Objectives: Clinician reported outcomes (CROs) are the most commonly observed endpoint in FDA approved product labels (Wilke et al, 2004) but few have been adequately scrutinized in terms of their suitability as endpoints.  This study evaluates four widely used CROs in order to assess their suitability as endpoints for regulatory approvals.Methods: Published evidence on the Karnofsky Performance Status Scale (KPS), Spitzer QOL-Index, Expanded Disability Status Scale (EDSS), and the Hamilton Rating Scale for Depression (HAM-D) were evaluated in terms of: conceptual framework; patient, literature and clinician contribution to development; process for deriving items; content validity; item reduction; linguistic and cultural adaptation; scoring;  and reliability, validity, and ability to detect change. Results: The FDA discourages the use of CROs for symptoms that can only be known to the patient, whereas clinical signs are usually observed and interpreted by the clinician.  Despite the widespread use of the KPS as a classification of functional status in patients with cancer, there is little data supporting the development, content validity, and statistical measurement properties of the scale.  Among other critiques, the EDSS has questionable inter-rater reliability.  Although the Spitzer QOL-index was developed with patient input and has documented measurement properties, the use of proxy for QOL/HRQL evaluations is widely discouraged.  The HAM-D is considered the ‘gold standard’ of depression rating scales with good psychometric properties, but with questionable content validity. Conclusions: The suitability of the selected CROs as endpoints for regulatory approvals varied widely.  CROs are essential and complimentary primary and secondary endpoints for drug evaluations for the purpose of FDA regulatory submissions, it is likely that sponsors will face increasing FDA scrutiny of CRO endpoints for the purpose of label claims.