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A \u201cone\u2010and\u2010done\u201d simplification of PEP has the potential to serve the HIV prevention needs of individuals not being met with traditional services and expand overall biomedical HIV prevention coverage. We discuss challenges with the assessment of PEP effectiveness in human trials and potential study designs that could generate evidence needed to inform the use of new, single\u2010administered, long\u2010acting ARVs for PEP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Challenges with determining the effectiveness of new long\u2010acting PEP agents in human trials include the low likelihood of observing an HIV acquisition and the short period for outcome assessment (likely 1 month) following PEP administration. Additional challenges include recruiting individuals in the brief window in which they could benefit (&lt;72 hours of a potential HIV exposure) and ethics of conducting informed consent during a period of high stress\/vulnerability. Consequently, design approaches where the efficacy goal is to establish that the HIV incidence rate following PEP administration (of the standard or a novel agent) approaches zero should be considered. HIV RNA testing conducted within 5 days of a potential exposure could define prevention per exposure. Novel recruitment venues\u2014such as community\u2010based retail or online pharmacies\u2014could be used to reach individuals after a potential exposure. Potential study designs include one\u2010 or two\u2010arm individual\u2010level product assignment aimed at demonstration of short\u2010course efficacy or longer\u2010term effectiveness compared to a background rate; cluster\u2010randomized controlled trials of recruitment venues; and novel individual\u2010level approaches that either do not or do utilize randomization in combination with choice, enabling assessment of preferences and effectiveness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Over the past decade, multiple new HIV PrEP products\u2014but no new PEP products\u2014have been developed to meet the diverse needs of individuals seeking HIV prevention services. Challenges exist with generating PEP effectiveness evidence, but they are not insurmountable. Effectiveness research on new PEP products could advance the number of HIV prevention options available.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.26475","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T13:22:06Z","timestamp":1750944126000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Research designs to generate evidence of HIV post\u2010exposure prophylaxis effectiveness for new long\u2010acting agents"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5675-8836","authenticated-orcid":false,"given":"Katrina F.","family":"Ortblad","sequence":"first","affiliation":[{"name":"Public Health Sciences Division Fred Hutchinson Cancer Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-2111","authenticated-orcid":false,"given":"Elizabeth 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