Are Surrogate Endpoints Unbiased Metrics in Clinical Benefit Scores of the ASCO Value Framework?

BACKGROUND: Clinical benefit scores (CBS) are key elements of the ASCO Value Framework (ASCO-VF) and are weighted based on a hierarchy of efficacy endpoints: hazard ratio for death (HR OS), median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, the other endpoints serve as "surrogates" to calculate CBS. CBS are computed from PFS or RR in 39.6% of randomized controlled trials. This study examined whether surrogate-derived CBS offer unbiased scoring compared with HR OS-derived CBS. METHODS: Using the ASCO-VF, CBS for advanced disease settings were computed for randomized controlled trials of oncology drug approvals by the FDA, European Medicines Agency, and Health Canada in January 2006 through December 2017. Mean differences of surrogate-derived CBS minus HR OS-derived CBS assessed the tendency of surrogate-derived CBS to overestimate or underestimate clinical benefit. Spearman's correlation evaluated the association between surrogate- and HR OS-derived CBS. Mean absolute error assessed the average difference between surrogate-derived CBS relative to HR OS-derived CBS. RESULTS: CBS derived from mOS, HR PFS, mPFS, and RR overestimated HR OS-derived CBS in 58%, 68%, 77%, and 55% of pairs and overall by an average of 5.62 (n=90), 6.86 (n=110), 29.81 (n=101), and 3.58 (n=108), respectively. Correlation coefficients were 0.80 (95% CI, 0.70-0.86), 0.38 (0.20-0.53), 0.20 (0.00-0.38), and 0.01 (-0.18 to 0.19) for mOS-, HR PFS-, mPFS-, and RR-derived CBS, respectively, and mean absolute errors were 11.32, 12.34, 40.40, and 18.63, respectively. CONCLUSIONS: Based on the ASCO-VF algorithm, HR PFS-, mPFS-, and RR-derived CBS are suboptimal surrogates, because they were shown to be biased and poorly correlated to HR OS-derived CBS. Despite lower weighting than OS in the ASCO-VF algorithm, PFS still overestimated CBS. Simple rescaling of surrogate endpoints may not improve their validity within the ASCO-VF given their poor correlations with HR OS-derived CBS.

Do the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology Magnitude of Clinical Benefit Scale Measure the Same Construct of Clinical Benefit?

Purpose Whether the ASCO Value Framework and the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) measure similar constructs of clinical benefit is unclear. It is also unclear how they relate to quality-adjusted life-years (QALYs) and funding recommendations in the United Kingdom and Canada. Methods Randomized clinical trials of oncology drug approvals by the US Food and Drug Administration, European Medicines Agency, and Health Canada between 2006 and August 2015 were identified and scored using the ASCO version 1 (v1) framework, ASCO version 2 (v2) framework, and ESMO-MCBS by at least two independent reviewers. Spearman correlation coefficients were calculated to assess construct (between frameworks) and criterion validity (against QALYs from the National Institute for Health and Care Excellence [NICE] and the pan-Canadian Oncology Drug Review [pCODR]). Associations between scores and NICE/pCODR recommendations were examined. Inter-rater reliability was assessed using intraclass correlation coefficients. Results From 109 included randomized clinical trials, 108 ASCOv1, 111 ASCOv2, and 83 ESMO scores were determined. Correlation coefficients for ASCOv1 versus ESMO, ASCOv2 versus ESMO, and ASCOv1 versus ASCOv2 were 0.36 (95% CI, 0.15 to 0.54), 0.17 (95% CI, -0.06 to 0.37), and 0.50 (95% CI, 0.35 to 0.63), respectively. Compared with NICE QALYs, correlation coefficients were 0.45 (ASCOv1), 0.53 (ASCOv2), and 0.46 (ESMO); with pCODR QALYs, coefficients were 0.19 (ASCOv1), 0.20 (ASCOv2), and 0.36 (ESMO). None of the frameworks were significantly associated with NICE/pCODR recommendations. Inter-rater reliability was good for all frameworks. Conclusion The weak-to-moderate correlations of the ASCO frameworks with the ESMO-MCBS, as well as their correlations with QALYs and with NICE/pCODR funding recommendations, suggest different constructs of clinical benefit measured. Construct convergent validity with the ESMO-MCBS did not increase with the updated ASCO framework.

