Use Of Surrogate Outcomes Research Articles

Societal benefits of surrogate outcomes to support reimbursement decisions: The case of prostate cancer.

372 Background: Incorporating surrogate outcomes for survival into economic evaluations for localized prostate cancer (LPC) has the potential to reduce the time needed to subsidise new therapies but may increase uncertainty regarding true benefit. The ICECaP study demonstrated that metastasis-free survival (MFS) is a strong surrogate of overall survival (OS) in LPC. We sought to model the benefits to society of earlier funding decisions, and to understand the context of societal trade-offs between aspects of drug value and time to reimbursement decision-making in LPC. Methods: Societal benefits were modelled using a 4-health state (biochemical recurrence (BCR), BCR-free, metastasis and death) partitioned survival model to evaluate the cost-effectiveness of abiraterone plus prednisolone (AAP) plus standard of care (SoC) compared to SoC alone in LPC. Survival outcomes were dependent on the ICECaP surrogacy relationship. Treatment pathways and costs reflected Australian practice and quality of life was informed by the literature. The model evaluated the difference between deciding to reimburse AAP now, based on MFS, versus wait for OS 3 years. Societal trade-offs were captured using a population based discrete choice experiment exploring the influence on preference for drug reimbursement of cost-effectiveness, cost to Government, adverse events, proportions expected to benefit, nature of benefits, the completeness of data and the time of follow-up. Preferences were analysed using mixed logit analyses. Results: The analysis of societal benefits showed that using MFS as a surrogate for OS could prevent 117 patients from recurrence, 30 from metastases and save 63 lives in the short-term when AAP is compared with SoC for LPC patients in Australia. Delaying the reimbursement decision for 3 years results in a loss of 4.48 years, 0.47 quality adjusted life years, and increase the cost to $11,558 per patient over the lifetime. The analysis of societal trade-offs reflected results from 1,003 community members and showed an inclination to favour reimbursing interventions that benefit a high proportion of patients (OR=2.10 CI 95%=1.91, 2.32), have a lower cost-effectiveness ratio (OR=0.81 CI 95%= 0.78, 0.88) and an aversion for evidence from ongoing studies (OR= 0.83 CI 95%= 0.78, 0.88). Conclusions: Using MFS as surrogate for funding decision in LPC is likely to produce benefits to society in terms of improved short and long-term outcomes. This contrasts with societal preferences to delay reimbursement decisions to increase certainty. This suggests, improved cost-effectiveness could be used to compensate for the uncertainty arising from the use of surrogate outcomes in reimbursement decisions. The use of evidence-based surrogate outcomes in economic evaluations to support reimbursement decisions can reduce the time it takes new interventions to become available improving the benefits to society.

CO155 Evaluation of the Use of Surrogate Outcomes in Oncology Clinical Trials

Overall survival (OS) is considered the gold standard efficacy measure in oncology clinical trials. Over the last decade other outcomes such as progression-free survival (PFS) and overall response rates (ORR), have been recognized by the FDA as efficacy surrogate markers, but use of surrogate outcomes may not be generalizable or appropriate across all cancer types. The purpose of this analysis was to identify and quantify the frequency and trends of surrogate outcomes across oncology clinical trials.

OP123 The Use Of Surrogate Outcomes In National Institute For Health And Care Excellence (NICE) Highly Specialised Technology Evaluations: A Review Of Published Guidance

IntroductionThe use of surrogate outcomes in health technology assessment (HTA) is increasing and methods for validating surrogate relationships have been published. However, these may not be fully applicable to ultra-rare diseases due to challenges such as scarcity of evidence and heterogenous populations. This study reviews and summarizes the use of surrogate outcomes and committee's considerations in the evaluations within the National Institute for Health and Care Excellence's (NICE) Highly Specialised Technology (HST) programme, which was established in 2013 in response to the challenges associated with the assessment of ultra-rare diseases.MethodsAll HST evaluation documents published before November 2020 were reviewed. Data extracted included surrogate outcomes used, rationales, the committee's considerations on the validity and generalizability of the surrogate relationships, related uncertainties, and other factors considered in decision-making.ResultsSeven out of the eighteen published HST topics used surrogate outcomes. The rationale for most of the surrogate relationships focused on biological plausibility. Common concerns raised by the committee included the generalizability of the surrogate relationship to the condition of interest, the lack of validation, and inability to prove or quantify the magnitude of benefits associated with the surrogate relationships. In some topics, other aspects of the evidence and clinical/patient expert's opinions were also considered by the committee.ConclusionsThe use of surrogate outcomes is common in NICE HST evaluations and the challenges in supporting surrogate relationships with more than biological plausibility are recognized. However, our review indicates that, the committee considers more than just biological plausibility and will take into account other related factors.

