SUPPLEMENTARY INFORMATION:

I. Background

The purpose of the public meeting announced in this notice is to solicit input from stakeholders ( e.g., sponsors, investigators, clinical sites, contract research organizations and other entities that supply or otherwise label investigational drugs, regulators, professional organizations, and study participants) on the risk of medication errors potentially related to the content and format of the information on investigational drug container labels, the prevalence and nature of such errors, and to gather information on practices that minimize the potential for medication errors.

For the purpose of this meeting, an investigational drug means a drug or ( printed page 14458) biological product that is used in a clinical investigation under an investigational new drug application. FDA definitions and requirements related to investigational new drug applications are provided in 21 CFR part 312. The requirements for labeling an investigational new drug include: (1) The immediate package of an investigational new drug intended for human use shall bear a label with the statement “Caution: New Drug—Limited by Federal (or United States) law to investigational use” and (2) the label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated (21 CFR 312.6). While not a regulatory requirement, some investigational new drug container labels may include additional information such as the protocol/clinical trial number, concentration and/or strength, dosage form ( e.g., tablets, injection), quantity per container, storage requirements, and lot number. Sponsors of an investigational new drug application are required to report to FDA any suspected adverse reaction that is both serious and unexpected (21 CFR 312.32(c)(1)(i)) ^[1] . Adverse reactions that are not serious or unexpected or medication errors that do not result in adverse reactions may be reported in the annual report, or not reported at all. FDA is aware that globally, other regulatory agencies have varying requirements related to investigational drug labeling and safety reporting (Refs. 1 to 3).

The incidence and scope ( e.g., error type; stage in the medication use system where the error occurred; actual, or potential for, adverse events; reporting practices) of medication errors associated with investigational drugs is unknown. FDA recognizes that clinical research is conducted globally (Ref. 4). Published literature from outside the United States has pointed to the container labels as a contributing factor for potential medication errors with investigational drugs and recommended global harmonization of the information on the labels (Refs. 5 and 6). For example, a Canadian study that included labels from blinded protocols provided by European and American sponsors found almost half of the labels affixed to investigational drug containers were missing important information (usually the expiration date, sponsor address, or storage conditions) (Ref. 5). The study also found other factors that may contribute to medication errors, including the use of small font sizes (less than 8 point), variable formats for expiration dates and lot numbers, the presence of error-prone abbreviations, limited use of color or other differentiation techniques, and highly similar product or protocol identification numbers (Ref. 5). A French simulation study using investigational drug container labels found an error rate of approximately 12 percent (most errors were related to dosage unit, trial code, drug confusion, or expiration date) (Ref. 6).

Best practice guidelines, such as those released by the American Society of Health System Pharmacists, have recommended specific content and format for investigational drug container labels (Ref. 7). In 2018, the Institute for Safe Medication Practices (ISMP) published two reports on medication error risks with investigational drugs (Refs. 8 and 9). The first report (published in April 2018) explored reported risks with investigational drug nomenclature, labeling, and packaging, which included unlabeled containers and look-alike product identifiers, confusing or missing information ( e.g., container labels missing, route of administration, dosage form, or net quantity) to support safe use, small unreadable text, and the use of codes and error-prone abbreviations on container labels (Ref. 9). The second report (published in May 2018) recommended error mitigation strategies for clinical sites, sponsors, and other entities that supply investigational drugs and included the recommendation to standardize the content and format of information on investigational drug container labels (Ref. 8).

FDA reviewed additional reports of medication error concerns related to unlabeled or poorly labeled investigational drug container labels (Refs. 10 to 13). The design of container labels can impact the ability of healthcare providers to readily locate and understand critical information for product use (Ref. 14), which in turn may threaten the integrity of clinical investigations and impact the safety and protection of subjects who participate in these investigations.

II. Topics for Discussion at the Public Meeting

During the public meeting, speakers and participants will cover a range of issues related to medication errors and investigational drugs. Discussion topics related to the format and content of information on investigational drug container labels include: (1) The prevalence and types of medication errors attributed to container labels; (2) the impact of such errors on clinical investigations; (3) information that should always be on the container label, and how that information should be presented to facilitate safe use; (4) entities responsible for labeling containers; (5) existing processes for reporting and analyzing medication errors and complaints related to container labels; and (6) global regulatory convergence and differences for the information on container labels.

III. Participating in the Public Meeting

Registration: To register for the public meeting, complete the registration form at https://reaganudall.org/​news-and-events/​events/​investigational-drug-labels. Please provide complete contact information for each attendee, including name, title, affiliation, address, email, and telephone number. Registration is free.

If you need special accommodations due to a disability, please contact Jo Wyeth (see FOR FURTHER INFORMATION CONTACT ) no later than May 5, 2021.

Requests for Oral Presentations: During online registration you may indicate if you wish to present during a public comment session or participate in a specific session, and which topic(s) you wish to address. We will do our best to accommodate requests to make public comments and requests to participate in the focused sessions. Individuals and organizations with common interests are urged to consolidate or coordinate their presentations, and request time for a joint presentation, or submit requests for designated representatives to participate in the focused sessions. All requests to make oral presentations must be received by April 28, 2021. We will determine the amount of time allotted to each presenter and the approximate time each oral presentation is to begin, and will select and notify participants by May 3, 2021. If selected for presentation, any presentation materials must be emailed to Jo Wyeth (see FOR FURTHER INFORMATION CONTACT ) no later than May 10, 2021. No commercial or promotional material will be permitted to be presented or distributed at the public meeting.

