A Victory We Aren’t Celebrating—Yet
During my term as president of the Society of Nuclear Medicine (And Molecular Imaging, now appended), we were in the midst of the Molecular Imaging Campaign that was successful in increasing the visibility of nuclear medicine as a measure of physiologic and metabolic parameters in diagnosing our patients.
As the campaign moved toward completion, the society began a parallel effort to accomplish two substantial goals simultaneously. One was to engage the conventional pharmaceutical industry in discussions about how molecular imaging can assist them in drug development. In many cases, we were preaching to the choir. One example was Merck, who had an imaging capability that was the envy of most community hospital radiology departments. There were others who had a firm grasp of the value of molecular imaging. And this appreciation moved in two different directions, harking back to the debate about the definition of molecular imaging. In one instance, the drug of interest was radiolabeled for pharmacokinetic and pharmacodynamics studies (PK/PD). Obviously, Carbon-11 was the isotope of choice for these studies since it did little to change the behavior of the compound of interest.
The second option was to use a biomarker that would measure the biologic activity of the pharmaceutical. The first choice was to test whether FDG could serve in that role. We have numerous studies that have demonstrated the value of FDG in determining the efficacy of cancer treatment, often within hours of the initiation of treatment. But FDG is a little too crude to be truly effective, showing increased metabolic activity that results from inflammation or other benign activity. As the first alternative for measuring anti-cancer activity, we began to explore F-18 fluorothymidine, a marker for DNA synthesis. It had been investigated long enough that there was little opportunity to develop any intellectual property around its development as an imaging agent. But its value in assessing the physiology of the tumor under investigation was undeniable, especially if one is interested in examining activity in sites that have high FDG uptake, such as the brain. The SNM worked with the FDA to establish a multi-site IND to facilitate the utilization in later stage drug development. Simultaneously, we began to enroll sites that were interested in participating in clinical trials utilizing FLT, both for production and for the imaging studies.
But, this would have been useless unless the second goal was successfully achieved. Up to that point, the gold standard for assessing treatment success against a tumor was to use CT imaging to measure the volume of the tumor. The RECIST criteria (Response Evaluation Criteria In Solid Tumors) has the disadvantage of a significant lag time between treatment and any substantive result, either by tumor shrinkage, stable volume, or increase in volume. The cost of late stage drug development is well understood to be staggering. Any way to expedite its timeline would be valuable.
Our successful discussions with the FDA were focused on the option of using a surrogate endpoint to RECIST for assessing efficacy. And, to push the envelope further, to accept the use of unapproved radiopharmaceuticals that have been proven to have value in defining that surrogate endpoint. Obviously, FLT demonstrating the cessation of DNA synthesis was an excellent example. We have now forged into a new era in drug development where probing specific molecular activity in a disease can be used in determining the value of a drug under development rather than using cruder measures that take more time. And that is a phenomenal victory for molecular imaging.