Table 1.

Off-label guidance taxonomized relative to the regulatory process

Off-label type regulatory process	Relationship to regulatory process	Justification for the treating physician	Example(s)
New approaches with compelling evidence of strong benefit that have NOT YET been approved (either in-process of regulatory review or will soon be submitted for regulatory review). These may include named patient and expanded access programs	Respectful, anticipatory	Patient beneficence: expert evaluation of data that there is major benefit and anticipation that it will pass review	Early uptake of maintenance olaparib in first remission for BRCA mutated ovarian cancer
Approaches approved by regulatory authority BUT not for this specific subgroup of patients	Justifiable extrapolation	Patient beneficence: evaluation that the target population in the label is excessively narrow and that there is justifiable reason to anticipate benefit in a wider patient group	CDK 4/6 inhibitors for premenopausal women with ovarian suppression
			Guidance on prescribing for children, pregnant women, patients with organ failure, patients with poor performance status
			Use of durvalumab for stage III NSCLC PD-L1 expression <1% (based on ITT data)
Approaches, supported by adequate data, that have not been submitted for regulatory review and are not likely to be submitted (for example rare diseases, generic medicine with no sponsor, evidence not compliant with regulatory requirements)	Substitute expert review	Deficiencies and stringencies in the regulatory process (such as very high sponsor cost and regulatory inflexibilities) discourage submission for rare diseases, off-patent medications and indication expansion	FLOT/FOLFIRINOX chemotherapy (oxaliplatin off-patent)
			Immunotherapy for MSI-H/dMMR tumors (in Europe)
Approaches that have been submitted for regulatory review and which were rejected	Undermining	Disregard of a negative regulatory authority evaluation	NCCN recommendation of bevacizumab with chemotherapy in patients with recurrent or stage IV HER2 negative breast cancer
Approaches with weak evidence of benefit that have not been submitted for regulatory review and are not likely to be submitted	Undermining	Consideration of any therapeutic option that may be of patient benefit. Precision medicine with low ESCAT grade	Immune checkpoint inhibitors in settings where level of benefit is so low that the manufacturer has not submitted application for indication approval

T-DM1, trastuzumab emtansine; CDK 4/6, cyclin-dependent kinase 4/6; NSCLC, non-small-cell lung cancer; ITT, intention to treat; FLOT, fluorouracil, leucovorin, oxaliplatin, and docetaxel; FOLFIRINOX, folinic acid, 5-fluorouracil, irinotecan, oxaliplatin; MSI-H, microsatellite-instability-high; dMMR, mismatch repair-deficient; NCCN, National Comprehensive Cancer Network.