Study design flaws and statistical challenges in evaluating fertility treatments.

SummaryHealth interventions should be tested before being introduced into clinical practice, to find out whether they work and whether they are harmful. However, research studies will only provide reliable answers to these questions if they are appropriately designed and analysed. But these are not trivial tasks. We review some methodological challenges that arise when evaluating fertility interventions and explain the implications for a non-statistical audience. These include flexibility in outcomes and analyses; use of surrogate outcomes instead of live birth; use of inappropriate denominators; evaluating cumulative outcomes and time to live birth; allowing each patient or couple to contribute to a research study more than once. We highlight recurring errors and present solutions. We conclude by highlighting the importance of collaboration between clinical and methodological experts, as well as people with experience of subfertility, for realising high-quality research.Lay summaryWe do research to find out whether fertility treatments are beneficial and to make sure they don’t cause harm. However, research will only provide reliable answers if it is done properly. It is not unusual for researchers to make mistakes when they are designing research studies and analysing the data that we get from them. In this review, we describe some of the mistakes people make when they do research about fertility treatments and explain how to avoid them. These include challenges which arise due to the large number of things that can be measured and reported when looking to see if fertility treatments work; failure to check whether the treatment increases the number of live births; failing to include all study participants in calculations;challenges in studies where participants may have more than one treatment attempt. We conclude by highlighting the importance of collaboration between clinical and methodological experts, as well as people with experience of fertility problems.

Guideline-Directed Heart Failure Therapy in Patients after Left Ventricular Assist Device Implantation

Background: Left ventricular assist devices (LVADs) are used as an advanced therapy option for patients with stage D heart failure. These devices provide mechanical unloading of the heart as either a bridge to transplant or recovery, or as destination therapy. In patients with LVADs, there are emerging data on the use of heart failure guideline-directed medical therapy (GDMT) to improve outcomes. This review describes the current evidence available for the use of neurohormonal blocking agents in patients with LVADs. Methods: Articles were found using PubMed and web searches for heart failure therapies/neurohormonal blockade and LVADs. Studies were included if they evaluated the use of the heart failure therapies, either retrospectively or prospectively. Results: A total of 17 articles and 9 abstracts were reviewed. The totality of data surrounding the use of GDMT neurohormonal blockade in patients with LVADs are limited in nature. Much of the data are limited either by use of surrogate outcomes, single center evaluations, and/or small sample sizes. However, the evidence does support clinical benefit with associated mechanistic plausibility. More research is needed to understand appropriate patient selection and means to optimize these therapies in the LVAD population. Conclusion: Combined neurohormonal blockade appears to reduce morbidity and mortality in patients with LVAD implants.

How researchers should select the best outcomes for randomised clinical trials in paediatric dentistry?

Randomised clinical trial (RCT) is the best study design to evaluate the effect of the treatment and preventive healthcare procedures. The effects of the tested treatments on patient's health are compared in terms of outcomes, which are used to evaluate the participants' health changes. However, these outcomes should be relevant for the target population. In that way, RCTs represent the type of primary study design that provides the most reliable evidence to implement therapies into the clinical practice. In this review, an outline of some aspects related to the choice of RCTs' outcomes was presented, focusing on the conduction of relevant trials in Paediatric Dentistry. The importance and necessity of defining a primary outcome were addressed, preferentially a clinically relevant endpoint. The patients should perceive this outcome, and changes in this variable should reflect directly patient's health improvement or impairment. Moreover, considerations about the objective or subjective variables, use of surrogate outcomes, and the increasing tendency to develop core outcome sets were also presented in this review. The main idea of this manuscript is the RCTs must evaluate outcomes relevant to the children's oral health in order to contribute to the implementation of treatments in the evidence-based health practice.

