and physicists to prepare and check every dose, and there simply are not enough of them. Hospitals in Europe, the US and Canada are all reporting job vacancies that stay open for months.","summary":"A 2024 EANM cross-sectional survey of the European nuclear medicine workforce (239 respondents, 31 countries) found that 80.2% of departments reported at least one open vacancy, with technologists/radiographers hit hardest (61.6% vacancy rate) followed by physicians (57.1%); more than half of all open positions (57.7%) had remained unfilled for six months or longer. In the United States, a 2026 SNMMI-TS/NMTCB salary and workforce study surveyed 26,336 nuclear medicine technologists and received 2,271 responses, finding median hourly pay had risen 15% (to $51.28) since 2022 -- itself a sign of a tight labour market pushing wages up to attract staff.\n\nThe pipeline problem is structural, not just cyclical: a US analysis found the certified nuclear medicine technologist workforce shrank by about 1,438 people (6%) between 2012 and 2022 as training programmes closed and experienced staff left the field, and a follow-up regional survey found roughly a quarter of working technologists plan to retire or leave direct patient care within 5-10 years. SNMMI's own 2025 Theranostics Stakeholders Summit survey found 70.5% of responding institutions had current hiring vacancies in nuclear medicine or theranostics.\n\nThis workforce gap sits underneath, and partly explains, several of the field's other access problems: without enough technologists to run cameras and generators, and physicists to support dosimetry and quality assurance, expanding hot-lab and treatment-room capacity does not translate into more patients treated.","asOf":"2026-09-22","links":[{"label":"EANM nuclear medicine workforce survey (European Journal of Nuclear Medicine, 2024 data)","url":"https://boa.unimib.it/retrieve/2b572834-6cd0-4a4d-af21-27e8aa4987a1/Van%20den%20Wyngaert%20et%20al-2026-The%20EANM%20Journal-VoR.pdf"},{"label":"SNMMI-TS and NMTCB 2026 Salary and Workforce Study","url":"https://snmmi.org/common/Uploaded%20files/Web/Research-Publications/2026%20Salary%20and%20Workforce%20Study.pdf"},{"label":"Future challenges and occupational prospects of nuclear medicine technologists (JNM abstract)","url":"https://jnm.snmjournals.org/content/64/supplement_1/TS19"},{"label":"SNMMI Theranostics Stakeholders Summit white paper (2025), staffing survey","url":"https://snmmi.org/common/Uploaded%20files/News/Theranostics_Stakeholders_Summit_White_Paper_FINAL_6-2025.pdf"}],"tags":["workforce","technologists","training"],"related":["b-authorized-user-shortage","b-hot-lab-capacity"],"indications":[],"sections":[],"technologies":["radiopharmacy-network","radioligand-dosimetry","nuclear-medicine-hardware"],"targets":[],"drugs":[],"companies":[],"institutions":["snmmi","eanm"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"people-culture","severity":"major","metrics":[{"label":"European nuclear medicine departments reporting an open vacancy (EANM 2024 survey)","value":"80.2%","url":"https://boa.unimib.it/retrieve/2b572834-6cd0-4a4d-af21-27e8aa4987a1/Van%20den%20Wyngaert%20et%20al-2026-The%20EANM%20Journal-VoR.pdf"},{"label":"Technologist/radiographer vacancy rate in Europe (EANM 2024 survey)","value":"61.6% of departments","url":"https://boa.unimib.it/retrieve/2b572834-6cd0-4a4d-af21-27e8aa4987a1/Van%20den%20Wyngaert%20et%20al-2026-The%20EANM%20Journal-VoR.pdf"},{"label":"European vacancies unfilled for 6 months or longer","value":"57.7% of open positions","url":"https://boa.unimib.it/retrieve/2b572834-6cd0-4a4d-af21-27e8aa4987a1/Van%20den%20Wyngaert%20et%20al-2026-The%20EANM%20Journal-VoR.pdf"},{"label":"US nuclear medicine technologist workforce change, 2012–2022","value":"-1,438 (-6%)","url":"https://jnm.snmjournals.org/content/64/supplement_1/TS19"},{"label":"US NMTs surveyed who plan to retire or leave direct patient care within 5–10 years","value":"~26% (regional survey)","url":"https://jnm.snmjournals.org/content/64/supplement_1/TS19"},{"label":"SNMMI 