Protocol for the pipeline: Endpoints for PET tracer trials
Following two conferences held by the Medical Imaging & Technology Alliance (MITA) and a variety of stakeholders, a new focus on diagnostic PET tracers’ effect on patient management rather than direct health benefits is being presented for potential clinical trials, according to a review published August 1 in the Journal of Nuclear Medicine.
Bruce J. Hillman, MD, from the department of radiology and medical imaging and the department of public health sciences at the University of Virginia in Charlottesville, and colleagues made a case for a major shift in the way PET pharmaceuticals should be presented for regulatory approval and reimbursement. MITA and other interested parties have been actively working with payers to determine appropriate endpoints for clinical trials of new PET radiopharmaceuticals, including setting up intermediate outcomes as a reasonable goal instead of definitive disease-specific outcomes to be considered by CMS when making coverage decisions.
A preliminary conference was held in 2011 followed by another conference last year involving medical societies, regulatory and payer representatives, experts in the field of imaging and research and PET service providers. The resulting prospectus could be chiseling away at an old regulatory stalemate.
“The outcomes of that conference helped shape CMS’ decision to reconsider its current National Coverage Determination (NCD) for PET, which precludes reimbursement for any PET procedures that are not covered under the NCD (or via a coverage with evidence development [CED] program); this current policy effectively requires that new PET radiopharmaceuticals must undergo the scrutiny of a national coverage analysis,” wrote Hillman et al.
All parties have agreed that diagnostic tests including imaging examinations do not have a direct and therapeutic effect on patients and cannot be held to that same standard as therapeutic drugs going through clinical trial. The authors noted the optimal endpoint for diagnostic tests was to improve staging and treatment planning and therefore patient outcomes, however indirectly. Potential benefits and adverse effects of these tests were determined to be due to downstream patient management. It was also agreed upon by all parties that diagnostic tests help clinicians avoid ordering unnecessary and even futile treatments.
“Advanced diagnostic imaging technologies, such as PET, are different,” wrote the authors. “A diagnostic test is nearly always embedded in a chain of other diagnostic tests and therapeutic interventions that constitute clinical care. Separating out the specific contribution to health of the test from all other care is almost always too expensive, too time consuming, and confounded by the multifactorial nature of patient management. Hence, directly measuring the effect of employing imaging is impractical for all but the most critical applications.”
The review presents intermediate outcomes as a means of evidence-based radiopharmaceutical approval, rather than measures such as disease-specific mortality. Instead of randomized controlled clinical trials, which were deemed “rarely necessary,” an ideal clinical trial for an oncologic agent might include a registry very much like the National Oncologic PET Registry (NOPR) to provide evidence based data regarding the examination under CMS deliberation.
“The outcomes, or endpoints, appropriate to assessing whether diagnostic interventions are reasonable and necessary are best characterized as ‘change in clinical management,’” the authors wrote. “This is distinct from the outcomes, or endpoints, classically applied in assessing whether therapeutic interventions are reasonable and necessary.”
The results of these conferences provide new guidelines for regulatory language and negotiation to be used in CMS proposals as well as subsequent coverage decisions for new diagnostic PET agents awaiting clinical trial.