Positive end-expiratory pressure and recruitment maneuvers during one-lung ventilation: A systematic review and meta-analysis

BackgroundIt is unclear how positive end-expiratory pressure (PEEP) and recruitment maneuvers impact patients during one-lung ventilation (OLV). We conducted a systematic review and meta-analysis of the effect of lung recruitment and PEEP on ventilation and oxygenation during OLV. MethodsA systematic review and random-effects meta-analysis were performed. Mean difference with standard deviation was calculated. Included studies were evaluated for quality and risk of bias using the Cochrane Risk of Bias tool and the modified Newcastle-Ottawa Score where appropriate. ResultsIn total, 926 articles were identified, of which 16 were included in meta-analysis. Recruitment maneuvers increased arterial oxygen tension (PaO2) by 82 mm Hg [20, 144 mm Hg] and reduced dead-space by 5.9% [3.8, 8.0%]. PEEP increased PaO2 by 30.3 mm Hg [11.9, 48.6 mm Hg]. Subgroup analysis showed a significant increase in PaO2 (P = .0003; +35.4 mm Hg [16.2, 54.5 mm Hg]) with PEEP compared with no PEEP but no such difference in comparisons with PEEP-treated controls. No significant difference in PaO2 was observed between “high” and “low” PEEP-treated subgroups (P = .29). No significant improvement in PaO2 was observed for subgroups coadministered PEEP, lung recruitment, and low tidal volumes. PEEP was associated with a modest but statistically significant increase in compliance (P = .03; 4.33 mL/cmH2O [0.33, 8.32]). High risk of bias was identified in the majority of studies. Considerable heterogeneity was observed. ConclusionsRecruitment maneuvers and PEEP have physiologic advantages during OLV. The optimal use of PEEP is yet to be determined. The evidence is limited by heavy use of surrogate outcomes. Future studies with clinical outcomes are necessary to determine the impact of recruitment maneuvers and PEEP during OLV.

Xiao Chai Hu Tang, a herbal medicine, for chronic hepatitis B.

Xiao Chai Hu Tang, a herbal medicine, for chronic hepatitis B.

PNS183 WHAT METHODS ARE APPLIED IN ASSESSESSING THE CLINICAL AND COST EFFECTIVENESS OF HEALTH TECHNOLOGIES BASED ON THE USE OF SURROGATE OUTCOMES: A COMPARISON OF EVALUATION REPORTS ACROSS INTERNATIONAL HEALTH TECHNOLOGY ASSESSMENT AGENCIES

Health technology assessment (HTA) agencies across the globe often rely on surrogate outcomes instead of final patient-relevant outcomes to conduct early evaluations of innovative treatments. Despite of recognition of the risk of the use of surrogates, there is limited methodological guidance available on validating surrogate outcomes in an HTA setting. We sought out to map the range of methodological approaches adopted in practice regarding the use of surrogate outcomes based on a detailed analysis of HTA reports across a sample of international HTA agencies. We selected agencies based on existing methodological guidance for the handling of surrogates. These included agencies from Australia (MSAC, PBAC), Canada (CADTH), France (HAS), Germany (G-BA, iQwiG), Netherlands (ZiN) and the United Kingdom (NICE, HIS). Based on a review of both pharmaceuticals and medical devices appraised by NICE since 2013, we selected a sample of technologies whose evaluations were explicitly based on surrogate outcomes e.g. alirocumab and degarelix. Evaluation reports for the same technologies and indication were then sought from the other agencies. Reports were screened and we extracted data on how surrogate outcomes were considered and validated in the context of the assessment of both clinical and cost-effectiveness. In particular, we focused on the consideration of their acceptability, justification, validation and method of incorporation in the cost-effectiveness model. We identified 26 technologies whose evaluation relied on surrogate outcomes. 92% of these technologies were medicines, with one medical device and one diagnostic technology, covering oncology, cardiovascular, infectious diseases and endocrine areas. We were able to identify equivalent reports across the majority of HTA agencies. Surrogate validation was typically not or loosely addressed in the reports with some between-agencies variability. Although many agencies have methods guidance on the use of surrogates, our preliminary results indicate that, the implementation of these methods in evaluation reports is limited.