2026 median NMT hourly pay, and change since 2022","value":"$51.28, up 15% from $44.65","url":"https://snmmi.org/common/Uploaded%20files/Web/Research-Publications/2026%20Salary%20and%20Workforce%20Study.pdf"},{"label":"US institutions reporting current hiring vacancies in nuclear medicine/theranostics (SNMMI Summit survey)","value":"70.5%","url":"https://snmmi.org/common/Uploaded%20files/News/Theranostics_Stakeholders_Summit_White_Paper_FINAL_6-2025.pdf"}],"causes":["Accredited nuclear medicine technologist training programmes have closed in several countries, shrinking the pipeline just as radioligand therapy caseloads are growing.","A wave of experienced technologists and physicists is approaching retirement at the same time demand is rising.","COVID-era attrition reduced the healthcare workforce broadly, and nuclear medicine has not recovered as quickly as some other specialties.","Pay and career-pathway visibility have historically lagged other imaging professions, making recruitment harder even where training capacity exists."],"currentEfforts":["University of Alabama at Birmingham / SNMMI Nuclear Medicine Therapy Intensive (launched 2024) providing dedicated short-course training for the theranostics workforce.","EANM educational outreach, career pathway resources and professional development initiatives flagged in its 2024 workforce survey.","Canadian Association of Nuclear Medicine's 2025 National White Paper on the technologist shortage, informing provincial training-capacity planning.","Rising technologist pay (SNMMI-TS/NMTCB 2026 study) as institutions compete for a limited pool of qualified staff."],"successLooksLike":"Vacancy rates for nuclear medicine technologists and physicists fall towards the low single digits, and training-programme capacity grows in step with radioligand therapy caseload growth rather than lagging behind it."},{"id":"b-radioactive-waste-regulation","kind":"bottleneck","name":"Radioactive waste handling and disposal regulation","aka":[],"tldr":"Every radioactive treatment leaves behind radioactive waste, such as used vials and, for a short time, the patient's own urine, which has to be safely stored until it stops being radioactive. The rules and the physical space needed for this differ from hospital to hospital and country to country, and building enough of that safe storage takes time.","summary":"US NRC rule 10 CFR 35.92 allows medical licensees to hold low-level radioactive waste for 'decay-in-storage' -- keeping it until a survey shows its radiation level is indistinguishable from background, then disposing of it as ordinary or medical waste -- but only for byproduct material with a physical half-life under 120 days. Most therapeutic isotopes qualify (lutetium-177's 6.65-day half-life decays in weeks), but contaminants complicate this: NRC guidance on Lutathera and Pluvicto notes that the metastable isotope lutetium-177m, with a 161-day half-life, can be present at roughly 0.02% of total activity and, when detected, must instead be handled as formal low-level radioactive waste under 10 CFR Part 20, a different and more burdensome disposal route.\n\nLow-level radioactive waste itself is classified by the NRC into Classes A, B and C by hazard; Class A, the least hazardous, makes up about 96% of total LLRW volume. A UK health-system readiness review lists radioactive-waste management -- decay-tank capacity, shielded 'hot' toilets for patients who have received a therapeutic dose, and staying within site-specific disposal limits -- as one of five mandatory steps any facility must have in place before it can deliver radioligand therapy at all, alongside licensing, imaging, treatment planning and follow-up.