The Society of Nuclear Medicine and Molecular Imaging (SNMMI) has proposed three solutions for the shortage of generators used in the production of Gallium-68 throughout the U.S.

In a letter addressed to the FDA, the organization outlined the need for greater production, pointing to the demand for and benefits of GMP-grade germanium-68/gallium-68 generators, used to produce 68Ga for the subsequent production of NETSPOT, a kit for the preparation of gallium 68Ga dotatate injections.

“NETSPOT is currently approved for use only with the GalliaPharm 68Ga generator from Eckert & Ziegler,” said the signatories in their letter. “NETSPOT has experienced rapid adoption in the U.S. Advanced Accelerator Applications (AAA) and has been expanding the network of pharmacies that distribute NETSPOT since its approval. As of June 2018, approximately 500 imaging sites were requesting doses of NETSPOT for their neuroendocrine tumor patients.”

Since its 2016 approval under E&Z, demand for the somatostatin receptor PET tracer has increased among those treating neuroendocrine tumors (NETs) in adult and pediatric patients, quickly replacing its market predecessor due to its patient-friendly regimen as an injection, reduction of imaging exams to approximately three hours, and its coverage by payors.

The solution is approved for 400 elutions or for use of up to one year, adding to demand with requests for replacements when such marks are reached. The AAA reports that many often hit their elution limit before the end of one year.

Such needs have exacerbated production of Ge-68/Ga-68 generators, leading to waiting periods of between 14 and 18 months. Though planning to expand production with the construction of a new facility, E&Z will not be able to commence manufacturing there until mid-2019.

“The three companies able to sell generators or with generators under development underestimated the volume,” Richard Zimmermann, co-founder and partner of MEDraysintell and founder and senior consultant of nuclear medicine at Chrysalium Consulting SARL, told HCB News. “E&Z needs to build a new facility that itself needs approval from authorities, hence the date of mid-2019 to be ready. IRE has now a generator with MA but due to internal reorganization, has not yet started growing capacity. ITM had a generator for a long time under development that could compensate shortages for at least the next two years, but it still is not approved.”

To conserve generator lifespan, distributors have resorted to self-imposed blackouts for NETSPOT doses, creating insufficient supplies and delays in procedures.

In an interview with nine academic sites from its Gallium Users Group, SNMMI found that seven possessed a total of 11 generators, with none at the other two due to lack of availability and waiting times.

Of the seven that did have at least one, six experienced delays in replacement with one still waiting after two months and another after six. Three recently received one each after waiting between two and six months, while four canceled or rescheduled scans and clinical trials. One site, Washington University St. Louis, even cut down dose production from 14 to six or less weekly and instituted a two-week blackout during which none were available to its six area hospitals.

The signatories propose a temporary exemption to the 400-elution limit almost immediately, and for the deployment of the IRE ELiT’s generator, for which a type II drug master file has been submitted to the FDA. They also call for the use of cyclotron-generated gallium with an acqueous target, claiming such actions would increase production at mostly academic sites for the next three to six months and alleviate the need for a GMP-grade generator in particular locations.

Zimmermann agrees that such tactics may help, but warns that the predicament associated with Ge-68/Ga-68 generator production is a complex one that will require more actions; and for Novartis, which owns the rights to NETSPOT, to adjust its protocols around the commercialization of 68Ga to help address the short supply of generators.

“The industry (Novartis) will have to adapt the sales of their therapeutics to the diagnostic agent availability as it is directly linked,” he said. “It will also impact the development of other advanced therapeutics, such as 177Lu-PSMA-617, which rely on 68Ga for the selection of their patients.”

NETSPOT and Lutathera (177Lu-PSMA-617) are produced by AAA, a subsidiary of Novartis.

Letter signatories include Cathy S. Cutler, SNMMI director of the medical isotope research and production program (MIRP) collider-accelerator department at Brookhaven National Laboratory; and SNMMI President Satoshi Minoshima, chair of the department of radiology and imaging sciences at the University of Utah.