Systems and methods for drug delivery with pressure sensitive control are disclosed. A drug delivery system may include a reservoir filled or fillable with a drug, a drug delivery device coupled to the reservoir to deliver the drug from the reservoir to a patient, a pressure sensor, an output device, and a controller. The controller may be configured to determine if the drug delivery device has completed delivering a dose of the drug to the patient, and if delivery of the dose of the drug is complete, to measure tissue back pressure using the pressure sensor. Subsequently, the controller may be configured to determine if the tissue back pressure is below a first predetermined value, and if so, control the output device at least once and/or control a mechanism to retract an administration member from the patient.