\n\nRegulatory fragmentation adds friction on top of the physical constraint: in the US, medical radioactive-material licensing is split between the NRC directly and 39 'Agreement States' that have taken on their own licensing authority, so requirements are not identical nationwide, and a site opening a new radioligand therapy programme must navigate whichever regime applies locally, often adding months to programme start-up alongside the physical build-out of shielded waste storage.","asOf":"2026-09-22","links":[{"label":"NRC: Decay-in-storage (DIS) of low-level radioactive waste, toolbox guidance","url":"https://www.nrc.gov/materials/toolboxes/llrw/decay-in-storage"},{"label":"NRC STC-22-074: Medical use, radiation safety and waste guidance for Lu-177 (Lutathera/Pluvicto)","url":"https://scp.nrc.gov/asletters/tech/sp22074.pdf"},{"label":"NRC: Low-level radioactive waste (LLRW) toolbox overview and classification","url":"https://www.nrc.gov/materials/toolboxes/llrw-waste"},{"label":"Establishing a robust radioligand therapy programme (licensing and Agreement State detail)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10905220/"},{"label":"Health system readiness for radioligand therapy in the UK: service provision","url":"https://www.healthsystemreadiness.com/app/uploads/Health-system-readiness-for-radioligand-therapy-in-the-UK-Service-provision.pdf"}],"tags":["regulation","waste disposal","radiation safety"],"related":["b-hot-lab-capacity","b-site-readiness-referral","lu-177"],"indications":[],"sections":[],"technologies":["radiopharmaceutical-gmp-release","radiopharmacy-network","lu177-radioligand-therapy"],"targets":[],"drugs":["pluvicto","lutathera"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"regulation-manufacturing","severity":"moderate","metrics":[{"label":"Maximum half-life NRC allows for medical decay-in-storage of radioactive waste (10 CFR 35.92)","value":"under 120 days","url":"https://www.nrc.gov/materials/toolboxes/llrw/decay-in-storage"},{"label":"Lutetium-177m contaminant activity in Lutathera/Pluvicto (161-day half-life, requires formal LLW disposal if detected)","value":"~0.02% of total Lu-177 activity","url":"https://scp.nrc.gov/asletters/tech/sp22074.pdf"},{"label":"Share of total US low-level radioactive waste volume that is Class A (least hazardous)","value":"~96%","url":"https://www.nrc.gov/materials/toolboxes/llrw-waste"},{"label":"US states with their own ('Agreement State') authority to license medical radioactive materials, as of 2024","value":"39 states","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10905220/"}],"causes":["Decay-tank and shielded-toilet capacity is a fixed physical build-out at each site, so it does not scale automatically with rising patient volume.","US medical radioactive-material licensing is split between the NRC and 39 individual Agreement States, producing inconsistent requirements across the country.","Longer-lived contaminants generated during isotope production (such as lutetium-177m) fall outside the simple decay-in-storage rule and require a separate, more burdensome low-level-waste disposal pathway.","New alpha-emitter therapies introduce longer-lived daughter radionuclides in the decay chain, which existing decay-in-storage assumptions built around beta emitters do not automatically cover."],"currentEfforts":["NRC Regulatory Issue Summary 2004-17 (revised) clarifying performance-based decay-in-storage criteria, removing the older fixed ten-half-life holding requirement in favour of a background-radiation survey standard.","Site-level engineering firms offering modular decay-tank retrofits to expand waste-storage capacity without a full facility rebuild.","UK and other national health-system readiness frameworks setting out waste-management capacity as an explicit, checkable prerequisite for opening a radioligand therapy service."],"successLooksLike":"Harmonised, performance-based radioactive-waste rules that scale predictably with a site's radioligand therapy volume, so waste-handling capacity is planned alongside clinical capacity rather than becoming a late, site-specific licensing surprise."