Time, costs and risks of chronic disease therapeutic development have caused a crisis.Prospects for innovation and substantial advances in metabolic, cardiovascular, and respiratory disease treatment and prevention are dimming in contrast to the soaring prospects of agents for cancer and orphan diseases.A root cause of the crisis is expense and even feasibility of producing credible clinical outcome data that are increasingly being required by regulators prior to registration and invariably by payers and experts after registration.The needs for data now exceed the capacity of traditional sources of patients and investigators to produce them.Often a combinatorial therapeutic approach is required to fully attack the disease and this further compounds the data crisis.A major solution for expanding sources of credible controlled data and reducing their costs is to conduct controlled clinical trials in the setting of ordinary clinical care settings.This approach does not supplant the role of conventional, intensively monitored phase 3 trials but can serve a complementary pivotal role in phase 3 and phase 4.Evidence will be presented to address conventional beliefs that such trials cannot feasibly or ethically be conducted prior to registration.The role of regulators in further adapting a stepwise registration will also be discussed.These new ways are essential for achieving the prevention or reversal of diabetes, cardiovascular, and chronic pulmonary disease, and even modification of the aging process itself.Every human and all organizations are stakeholders in this change process.