PRM127 - ECONOMIC MODELLING CONSIDERATIONS IN RARE DISEASES: A TARGETED REVIEW OF HIGHLY SPECIALISED TECHNOLOGY APPRAISALS

Economic evaluation of rare diseases is associated with methodological challenges. This study will assess models submitted under the National Institute for Health and Care Excellence (NICE) highly specialised technologies (HST) programme to identify challenges associated with rare disease model development. A targeted review of the NICE website was conducted on 7th June 2018. All published HST appraisals were included. Data were extracted from identified studies regarding modelling approach, patient population, interventions, results, NICE recommendation, and modelling challenges cited by the evidence review group (ERG). A total of 7 published HST appraisals were identified. All 7 HST appraisals received a positive recommendation. A further 10 HST guidelines are in development. Of 7 published HST appraisals identified, 6 presented cost-consequence analyses while only 1 presented a fully incremental cost-utility analysis. All models employed a Markov state-transition structure. The primary challenge noted by the ERG was a lack of high-quality randomised clinical trial data, cited in 6 of 7 published HST appraisals. Further common challenges included use of surrogate outcomes in clinical trials, a lack of robust utility data, and uncertainty surrounding the natural history of the disease. Moreover, it is often unclear how best to reflect societal benefits associated with new treatments for rare diseases. The review identified barriers to achieving traditional cost-effectiveness thresholds, including high drug acquisition costs and the use of specialist administration centres. Non-randomised clinical trial data obtained from small samples will lead to substantial model input uncertainty. The use of surrogate outcomes in trials leads to the requirement for extrapolation to endpoints pertinent to the model time horizon. Such challenges should be explicitly recognised as it is often impossible to follow best practice when conducting economic evaluations in rare diseases. Patient and clinician involvement throughout model development is key to bridge such data gaps.

Quality of evidence considered by Health Canada in granting full market authorisation to new drugs with a conditional approval: a retrospective cohort study

ObjectivesThis study examines the characteristics of studies that Health Canada uses to grant full marketing authorisation for products given a conditional approval between 1 January 1998 and 30 June 2017.DesignCohort...

Cooperation between geriatricians and general practitioners for improved pharmacotherapy in home-dwelling elderly people receiving polypharmacy \u2013 the COOP Study: study protocol for a cluster randomised controlled trial

BackgroundPolypharmacy and inappropriate drug use is associated with negative health outcomes among older people. Various interventions for improving drug treatment have been evaluated, but the majority of studies are limited by the use of surrogate outcomes or suboptimal design. Thus, the potential for clinically significant improvements from different interventions is still unclear. The main objective of this study is therefore to evaluate the effect upon patient-relevant endpoints of a cooperation between geriatricians and general practitioners on complex drug regimens in home-dwelling elderly people.MethodsThis is a cluster randomised, single-blind, controlled trial where general practitioners are invited to participate with patients from their lists. The patients must be 70 years or older, use at least seven different medications and have their medications administered by the home nursing service. We plan to recruit 200 patients, with randomisation at physician level. The intervention consists of three main parts: (1) clinical geriatric assessment of the patient, combined with a thorough review of their medications; (2) a meeting between the geriatrician and general practitioner, where the two physicians combine their competence and knowledge and discuss the drug list systematically; (3) clinical follow-up, depending on the medication changes that have been done. The study period is 24 weeks, and the patients are assessed at baseline, 16 and 24 weeks. The primary outcome measure is health-related quality of life according to the 15D instrument. Secondary outcome measures include physical and cognitive functioning, medication appropriateness, falls, carer burden, use of health services (hospital or nursing home admissions, use of home nursing services) and mortality.DiscussionOur choice of patient-relevant outcome measures will hopefully provide new knowledge on the potential for clinical improvements after performing comprehensive medication reviews in home-dwelling elderly people receiving polypharmacy.Trial registrationClinicalTrials.gov, NCT02379455. Registered on 27 February 2015.