},{"id":"b-reimbursement-coding","kind":"bottleneck","name":"Reimbursement and coding for radiopharmaceuticals","aka":[],"tldr":"In the US, insurance pays extra for a new radioactive scan for a couple of years, then that extra payment can suddenly stop, even though the drug still costs the same to make. That cliff has already made at least one scan much harder for patients to get.","summary":"US Medicare has historically packaged diagnostic radiopharmaceuticals into the payment for the imaging test itself, treating them as a 'supply' rather than reimbursing their actual cost. New diagnostic radiopharmaceuticals typically get two to three years of transitional 'pass-through' status, during which their cost is separately and fully reimbursed; once pass-through expires, additional payment can drop to zero, which the American College of Radiology cites as the reason amyloid PET imaging has had persistently limited availability.\n\nAfter years of lobbying by SNMMI, ACR and others, CMS's CY2025 Hospital Outpatient Prospective Payment System (HOPPS) final rule, released 1 November 2024 and effective 1 January 2025, created a new middle tier: any diagnostic radiopharmaceutical without pass-through status, whose per-day cost exceeds a $630 threshold (set at twice the average $314 CMS assumed was already bundled into existing payments), now receives ongoing separate payment based on Mean Unit Cost (MUC) derived from hospital claims data. Twenty-six products qualified for 2025, more than half of them PET tracers; the threshold is indexed to the Producer Price Index for Pharmaceuticals from 2026 onward.\n\nA parallel change took effect for the isotope supply chain itself: from 1 January 2026, CMS pays a $10-per-dose add-on for technetium-99m derived from domestically produced (non-highly-enriched-uranium) molybdenum-99, intended to reward and de-risk the US reshoring effort described under the Mo-99 supply bottleneck. Therapeutic radiopharmaceuticals remain reimbursed at ASP+6% where average sales price data exists, but manufacturers are not mandated to report ASP, so many still fall back to the same claims-based MUC methodology CMS uses for diagnostics.","asOf":"2026-09-22","links":[{"label":"SNMMI FAQ on CMS CY2025 HOPPS diagnostic radiopharmaceutical payment reform","url":"https://snmmi.org/Web/Web/News/Articles/FAQs-on-the-Centers-for-Medicare---Medicaid-Services--CMS--Major-Payment-Policy-Reform-for-Diagnosti.aspx"},{"label":"ACR Bulletin: Changes to reimbursement for high-cost radiopharmaceuticals","url":"https://www.acr.org/Clinical-Resources/Publications-and-Research/ACR-Bulletin/Changes-to-Reimbursement-for-High-Cost-Radiopharmaceuticals"},{"label":"McGuireWoods: Radiopharmaceutical industry update, CY2025 HOPPS rule detail","url":"https://www.mcguirewoods.com/client-resources/alerts/2025/4/radiopharmaceutical-industry-update-q4-q1-2024-2025/"},{"label":"ASTRO summary of the 2025 HOPPS final rule (radiopharmaceutical payment policy)","url":"https://www.astro.org/getmedia/8ac4db0c-cd58-42bd-b693-7caa40928919/2025HOPPSFinalRuleSummary.pdf"}],"tags":["reimbursement","CMS","coding","access"],"related":["b-site-readiness-referral","b-mo99-supply","tc-99m","mo-99"],"indications":[],"sections":[],"technologies":["pet-tracer-manufacturing","radiopharmacy-network"],"targets":[],"drugs":["pylarify","illuccix","locametz","pluvicto","lutathera"],"companies":["novartis","telix","lantheus"],"institutions":["snmmi"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"funding-incentives","severity":"moderate","metrics":[{"label":"CY2025 HOPPS separate-payment threshold for diagnostic radiopharmaceuticals","value":"$630 per day (2x the $314 CMS assumed was already packaged)","url":"https://snmmi.org/Web/Web/News/Articles/FAQs-on-the-Centers-for-Medicare---Medicaid-Services--CMS--Major-Payment-Policy-Reform-for-Diagnosti.aspx"},{"label":"Diagnostic radiopharmaceuticals qualifying for separate payment in 2025","value":"26 products, >half PET tracers","url":"https://www.acr.org/Clinical-Resources/Publications-and-Research/ACR-Bulletin/Changes-to-Reimbursement-for-High-Cost-Radiopharmaceuticals"},{"label":"New Mo-99 domestic-sourcing add-on payment, effective 1 January 2026","value":"$10 per dose","url":"https://www.mcguirewoods.com/client-resources/alerts/2025/4/radiopharmaceutical-industry-update-q4-q1-2024-2025/"},{"label":"Typical