A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials

Ciani, Oriana; Manyara, Anthony M.; Davies, Philippa; Stewart, Derek; Weir, Christopher J.; Young, Amber E.; Blazeby, Jane; Butcher, Nancy J.; Bujkiewicz, Sylwia; Chan, An-Wen; Dawoud, Dalia; Offringa, Martin; Ouwens, Mario; Hróbjartsson, Asbjørn; Amstutz, Alain; Bertolaccini, Luca; Bruno, Vito Domenico; Devane, Declan; Faria, Christina D.C.M.; Gilbert, Peter B.; Harris, Ray; Lassere, Marissa; Marinelli, Lucio; Markham, Sarah; Powers, John H.; Rezaei, Yousef; Richert, Laura; Schwendicke, Falk; Tereshchenko, Larisa G.; Thoma, Achilles; Turan, Alparslan; Worrall, Andrew; Christensen, Robin; Collins, Gary S.; Ross, Joseph S.; Taylor, Rod S.

doi:10.1016/j.eclinm.2023.102283

Cited by 17 publications

(10 citation statements)

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“…Although correlation coefficients and coefficients of determination from meta-analyses of clinical trials are often used to evaluate the strength of association between surrogate markers and clinical outcomes, these values are purely statistical, rely on arbitrary cutoffs, and fail to capture information about the study design, target outcome, and generalizability of the evidence. Although more comprehensive methods to establish surrogacy have been proposed (eg, the Biomarker-Surrogacy Evaluation Schema), enhanced clinical trial reporting and greater availability of shared individual patient-level data will facilitate more precise analyses and estimates.…”

Section: Discussionmentioning

confidence: 99%

“…linical trials increasingly use surrogate markers, such as imaging findings or laboratory measurements, as primary end points. [1][2][3] Surrogate markers, which are expected to predict target outcomes of interest (eg, clinical outcomes that directly measure how people feel, function, or survive), 4 offer the advantage of reducing the duration, size, and total cost of trials. 5,6 In 2018, the Food and Drug Administration (FDA) publicly released an Adult Surrogate Endpoint Table of more than 100 surrogate markers that may be used as primary end points in clinical trials that form the basis of traditional or accelerated approval of new drugs or biologics.…”

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confidence: 99%

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Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Wallach,

Yoon,

Doernberg

et al. 2024

JAMA

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ImportanceSurrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.ObjectiveTo systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases.Data sourcesThe Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.Study SelectionThree reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.Data Extraction and SynthesisTwo reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes.Main Outcomes and MeasuresCorrelation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized.ResultsThirty-seven surrogate markers listed in FDA’s table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker–clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result.Conclusions and RelevanceMost surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Wallach,

Yoon,

Doernberg

et al. 2024

JAMA

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“…Based on these results, it is hypothesised that increases in methaemoglobin may serve as a proxy for 8-aminoquinoline antihypnozoite activity and, as such, a potential surrogate endpoint for clinical trials to quantify the antirelapse efficacy of 8-aminoquinoline drugs in vivax malaria. A surrogate endpoint is a patient characteristic, such as a biomarker, intended to substitute for a clinical outcome [11]– specifically vivax recurrence in this context. To validate surrogacy, high-quality studies need to demonstrate that a putative biomarker is affected by the drug intervention and that drug-induced change in the biomarker level can predict the effect on the outcome of interest [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity inPlasmodium vivaxmalaria: a systematic review and individual patient data meta-analysis

Fadilah,

Commons,

Chau

et al. 2024

Preprint

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Background The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Prior evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. Methods We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022 inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log2 transformed), adjusted for the partner schizontocidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). Findings We identified 219 P. vivax efficacy studies, of which eight provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis dataset, there were 1747 G6PD-normal patients enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of vivax recurrence (adjusted hazard ratio = 0.70; 95% CI = [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Conclusions For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a surrogate endpoint for primaquine antihypnozoite activity in G6PD normal patients with P. vivax malaria.

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“…In practice, there is a critical ambiguity about the meaning of the term surrogate (1). A surrogate endpoint (SEP) may be used to predict a clinical endpoint (CEP) of interest in an individual patient or predicts the average treatment effect on the clinical endpoint.…”

Section: Introductionmentioning

confidence: 99%

Individual level surrogacy of MRI T2 lesion information for future disease severity: a methodological discussion and application to recent MS Phase II and III trials

Buchka,

Joachim,

Begüm

et al. 2024

Preprint

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Background: Individual-level surrogacy (ILS) describes settings where individual-patient information on a biomarker captures information on future patient-relevant clinical outcomes. For persons with relapsing-remitting multiple sclerosis (PwRRMS), whether the number of new or newly enlarged hyperintense lesions in T2 magnetic resonance images (MRI) or the T2 lesions’ volume can act as ILS for disability progression and disease activity is of interest. However, ILS of new T2 lesions for individual PwRRMS has not yet been demonstrated, although new T2 lesions already serve as a primary outcome parameter for pivotal trials. Methods: Our synthesis used individual-patient data from ten randomized controlled trials (n = 5673 PwRRMS). Longitudinal data on either the number or volume of new T2 lesions were analyzed as potential ILS for disability progression measured by the expanded disability status scale (EDSS) and disease activity shown by clinical relapses. ILS metrics were calculated: R2A) for the Meta-analytic (MA) and LRF (likelihood reduction factor) for the information theoretic (IT) approach. A simulation study elucidates the approaches’ potential to detect ILS and provides the basis to interpret the results derived from the trial data. Results: The simulation study demonstrates good performance for the IT approach. MA algorithms work well when applied to continuous data. When applied to counting data, the results may numerically be unstable. However, transformations of the counting data allow successful calculations with methods for Gaussian data. Analyses following IT methodology provide in all trial-based settings reliable results on ILS and identified two studies with weak ILS for the combination of T2 Volume and EDSS (LRF = 0.21, CI95%: 0.16 – 0.26; LRF = 0.28, CI95%: 0.23 – 0.34). Conclusion: The simulation study showed robust and sensitive results for IT and MA when not applied to counting data outcomes-based ILS strategies. The high potential of these algorithms to detect ILS strengthens the interpretation of our findings. Within most arms of ten pivotal MS trials, ILS measures were close to zero. Evidence on the surrogacy of T2 lesion measures and disease progression and activity as a general principle could not be generated. More research using proper designs and methodology is needed.

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A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials

Cited by 17 publications

References 42 publications

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity inPlasmodium vivaxmalaria: a systematic review and individual patient data meta-analysis

Individual level surrogacy of MRI T2 lesion information for future disease severity: a methodological discussion and application to recent MS Phase II and III trials

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