Use of Surrogate Outcomes in Nephrology Research.

Clinical trials are large and expensive and could require exceedingly long-term follow-up for subjects to reach clinically meaningful end points. To combat these methodologic issues, researchers sometimes use biomarkers as surrogate end points. A biomarker is an objectively measured characteristic that is indicative of some underlying phenomenon or process, while a surrogate is a biomarker that "takes the place" of a clinically meaningful outcome, usually earlier in the disease process. This paper reviews the history, strengths, and weaknesses of surrogate outcome use in clinical research and then discusses potential surrogate outcomes in nephrology research.

Accounting for treatment by center interaction in sample size determinations and the use of surrogate outcomes in the pessary for the prevention of preterm birth trial: a simulation study

BackgroundThe Pessary for the Prevention of Preterm Birth Study (PS3) is an international, multicenter, randomized clinical trial designed to examine the effectiveness of the Arabin pessary in preventing preterm birth in pregnant women with a short cervix. During the design of the study two methodological issues regarding power and sample size were raised. Since treatment in the Standard Arm will vary between centers, it is anticipated that so too will the probability of preterm birth in that arm. This will likely result in a treatment by center interaction, and the issue of how this will affect the sample size requirements was raised. The sample size requirements to examine the effect of the pessary on the baby’s clinical outcome was prohibitively high, so the second issue is how best to examine the effect on clinical outcome. The approaches taken to address these issues are presented.ResultsSimulation and sensitivity analysis were used to address the sample size issue. The probability of preterm birth in the Standard Arm was assumed to vary between centers following a Beta distribution with a mean of 0.3 and a coefficient of variation of 0.3. To address the second issue a Bayesian decision model is proposed that combines the information regarding the between-treatment difference in the probability of preterm birth from PS3 with the data from the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study that relate preterm birth and perinatal mortality/morbidity. The approach provides a between-treatment comparison with respect to the probability of a bad clinical outcome. The performance of the approach was assessed using simulation and sensitivity analysis.Accounting for a possible treatment by center interaction increased the sample size from 540 to 700 patients per arm for the base case. The sample size requirements increase with the coefficient of variation and decrease with the number of centers. Under the same assumptions used for determining the sample size requirements, the simulated mean probability that pessary reduces the risk of perinatal mortality/morbidity is 0.98. The simulated mean decreased with coefficient of variation and increased with the number of clinical sites.ConclusionEmploying simulation and sensitivity analysis is a useful approach for determining sample size requirements while accounting for the additional uncertainty due to a treatment by center interaction. Using a surrogate outcome in conjunction with a Bayesian decision model is an efficient way to compare important clinical outcomes in a randomized clinical trial in situations where the direct approach requires a prohibitively high sample size.

Statistical approaches for evaluating surrogate outcomes in clinical trials: A systematic review

ABSTRACTThe use of surrogate outcomes that predict treatment effect on an unobserved true outcome may have substantial economic and ethical advantages, through reducing the length and size of clinical trials. There has been extensive investigation of the best means of evaluating putative surrogates. We present a systematic review on the evolution of statistical methods for validating surrogates starting from the defining paper of Prentice (1989). We highlight the fundamental differences in the current statistical evaluation approaches, their advantages and disadvantages, and examine the understanding and perceptions of investigators in this area.

Use of surrogate outcomes in US FDA drug approvals, 2003–2012: a survey

ObjectiveTo evaluate, across a spectrum of diseases, how often surrogate outcomes are used as a basis for drug approvals by the US Food and Drug Administration (FDA), and whether and...