pass-through period before reimbursement can drop to zero","value":"2–3 years","url":"https://www.acr.org/Clinical-Resources/Publications-and-Research/ACR-Bulletin/Changes-to-Reimbursement-for-High-Cost-Radiopharmaceuticals"}],"causes":["Diagnostic radiopharmaceuticals were historically bundled into HOPPS payment for the imaging test as a 'supply', which undervalued high-cost tracers relative to their actual acquisition cost.","Transitional pass-through payment periods expire after 2–3 years, creating a reimbursement cliff exactly when a product is scaling into routine use.","Manufacturers are not required to report average sales price (ASP) data, so CMS has had to rely on claims-derived Mean Unit Cost as a proxy, which lags real-world pricing.","Reimbursement policy has historically been set per-product rather than for the radiopharmaceutical drug class as a whole, so each new tracer or therapy faces the same fight from scratch."],"currentEfforts":["SNMMI and ACR multi-year advocacy that led directly to the CY2025 HOPPS separate-payment policy for diagnostic radiopharmaceuticals.","CMS commitment to index the $630 threshold annually to the Producer Price Index for Pharmaceuticals from 2026, rather than leaving it fixed.","CMS's new domestic Mo-99 sourcing add-on payment, aligning reimbursement incentives with the isotope-supply-chain resilience goals described elsewhere in this graph."],"successLooksLike":"Radiopharmaceutical reimbursement that follows the product's real cost continuously from launch through the life of the pass-through period and beyond, so no approved, clinically useful tracer or therapy loses access because of a coding cliff."},{"id":"b-site-readiness-referral","kind":"bottleneck","name":"Site readiness and referral pathway delays","aka":[],"tldr":"Getting a patient from 'this treatment might help you' to actually receiving it can take weeks or months, because the scan, the specialist review and the treatment often happen at different places, and not every hospital is equipped to give the treatment at all.","summary":"Radioligand therapy referral is a multi-step journey: a treating physician suspects eligibility, the patient needs a PSMA- or somatostatin-receptor PET scan (often at a different centre from where the eligibility decision or treatment happens), a multidisciplinary team reviews the scan, and only then is the patient scheduled at a licensed, hot-lab-equipped centre. A 2025 IQVIA Institute study of the mCRPC referral pathway in Germany, France, Italy and China found this took a minimum of about 7 weeks in Germany, 8-9 weeks in France and China, and roughly 11 weeks in Italy, with limited PSMA PET-CT capacity and unclear division of responsibility between urologists, oncologists and nuclear medicine physicians cited as common barriers across all four countries.\n\nA report from Dana-Farber Cancer Institute tracking 146 patients referred for 177Lu-PSMA-617 between May and October 2022 found the median time from tumour-board review to first treatment cycle rose from 41 days in May to 96 days in October as supply tightened; 35% of patients (45 of 146) started or continued a different therapy rather than wait, and 5% of approved patients (6 of 127) died during the wait. A 2022 international SNMMI survey of prostate cancer theranostics sites found a mean PSMA PET waiting time of 17±16 days (median 10, range 1-120), with the longest waits reported in Africa, and one-third of responding centres saying they lacked sufficient PET imaging capacity to meet demand.