Objectives: Our aim was to review the recommendations given by health technology assessment (HTA) institutions in their methodological guidelines concerning the use of surrogate outcomes in their assessments. In a second step, we aimed at quantifying the role surrogate parameters take in assessment reports.

Methods: We analyzed methodological papers and guidelines from HTA agencies with International Network of Agencies for Health Technology Assessment membership as well as from institutions related to pharmaceutical regulation (i.e., reimbursement, pricing). We analyzed the use of surrogate outcomes in a sample of HTA reports randomly drawn from the HTA database. We checked methods, results (including evidence tables), and conclusions sections and extracted the outcomes reported. We report descriptive statistics on the presence of surrogate outcomes in the reports.

Results: We identified thirty-four methodological guidelines, twenty of them addressing the issue of outcome parameter choice and the problematic of surrogate outcomes. Overall HTA agencies call on caution regarding the reliance on surrogate outcomes. None of the agencies has provided a list or catalog of acceptable and validated surrogate outcomes. We extracted the outcome parameter of 140 HTA reports. Only around half of the reports determined the outcomes for the assessment prospectively. Surrogate outcomes had been used in 62 percent of the reports. However, only 3.6 percent were based upon surrogate outcomes exclusively. All of them assessed diagnostic or screening technologies and the surrogate outcomes were predominantly test characteristics.

Conclusions: HTA institutions seem to agree on a cautious approach to the use of surrogate outcomes in technology assessment. Thorough assessment of health technologies should not rely exclusively on surrogate outcomes.

Objectives: The aim of this study was to explore the use of surrogate outcomes—a substitute outcome that predicts final patient-related outcomes—in cost-effectiveness models (CEM) within health technology assessment (HTA) reports and provide guidance for their future use.

Methods: Our sampling frame was all UK HTA Program monograph series reports published in 2005 and 2006. Reports were included if they addressed a treatment effectiveness/efficacy question and included a CEM based on a surrogate outcome. The two authors independently applied inclusion and exclusion criteria, and the following data was extracted from included reports: source of surrogate outcome, level of evidence for validation of the surrogate outcomes, methods used in report to quantify link between surrogate outcome and final outcome, and consideration of the uncertainty associated with using surrogate outcomes in the results or conclusions of report.

Results: Of 100 HTA reports, 35 complied with the inclusion criteria. Of these, four (11 percent) reports included a CEM based on a surrogate outcome. All four reports sourced treatment-related changes in surrogate outcome through a systematic review of the literature. One provided Level 1 surrogate evidence (randomized controlled trial data showing a strong association between the change in surrogate outcome and change final outcome); two reported Level 2 evidence (observational study data); and one provided Level 3 evidence (disease natural/ history data). The transparency of quantification and exploration of uncertainty of the surrogate and final outcome relationship varied considerably across all four reports.

Conclusions: Recommendations are made for the use of surrogate outcomes in future HTA reports.

In order to determine whether surrogate markers predict clinical outcome, randomized controlled trials (RCT) of nutrition support v. no nutrition support that have reported at least one clinical outcome (mortality, infections, total complications, or duration of hospitalization) and at least one nutritional outcome (energy or protein intake, weight gain, N balance, albumin, prealbumin, transferrin, three anthropometric measures, skin testing, lymphocyte count) were assessed for concordance. If changes in nutritional markers predict clinical outcome, changes in both outcomes should go in the same direction. Concordance is defined as both outcomes changing in the same direction or both outcomes showing no difference. Discordance is defined as one outcome changing and the other not (partial) or both outcomes changing in opposite directions (complete). Ninety-nine RCT were identified, of which most were underpowered to see statistically significant changes, especially in clinical outcomes. Thus, the results were analysed only in relation to the direction of the respective changes in outcomes. Forty-eight comparisons (4×12) were made. The rates of concordance were ≤50% in forty-one of forty-eight comparisons; the rate was never >75%. A complete discordance rate of ≥25% was present in forty-three (≥50% in thirteen) of the forty-eight comparisons. The discordance was usually a result of the nutritional outcome being better than the clinical outcome. Changes in nutritional markers do not predict clinical outcomes. Before adopting any surrogate marker as an end point for a clinical trial, it has to be known that improving it will result in patient benefit.