Streaming Webcast of the Public Meeting: This public meeting will be webcast. Persons interested in participating in the webcast are encouraged to register in advance (see Registration). The webcast will also be available on the day of the event without preregistration. Detailed ( printed page 14459) information for participating in the webcast is available at the following website: https://reaganudall.org/​news-and-events/​events/​investigational-drug-labels.

Registered participants will be sent technical system requirements in advance of the event. It is recommended that you review these technical system requirements before joining the streaming web conference of the public meeting.

FDA has verified the website addresses in this document, as of the date this document publishes in the Federal Register , but websites are subject to change over time.

Transcripts: Please be advised that as soon as a transcript of the public meeting is available, it will be accessible at https://www.regulations.gov. It may be viewed at the Dockets Management Staff (see ADDRESSES ). A link to the transcript will also be available on the internet at https://reaganudall.org/​news-and-events/​events/​investigational-drug-labels.

IV. References

The following references marked with an asterisk (*) are on display at the Dockets Management Staff (see ADDRESSES ) and are available for viewing by interested persons between 9 a.m. and 4 p.m., Monday through Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public display at https://www.regulations.gov because they have copyright restriction. Some may be available at the website address, if listed. References without asterisks are available for viewing only at the Dockets Management Staff. FDA has verified the website addresses, as of the date this document publishes in the Federal Register , but websites are subject to change over time.

* 1. European Commission, “EU Guidelines to Good Manufacturing Practice; Medicinal Products for Human and Veterinary Use,” Public release date: February 3, 2010 (available at https://ec.europa.eu/​health/​sites/​health/​files/​files/​eudralex/​vol-4/​2009_​06_​annex13.pdf).

2. Smith-Gick, J., N. Barnes, R. Barone, et al., “The Near-Term Viability and Benefits of eLabels for Patients, Clinical Sites, and Sponsors,” Therapeutic Innovation and Regulatory Science, vol. 52(5), pp. 537-545, 2018.

* 3. Health Canada, Good Clinical Practices Guidance Document, “Annex 13 to the Current Edition of the Good Manufacturing Practices Guidelines Drugs Used in Clinical Trials,” August 7, 2009 (available at https://www.canada.ca/​en/​health-canada/​services/​drugs-health-products/​compliance-enforcement/​good-clinical-practices/​guidance-documents/​annex-13-good-manufacturing-practices-guidelines-drugs-clinical-trials-0036.html#a8_​7).

* 4. FDA, Guidance for Industry and FDA staff, “FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND; Frequently Asked Questions,” March 2012 (available at https://www.fda.gov/​media/​83209/​download). For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents.

5. Duhamel, A., M. Thibault, D. Lebel, et al., “Investigational Drug Labeling Variability,” Clinical Trials, vol. 16(2), pp. 204-213, 2019.

6. Dollinger, C., V. Schwiertz, L. Sarfati, et al., “SIMulation of Medication Error Induced by Clinical Trial Drug Labeling: The SIMME-CT Study,” International Journal for Quality in Health Care, vol. 28(3), pp. 311-315, 2016.

7. Kay, S.C., D.G. Luke, and H.R. Tamer, “ASHP Guidelines for the Management of Investigational Drug Products,” American Journal of Health-System Pharmacy, vol. 75(8), pp. 561-573, 2018.

* 8. ISMP, “Investigational Drugs: Strategies for Sponsors, FDA, and Clinical Sites to Prevent Product-Related Errors (Part II),” Public release date: May 3, 2018 (available at https://www.ismp.org/​resources/​investigational-drugs-strategies-sponsors-fda-and-clinical-sites-prevent-product-related).

* 9. ISMP, “Investigational Drugs: Product-Related Issues Pose Significant Challenges (Part I),” Public release date: April 19, 2018 (available at https://www.ismp.org/​resources/​investigational-drugs-product-related-issues-pose-significant-challenges-part-i).

10. Cruz, J.L. and J.N. Brown, “Safety Risks With Investigational Drugs: Pharmacy Practices and Perceptions in the Veterans Affairs Health System,” Therapeutic Advances in Drug Safety, vol. 6(3), pp. 103-109, 2015.

11. Grissinger, M., “Reducing the Potential for Mistakes With Investigational Drugs,” Pharmacy and Therapeutics, vol. 36(3), pp. 120-138, 2011.

12. Brown, J.N., S.R. Britnell, A.P. Stivers, et al., “Medication Safety in Clinical Trials: Role of the Pharmacist in Optimizing Practice, Collaboration, and Education To Reduce Errors,” Yale Journal of Biology and Medicine, vol. 90(1), pp. 125-133, 2017.

* 13. ISMP, “Remdesivir Investigational Drug Labeling Confusion,” Acute Care, vol. 25(9), 2020.

* 14. FDA, Draft Guidance for Industry, “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors,” April 2013 (available at https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents/​safety-considerations-container-labels-and-carton-labeling-design-minimize-medication-errors). When final, this guidance will represent the FDA's current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents.

86 FR 14457