\n\nImaging-capacity concentration compounds the problem: a UK health-system-readiness review found only ten centres nationally offer gallium-68 DOTATATE/TOC PET-CT for neuroendocrine tumours, nine of them in or around London, forcing many patients to travel long distances simply to be assessed for eligibility before any decision about treatment itself.","asOf":"2026-09-22","links":[{"label":"IQVIA Institute: Developing efficient patient referral pathways for radioligand therapies (2025)","url":"https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/developing-efficient-patient-referral-pathways-for-radioligand-therapies"},{"label":"Targeted Oncology: Oncologists encounter challenges accessing PSMA-targeted therapy (Dana-Farber data)","url":"https://www.targetedonc.com/view/oncologists-encounter-challenges-to-accessing-psma-targeted-therapy-in-prostate-cancer"},{"label":"A 2022 international survey on the status of prostate cancer theranostics (JNM)","url":"https://jnm.snmjournals.org/content/64/1/47"},{"label":"Health system readiness for radioligand therapy in the UK: service provision","url":"https://www.healthsystemreadiness.com/app/uploads/Health-system-readiness-for-radioligand-therapy-in-the-UK-Service-provision.pdf"}],"tags":["access","referral","care pathway"],"related":["b-hot-lab-capacity","b-authorized-user-shortage","b-reimbursement-coding","ga-68","lu-177"],"indications":["prostate-mcrpc","neuroendocrine"],"sections":[],"technologies":["psma-pet","sstr-pet","radiopharmacy-network"],"targets":[],"drugs":["pluvicto","ga68-psma-11","ga68-dotatate"],"companies":[],"institutions":["dana-farber","snmmi"],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"access-delivery","severity":"major","metrics":[{"label":"Minimum referral-to-treatment-initiation time for mCRPC radioligand therapy (Germany, France, Italy, China)","value":"7–11 weeks, depending on country","url":"https://www.iqvia.com/insights/the-iqvia-institute/reports-and-publications/reports/developing-efficient-patient-referral-pathways-for-radioligand-therapies"},{"label":"Dana-Farber: median tumour-board-to-cycle-1 wait, May vs October 2022","value":"41 days → 96 days","url":"https://www.targetedonc.com/view/oncologists-encounter-challenges-to-accessing-psma-targeted-therapy-in-prostate-cancer"},{"label":"Dana-Farber cohort: patients who switched to a different therapy while waiting","value":"35% (45 of 146)","url":"https://www.targetedonc.com/view/oncologists-encounter-challenges-to-accessing-psma-targeted-therapy-in-prostate-cancer"},{"label":"Dana-Farber cohort: approved patients who died before starting treatment","value":"5% (6 of 127)","url":"https://www.targetedonc.com/view/oncologists-encounter-challenges-to-accessing-psma-targeted-therapy-in-prostate-cancer"},{"label":"Mean PSMA PET wait time, international 2022 survey","value":"17±16 days (median 10, range 1–120)","url":"https://jnm.snmjournals.org/content/64/1/47"},{"label":"UK centres offering Ga-68 DOTATATE/TOC PET-CT for neuroendocrine tumours","value":"10 nationally, 9 in/around London","url":"https://www.healthsystemreadiness.com/app/uploads/Health-system-readiness-for-radioligand-therapy-in-the-UK-Service-provision.pdf"}],"causes":["The referral pathway crosses multiple specialties (urology/oncology, nuclear medicine, radiology) with no universally standardised handoff or shared ownership.","PSMA- and SSTR-PET imaging capacity, which is required to confirm eligibility, is concentrated at a small number of centres, often geographically distant from the referring clinic.","Community oncology and urology clinics frequently lack the NRC/Agreement-State licensure and hot-lab infrastructure to administer the therapy themselves, so patients must be referred out.","Disease can progress or the patient's clinical status can change during the referral-to-treatment interval, sometimes invalidating the original eligibility scan."],"currentEfforts":["IQVIA Institute's proposed streamlined seven-step RLT referral pathway, estimated to cut referral-to-treatment time by one to four weeks depending on country and starting point.","Multidisciplinary tumour-board models bringing referring physicians, nuclear medicine physicians and radiologists together earlier in the pathway.","Ordering PSMA PET scans earlier in the disease course (before frank progression) to avoid the scan itself becoming the bottleneck at the point of eligibility.","UK NHS and other national health-system readiness reviews assessing where new PET-CT and radioligand therapy capacity is most needed."],"successLooksLike":"A defined, resourced multidisciplinary referral pathway that gets an eligible patient from suspected progression to first radioligand therapy cycle in under four weeks, everywhere, not only at flagship academic centres."