OBJECTIVE:  Gaining adequate market access and reimbursement can be particularly challenging for orphan drugs. Barriers include inadequate real world data on the disease’s epidemiology and its burden of illness. We deployed a unique combination of methodologies used in a multi-layered observational data capture approach to collect de-identified, publication-worthy clinical and resource utilization data in a probability sample of patients with a rare disease (pulmonary non-tuberculosis mycobacteria [PNTM]). We combine a new methodology (“blinded physician proportion survey”) with a new use of an old methodology (Delphi expert survey). METHODS: First-round studies in France, Germany, Italy, Spain, and the United Kingdom consisted of a “blinded physician specialty proportion” survey to determine the probability of physician selection by specialty (2,585 participating physicians), a nationally representative chart review with participating physicians to determine target patients by region (619 physicians – 1,429 patients) and a Delphi study (an anonymous collaborative estimating methodology completed by six internationally recognized PNTM experts) to gain consensus on annual prevalence of PNTM for each target country. A second-round of survey and use of the collaborative estimating process is currently being completed consisting of a chart review with physicians of a nationally representative sample (n=30 per country) in a treatment refractory sub-group of PNTM patients to capture country specific treatment patterns and disease-related costs. “Refractory” is defined as at least one post-diagnostic positive culture despite 6 months of treatment. RESULTS: We developed a rigorous methodology to identify a sub-group population to address the gap of actual disease prevalence by country. Publication reviewers have consistently and congruently confirmed the first-round epidemiologic study methodology met their respective required scientific standards. CONCLUSIONS: Observational chart surveys in rare diseases that obtain a probability sample, a requirement for sample validity, can be used to provide essential disease-related metrics to populate market access and reimbursement evaluation procedures.