US health care reform includes an abbreviated pathway for follow-on biologics, also known as biosimilars, in an effort to speed up access to these complex therapeutics. However, a key patient safety challenge emerges from such an abbreviated pathway: immunogenicity reactions. Yet immunogenicity is notoriously difficult to predict, and even cooperative approaches in licensing between companies have resulted in patient safety concerns, injury, and death. Because approval pathways for follow-on forms do not involve cooperative disclosure of methods and manufacturing processes by innovator companies and follow-on manufacturers, the potential for expanded immunogenicity must be taken into account from a risk management and patient safety perspective. The US Institute of Safe Medication Practices (ISMP) has principles of medication safety that have been applied in the past to high-risk drugs. We propose adapting ISMP principles to follow-on biologic forms and creating systems approaches to warn, rapidly identify, and alert providers regarding this emerging patient safety risk. This type of system can be built upon and provide lessons learned as these new drug forms are developed and marketed more broadly.