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The share of private sector funding, relative to public sector funding, for drug, vaccine, and diagnostic research & development (R&D) differs considerably across diseases. Private sector investment in overall health R&D exceeds $150 billion annually, but is largely concentrated on non-communicable chronic diseases with only an estimated $5.9 billion focused on "global health", targeting diseases that primarily affect low and middle-income countries (LMICs). We examine the evidence for five specific disincentives to private sector global health R&D investment: scientific uncertainty, weak policy environments, limited revenues and market uncertainty, high fixed and sunk costs, and downstream rents from imperfect markets. Though all five may affect estimates of net returns from an investment decision, they are worth examining separately as each calls for a different intervention or remediation to change behavior.