Comparative effectiveness research (CER) includes pragmatic clinical trials (PCTs) to address 'real-world' effectiveness. CER interest would be expected to stimulate biopharmaceutical manufacturer PCT investment; however, this does not seem to be the case. In this article we identify all industry-sponsored PCT studies from 1996 to 2010; analyze them across a variety of characteristics, including sponsor, research question, design, comparators and results; and suggest methodological and policy changes to spur future manufacturer PCT investment. Nine 'naturalistic', head-to-head versus standard of care or similar agent PCTs were identified. Two included a 'usual care' arm. Chronic care trials' length averaged 12 months (range: 6-24 months), six of which reported equivocal or no difference in effectiveness; results of two chronic and the single acute care PCTs favored the sponsor drug. None reported the sponsor drug inferior. Of seven that evaluated utilization or costs, six reported no differences and four of five studies comparing brand-generic drugs reported no difference. Whereas private investment in PCTs is in the public interest, manufacturers apparently have not yet seen the business case. To induce investment, we propose several methodological and regulatory policy innovations designed to reduce business risk by decreasing outcome variability and increasing trial efficiency, flexibility and market applicability.