Unsustainability in health care comprises diminishing returns and misalignment between the health care regime and the needs of the population. To deal with complex sustainability problems, niche solutions can be collaboratively designed and implemented through reflexive methods. For second-order sustainability, however, the institutionalization of the reflexive element itself is also needed. This paper aims to provide insight into the possibilities of embedding reflexivity into institutions to support second-order sustainability by reporting on two consecutive participatory research programs that sought to address unsustainability in terms of misalignment and diminishing returns. The first case study reflexively monitored the system’s innovation toward an integrated perinatal care system. Reflection within the project and implementation was supported successfully, but for stronger embedding and institutionalization, greater alignment of the reflexive practices with regime standards was needed. Building on these lessons, the second case study, which was part of the IMI-PARADIGM consortium, collaboratively built a structured tool to monitor and evaluate “the return on engagement” in medicine development. To institutionalize reflexivity, the creation of “reflexive standards” together with regime actors appears to be most promising. Broader and deeper institutionalization of reflexive standards can be attained by building enforcement structures for reflexive standards in the collaborative process as part of the reflexive methodologies for addressing complex sustainability problems.