},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","aka":[],"tldr":"Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.","summary":"Oncology inherited from cytotoxic chemotherapy the assumption that more drug is better, so phase 1 trials escalate to the maximum tolerated dose over a few weeks in a few dozen patients and that dose becomes the label. Targeted agents, antibodies, ADCs and immunotherapies saturate their targets far below toxicity, and chronic dosing exposes patients to months of grade 2 toxicity that the 28-day dose-limiting-toxicity window never measured. The consequences are dose reductions and discontinuations in a third or more of patients on many oral targeted agents, avoidable cost, and occasionally drugs that fail because nobody can stay on them. The FDA's Project Optimus (2021) and its 2024 guidance now require randomised comparison of at least two doses before registration, and trials such as PERSEPHONE show that duration can be halved without loss of efficacy. Dosimetry-based individualisation is the parallel challenge in radioligand therapy.","asOf":"2026-09-08","links":[{"label":"FDA Oncology Center of Excellence, Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"},{"label":"Shah, Rahman, Theoret & Pazdur, The drug-dosing conundrum in oncology: when less is more (NEJM 2021)","url":"https://doi.org/10.1056/NEJMp2109826"},{"label":"Earl et al., 6 versus 12 months of adjuvant trastuzumab (PERSEPHONE, Lancet 2019)","url":"https://doi.org/10.1016/S0140-6736(19)30650-6"}],"tags":[],"related":["idea-net-dosimetry-prrt","idea-total-body-pet-dosimetry"],"indications":["breast-her2-positive","neuroendocrine"],"sections":[],"technologies":["radioligand-therapy","prrt"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["dosimetry","alpha-vs-beta"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"stage":"trials","severity":"major","metrics":[{"label":"Patients requiring dose reduction of abemaciclib for adverse events in first-line MONARCH 3","value":"~43%","source":"Goetz et al., JCO 2017","url":"https://doi.org/10.1200/JCO.2017.75.6155"},{"label":"Six vs twelve months of adjuvant trastuzumab in HER2-positive breast cancer (PERSEPHONE): 4-year disease-free survival","value":"89.4% vs 89.8% (non-inferior)","source":"Earl et al., Lancet 2019","url":"https://doi.org/10.1016/S0140-6736(19)30650-6"}],"causes":["Phase 1 designs optimise for speed and identify the maximum tolerated dose rather than the optimal biological dose.","Dose-limiting toxicity is assessed in one cycle, missing cumulative and chronic toxicities.","Sponsors have no commercial incentive to study lower doses or shorter durations after approval.","Regulators historically accepted a single dose in registration trials.","Pharmacokinetic variability between patients is large but dosing is rarely individualised."],"currentEfforts":["FDA Project Optimus and the 2024 final guidance on dose optimisation require sponsors to compare multiple doses before registration.","PERSEPHONE, SOLD and Short-HER established that shorter adjuvant trastuzumab is non-inferior for many patients.","The CodeBreaK 100 randomised 960 mg vs 240 mg sotorasib comparison, required by the FDA, is the model for post-approval dose re-evaluation.","Dosimetry-personalised PRRT and radioligand therapy trials replace fixed activity with absorbed-dose-based dosing.","Intermittent and stop-and-restart dosing is being tested for nirogacestat in desmoid tumours and for venetoclax in AML.","Finaldose and academic pharmacometrics groups apply model-informed precision dosing to oncology drugs."],"successLooksLike":"Every new oncology drug is registered with a dose chosen by randomised comparison, the rate of dose reductions and discontinuations for toxicity on oral targeted agents falls below 20%, and duration of therapy is tested rather than assumed."}]