If we used the gold standard to retest the subjectsI asked Perplexity Ai the following question:
If we tracked all of the test subjects down or just the subjects for which there was disagreement between the tests and retested them with the gold standard Insulin Tolerance Test would that help solve the issue?
Perplexity Ai's response:
Your analysis of the situation is insightful. Retesting subjects, especially those with discordant results between macimorelin and the comparator tests (arginine and clonidine), using the gold standard Insulin Tolerance Test (ITT) could indeed help resolve the issue and provide valuable clarity. Here's why this approach could be beneficial: - Validation of results: The ITT is considered the gold standard for diagnosing growth hormone deficiency (GHD). Retesting with ITT would provide a more definitive assessment of each subject's GH status.
- Clarification of discrepancies: For subjects where macimorelin results differed from arginine and clonidine tests, ITT results could help determine which test was more accurate. This would be particularly useful given the unexpectedly high growth hormone stimulation seen with macimorelin in some subjects classified as GH deficient by the comparator tests.
- Optimal cut-off point validation: The surprisingly high 'optimal' GH cut-off point of 25.59 ng/mL found for macimorelin could be further evaluated against ITT results. This would help determine if this higher cut-off is indeed more appropriate for accurately diagnosing GHD in children.
- Addressing false positive concerns: If the ITT confirms that many subjects classified as GH deficient by arginine and clonidine tests are actually not deficient, it would support the hypothesis that the high false positive rate of comparator tests impacted macimorelin's ability to meet the primary efficacy endpoint.
- Improving diagnostic accuracy: The results could lead to a reassessment of current diagnostic criteria and potentially improve the overall accuracy of GHD diagnosis in children, reducing the risk of overdiagnosis and unnecessary treatment.
- Regulatory considerations: Additional data from ITT retesting could provide valuable information for discussions with regulatory agencies like the FDA and EMA regarding the interpretation of the DETECT trial results and the potential path forward for macimorelin in pediatric GHD diagnosis.
While this approach would require additional time and resources, it could provide crucial data to resolve the unexpected results of the DETECT trial and potentially support the further development of macimorelin as a diagnostic tool for childhood-onset GHD.