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Adaptive clinical trials and their potential to improve drug-development efficiency

Ever escalating costs of pharmaceutical research and development [1] have prompted a drive for greater efficiency in clinical trial design. This has included use of surrogate outcomes [2], biomarker/genetic-based designs [3] and promotion of a range of adaptive designs [4]. While the broader class of adaptive designs includes adaptive randomization (using either minimization or stratification), here we focus on response adaptive designs, where the design is modified during the course of the trial based on the responses (either on a safety indicator or an efficacy outcome or both) of participants who have already been enrolled in the trial. Here, we undertake a brief tour of three key areas in which adaptive designs provide an effective contribution to drug development and then consider some implications of applying adaptive designs in practice.

Funding source and the quality of reports of chronic wounds trials: 2004 to 2011

BackgroundCritical commentaries suggest that wound care randomised controlled trials (RCTs) are often poorly reported with many methodological flaws. Furthermore, interventions in chronic wounds, rather than being drugs, are often medical devices for which there are no requirements for RCTs to bring products to market. RCTs in wounds trials therefore potentially represent a form of marketing. This study presents a methodological overview of chronic wound trials published between 2004 and 2011 and investigates the influence of industry funding on methodological quality.MethodsA systematic search for RCTs for the treatment of chronic wounds published in the English language between 2004 and 2011 (inclusive) in the Cochrane Wounds Group Specialised Register of Trials was carried out.Data were extracted on aspects of trial design, conduct and quality including sample size, duration of follow-up, specification of a primary outcome, use of surrogate outcomes, and risks of bias. In addition, the prevalence of industry funding was assessed and its influence on the above aspects of trial design, conduct and quality was assessed.ResultsA total of 167 RCTs met our inclusion criteria. We found chronic wound trials often have short durations of follow-up (median 12 weeks), small sample sizes (median 63), fail to define a primary outcome in 41% of cases, and those that do define a primary outcome, use surrogate measures of healing in 40% of cases. Only 40% of trials used appropriate methods of randomisation, 25% concealed allocation and 34% blinded outcome assessors. Of the included trials, 41% were wholly or partially funded by industry, 33% declared non-commercial funding and 26% did not report a funding source. Industry funding was not statistically significantly associated with any measure of methodological quality, though this analysis was probably underpowered.ConclusionsThis overview confirms concerns raised about the methodological quality of RCTs in wound care and illustrates that greater efforts must be made to follow international standards for conducting and reporting RCTs. There is currently minimal evidence of an influence of industry funding on methodological quality although analyses had limited power and funding source was not reported for a quarter of studies.

PRM217 - Use of Surrogate Outcomes in Health Technology Assessments (HTAs)

This study analyzes how frequently surrogate outcomes are used in HTAs and if the validity of these outcomes are discussed and reported within the HTAs. A surrogate outcome is defined by the National Institutes of Health as a biomarker intended to substitute for a clinical endpoint. A surrogate outcome is used when a clinical endpoint of interest is not ideal or does not occur often enough to perform meaningful statistical analysis. It is appropriate to use a surrogate outcome only when there is a strong correlation with the clinical endpoint. Before using surrogate outcomes researchers should confirm that the surrogate outcome is biologically plausible, has a magnitude of association with the clinical endpoint, and reflects changes in the relevant clinical endpoint. Context Matters (CM) analyzed 1,056 HTAs spanning 38 disease conditions. Each HTA had a primary outcome that could be classified as either a surrogate outcome or a clinical endpoint. Data was analyzed for eight HTA agencies: AHRQ, DERP, SMC, HAS, PBAC, NICE, CADTH, and HIS Scotland. For those HTAs using a surrogate outcome as the primary outcome, CM then determined if the HTA agency reported the use of the surrogate and/or discussed the surrogate outcome’s validity. Ninety-one percent of HTAs used a surrogate outcome (966 HTAs), but only 11% (109 HTAs) identified it as a surrogate outcome and/or discussed its validity. The agencies that discussed the use of the surrogate outcome most often were AHRQ, DERP, and HIS Scotland at 48.1%, 28.6%, and 29.0% of the time, respectively. Surrogate endpoints are prevalent in HTAs, but the agencies rarely discuss the validity of these endpoints. All agencies failed to discuss the use of the surrogate endpoint in over 50% of their reviews. HTA agencies are not following best practice use of surrogate outcomes.