{"doi":"10.1093/infdis/jiae052","title":"Surrogate Endpoints in Pandemic Preparedness","abstract":null,"journal":"The Journal of Infectious Diseases","year":2024,"id":655122,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":932696,"name":"Jean‐Jacques Parienti","orcid":"0000-0002-4774-5590","position":1,"is_corresponding":false},{"id":1466642,"name":"Harm‐Jan de Grooth","orcid":"0000-0002-7499-076X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Surrogate Endpoints in Pandemic Preparedness","abstract":"To the Editor—To swiftly evaluate new therapies for a potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, reliable surrogate endpoints are essential. Based on an analysis of trial-level data, we previously found that nasopharyngeal viral load reduction reliably predicts a reduction in the risk of hospitalization or death across trials testing new SARS-CoV-2 therapies [1]. In a recent study, Giganti et al evaluated this relationship at the individual patient level. With data from 2 randomized controlled trials (RCTs) testing the effect of monoclonal antibody (mAb) therapy on the risk of hospitalization or death, they found that the proportion of treatment effect explained by nasopharyngeal SARS-CoV-2 RNA levels at day 3 was only modest, suggesting that nasopharyngeal viral RNA reduction may not be a reliable surrogate endpoint for mAb treatment effect [2]. In Figure 1, we present an updated systematic review and meta-analysis of RCTs among unvaccinated outpatients with coronavirus disease 2019 (COVID-19). Twenty-two studies representing 17 525 patients reported treatment effects on SARS-CoV-2 viral load and on the risk of hospitalization or death. The treatment effect (relative risk) on hospitalization or death among outpatients with COVID-19 was significantly (P = .0032) predicted by the magnitude of nasopharyngeal SARS-CoV-2 viral load reduction, corresponding to an R2 of 0.63. When evaluating only the 10 trials that tested mAb treatments, nasopharyngeal load reduction predicted reduction of hospitalization or death equally well (R2 = 0.95; P = .0043). The effects of treatments on severe acute respiratory syndrome coronavirus 2 viral load reduction (x-axis) compared to the effects of those treatments on the risk of hospitalization or death (y-axis) in outpatient coronavirus disease 2019 trials. Point size is proportional to sample size. The vertical dashed line denotes the surrogate threshold effect: the minimum increase in viral load reduction necessary to predict a significant reduction in hospitalization or death. Abbreviations: Conv., convalescent; ImmunoTx, Immunotherapy treatment; mAb, monoclonal antibody; RTV, ritonavir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STE, surrogate threshold effect; TDF/FTC, tenofovir disoproxil fumarate/emtricitabine. So, while Giganti and colleagues found that treatment effect on nasopharyngeal viral load is a poor surrogate for treatment effect on the risk of hospitalization or death at the individual patient level, we found that it is a good surrogate at the trial level. Why could the results of individual- versus trial-level data potentially differ? First, the specifics of the surrogate are different. We used viral clearance between baseline and day 5 or 7. The low proportion of treatment effect explained by viral clearance at day 3 may be the consequence of a too early measurement and additional random noise due to the variance of the timing of SARS-CoV-2 infection, at an individual level. It would be interesting to know the proportion of treatment effect explained by viral clearance between baseline and day 5 to allow direct comparison with our trial-level results. Second, a surrogate may capture average treatment effects at the trial level without necessarily tracking the treatment effect in every individual patient. Indeed, the US Food and Drug Administration guidance on surrogate endpoints does not make causal mediation (ie, a high proportion explained) an absolute prerequisite [3]. Hypothetically, the treatments investigated by Giganti et al could have reduced viral load in a causally relevant (but unprobed) anatomic-physiologic space, which, in turn, correlated imperfectly with measured nasopharyngeal viral load. This would explain the combination of results: The association between nasopharyngeal viral load reduction and improved outcomes is strong when aggregated at the trial level but weak when evaluated across individual patients. Here, it is important to note that nasopharyngeal viral load reduction was not intended to be a surrogate for individual clinical decisions, as waiting until day 5–7 for viral load measurement may disqualify participants from other early treatments. In conclusion, we maintain that nasopharyngeal RNA load reduction remains a valuable surrogate endpoint in pandemic preparedness. The statistical likelihood of reduced hospitalization or death associated with interventions leading to significant viral load reduction supports its utility. We do note that the validity of a surrogate endpoint should always be considered preliminary and conditional. We also acknowledge the potential ceiling effect in highly vaccinated populations with hopefully low rates of hospitalization or death, with or without antiviral therapies [4, 5].","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38323636","pmcid":null,"openalex_id":"https://openalex.org/W4391664652","authors":[],"funders":[],"total_grants":0,"fwci":1.205,"citation_percentile":0.75604609,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"bronze","license":"cc-by","oa_locations":[{"url":"https://academic.oup.com/jid/article-pdf/229/4/1244/57223200/jiae052.pdf","host_type":"journal"},{"url":"https://academic.oup.com/jid/article-pdf/229/4/1244/57223200/jiae052.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiae052/56742436/jiae052.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/infdis/jiae052","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38323636","host_type":"repository"},{"url":"https://research.vumc.nl/en/publications/1f218244-d391-4ec1-95de-79242e171833","host_type":"repository"},{"url":"https://pure.amsterdamumc.nl/en/publications/8d9c833c-7b6e-4064-95fe-d51f92409299","host_type":"repository"},{"url":"https://dspace.library.uu.nl/handle/1874/453768","host_type":"repository"},{"url":"https://pure.amsterdamumc.nl/ws/files/142059104/Surrogate-endpoints-in-pandemic-preparedness.pdf","host_type":"repository"}],"fields_of_study":["Viral Infections and Outbreaks Research","COVID-19 epidemiological studies","Vaccine Coverage and Hesitancy"],"mesh_terms":["Pandemic Preparedness","Biomarkers","Pandemics"],"keywords":["Preparedness","Pandemic","Coronavirus disease 2019 (COVID-19)","Political science","Medicine","Internal medicine","Law","Disease"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T09:45:25.130698Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}