To review the impact orphan drug (OD) legislation has had on innovation and pricing of therapeutic products for rare diseases in the US, EU, and Japan. A systematic literature review was conducted, seeking English-language studies published after the enactment of initial OD legislation in 1983. EMBASE, Medline, and Business Source Complete were searched and results screened for studies specifically assessing the impact of industry-focused policy interventions using 1) measurable innovation- and pricing-related outcomes, and 2) specifying appropriate comparators. In addition to being abstracted for information on research setting, counterfactuals, outcomes, and findings, the methodological quality of included studies was evaluated with an adapted tool. Twenty unique studies met the inclusion criteria: 14 discussing innovation outcomes and 7 discussing pricing outcomes. Increasingly strong study designs have been used to validate that that OD legislation has increased cross-market approvals and suggest the increasing role of small biotechnology companies. Select research also shows a positive relationship between disease prevalence and the likelihood of indicated ODs and is bolstered by well-controlled regression-continuity studies showing sustained innovation in higher prevalence OD markets. However, some concerns are raised regarding innovation in low prevalence conditions and conditions just above OD thresholds. Pricing studies were almost exclusively focused on the EU. A multiple-regression analysis demonstrated that merely having an OD designation leads to a higher price, with 4 weaker studies suggesting an inverse relationship between rare disease prevalence and acquisition price. Despite an abundance of opinion and case study pieces in OD literature, specific studies of high internal validity exist, as do defined and usable comparator group classifications. The reviewed studies ought to serve as valuable information for policymakers considering policy extensions for ultra-orphans, international markets, or other niche therapeutic areas, as well as demonstration of best-practices in designing well-controlled studies evaluating biopharmaceutical policies.