In its rush for the next breakthrough, the field of psychiatry often discards older, effective treatments due to historical stigma. For instance, MAO inhibitors and modern, safer Electroconvulsive Therapy (ECT) are highly effective for specific depression types but are underutilized because of past negative associations, a phenomenon driven more by politics than science.

The CREST trial showed benefit driven by patients with carcinoma in situ (CIS), while the Potomac trial showed a lack of benefit in the same subgroup. This stark inconsistency demonstrates that subgroup analyses, even for stratified factors, can be unreliable and are a weak basis for regulatory decisions or label restrictions.

An advisory panel split 50/50 on a two-year immunotherapy regimen but voted 7-to-1 for a one-year drug with similar efficacy. This reveals that for adjuvant therapies in non-metastatic cancer, halving the treatment duration and toxicity exposure can decisively shift the risk/benefit calculation in favor of approval.

The Uromigos score (0-3) provides a rapid expert consensus on new treatments. It bridges the gap between slow, formal guidelines and long, unprioritized lists of approved therapies, offering a more immediate assessment of a drug's place in the standard of care.

When debating immunotherapy risks, clinicians separate manageable side effects from truly life-altering events. Hypothyroidism requiring a daily pill is deemed acceptable, whereas toxicities like diabetes or myocarditis (each ~1% risk) are viewed as major concerns that heavily weigh on the risk-benefit scale for early-stage disease.

In the absence of direct evidence for adjuvant therapy in high-risk, non-clear cell kidney cancers, clinicians may justify off-label treatment by extrapolating from the drug's known efficacy in the metastatic setting for that specific histology. This highlights the difficult risk-benefit calculations made daily in data-poor clinical scenarios.

When a highly effective therapy like EV Pembro was approved for 'cisplatin ineligible' patients, the definition of 'ineligible' became very elastic in practice. This demonstrates that when a new treatment is seen as transformative, clinicians find ways to qualify patients, putting pressure on established guidelines.

The FDA is predicted to approve new PARP inhibitors from trials like AMPLITUDE only for BRCA-mutated patients, restricting use to where data is strongest. This contrasts with the EMA's potential for broader approvals or denials. This highlights the diverging regulatory philosophies that create different drug access landscapes in the US and Europe.

In the CREST trial, the FDA's critique heavily emphasized an overall survival hazard ratio above one. Though statistically insignificant and based on immature data, this single figure created a powerful suggestion of potential harm that overshadowed the positive primary endpoint and likely contributed to the panel's divided vote.