On July 15, 2022, the Food and Drug Administration (FDA) issued its final guidance on developing the content and format of patient Instructions for Use (IFU) for human prescription drug and biological products, as well as drug-led or biologic-led combination products submitted under a new drug application (NDA) or a biologics license application (BLA). The final guidance, issued over three years after the draft guidance, provides FDA’s expectations for the content and format of IFUs so that they are consistent across drug and biological products. The FDA’s final guidance does not modify its draft guidance in any major substantive way. Rather, as stated by the FDA, the final guidance merely includes “editorial changes to improve clarity.”

The IFU is intended for patients (or their caregivers) who use drug or biological products with complicated or detailed patient-use instructions and is considered part of the product user interface. Drugs with IFUs are typically complex to self-administer, requiring patients/caregivers to perform multiple steps to prepare, administer, store and/or dispose of the drug. The IFU forms part of the product labeling and is negotiated with FDA prior to NDA/BLA approval.

What are Key Takeaways from the Final Guidance?

• FDA expects drug sponsors to develop IFUs—often as early as the investigational new drug (IND) phase—that provide patients clear and concise information that is easily understood for the safe and effective use of the drug. Although it is clear that complicated self-administration drives necessity for an IFU, there is no one-size-fits all criteria for determining whether a drug requires an IFU. Manufacturers must assess the need for an IFU on a case-by-case basis.

• The FDA’s final guidance suggests that the need for an IFU can be informed by following a Human Factors (“HF”) Engineering Process, a method initially created to assess the efficacy of devices. This change from the draft guidance (see footnote 6) was requested by industry and underscores the importance of conducting HF studies for drugs with complicated administration.

• The guidance establishes overarching guidelines for IFU development, including recommendations that the IFU (i) be accurate and consistent with the FDA-approved (or “to be approved” pending NDA/BLA) Prescribing Information (PI); (ii) include additional details not typically discussed in the PI when those details are important for the safe and effective use of the drug product by patients (e.g., step-by-step instructions and visuals for how to self-administer the drug product using a co-packaged syringe); and (iii) be written at or below the national average reading level in a nontechnical (e.g., use “patch” instead of “transdermal system”) active voice (e.g., “shake” instead of “you should shake”).

• The bulk of the guidance contains FDA recommendations on the specific content for an IFU, as well as the order in which that content should be presented, along with a plethora of model language. Content should include, for example, pertinent information from the PI (e.g., dosage and administration, product handling, patient counseling information), along with patient-friendly information, such as detailed preparation instructions (e.g., information about supplier and materials for administering the dose, instructions to check the drug product for particles or discoloration, directions for product reconstitution and/or dilution) and administration instructions (e.g., easy-to-follow steps to administer a dose with an auto-injector, visuals showing appropriate injection sites).

• The guidance also provides detailed format suggestions, including font size and type, letter case, and page layout and design (e.g., visuals, spacing, colors).

• The IFU recommendations do not apply to stand-alone medical devices—including in vitro diagnostics, or device constituent parts of combination devices if the constituent part is marketed under a device authorization (i.e., a 510(k) clearance or premarket approval (PMA).

• Among other minor revisions to the draft guidance, the final guidance adds several new patient-protection provisions, including recommendations that IFU documents incorporate (i) instructions on how to safely dispose of unused or unexpired medicine; (ii) a phone number for reporting adverse reactions; and (iii) a controlled substance schedule, when applicable.