Reimbursement-Based Economics--What Is It and How Can We Use It to Inform Drug Policy Reform?

BACKGROUND: In Ontario, approximately $3.8 billion is spent annually on publicly funded drug programs. The annual growth in Ontario Public Drug Program (OPDP) expenditure has been limited to 1.2% over the course of 3 years. Concurrently, the Ontario Drug Policy Research Network (ODPRN) was appointed to conduct drug class review research relating to formulary modernization within the OPDP. Drug class reviews by ODPRN incorporate a novel methodological technique called reimbursement-based economics, which focuses on reimbursement strategies and may be particularly relevant for policy-makers. OBJECTIVES: To describe the reimbursement-based economics approach. METHODS: Reimbursement-based economics aims to identify the optimal reimbursement strategy for drug classes by incorporating a review of economic literature, comprehensive budget impact analyses, and consideration of cost-effectiveness. This 3-step approach is novel in its focus on the economic impact of alternate reimbursement strategies rather than individual therapies. RESULTS: The methods involved within the reimbursement-based approach are detailed. To facilitate the description, summary methods and findings from a recent application to formulary modernization with respect to the drug class tryptamine-based selective serotonin receptor agonists (triptans) used to treat migraine headaches are presented. CONCLUSIONS: The application of reimbursement-based economics in drug policy reforms allows policy-makers to consider the cost-effectiveness and budget impact of different reimbursement strategies allowing consideration of the trade-off between potential cost savings vs increased access to cost-effective treatments.

Perspectives of complementary and alternative medicine (CAM) practitioners in the support and treatment of infertility.

BACKGROUND: Infertility patients are increasingly using complementary and alternative medicine (CAM) to supplement or replace conventional fertility treatments. The objective of this study was to determine the roles of CAM practitioners in the support and treatment of infertility. METHODS: Ten semi-structured interviews were conducted in Ottawa, Canada in 2011 with CAM practitioners who specialized in naturopathy, acupuncture, traditional Chinese medicine, hypnotherapy and integrated medicine. RESULTS: CAM practitioners played an active role in both treatment and support of infertility, using a holistic, interdisciplinary and individualized approach. CAM practitioners recognized biological but also environmental and psychosomatic determinants of infertility. Participants were receptive to working with physicians, however little collaboration was described. CONCLUSIONS: Integrated infertility patient care through both collaboration with CAM practitioners and incorporation of CAM's holistic, individualized and interdisciplinary approaches would greatly benefit infertility patients.

A qualitative study of Ottawa university students' awareness, knowledge and perceptions of infertility, infertility risk factors and assisted reproductive technologies (ART).

BACKGROUND: Awareness of infertility risk factors is an essential first step to safeguard future fertility. Whereas several studies have examined university students' awareness of female fertility and related risk factors, the topic of male infertility has not been well examined. The objective of this study was to assess young men and women's awareness, knowledge and perceptions of infertility, male and female infertility risk factors and assisted reproductive technologies (ART). METHODS: Semi-structured interviews were conducted in 2008 with a multi-ethnic sample of sixteen male and twenty-three female Ottawa university students, followed by qualitative data analysis to identify major themes. Interview topics included awareness of male and female infertility risk factors, infertility diagnosis/treatments and personal options in the event of future infertility. RESULTS: Participants were generally familiar with infertility as a biomedical health problem, could identify sex-specific risk factors but overestimated fertility of women in their thirties and ART success rates. Reproductive health knowledge gaps and confusion of the physiological life-stage of menopause with infertility were apparent. Most participants would pursue in vitro fertilization or international adoption in the event of personal infertility. Some participants wished to use a 'natural' approach and were concerned with potential side effects of ART-related medications. CONCLUSIONS: The general awareness of infertility in young adults is promising and supports the potential uptake for health promotion of fertility preservation. This study underscores the continued need for comprehensive sexual and reproductive health education and promotion for adolescents and young adults.

University students' perceptions of environmental risks to infertility.

BACKGROUND: Canadian young adults may be at risk of future infertility due to the high incidence of sexually transmissible infections (STIs) in this population. Young adults' perceptions of environmental risks, including contaminants, STIs and lifestyle habits on infertility, have not been examined. We have therefore designed a qualitative study to explore risk perceptions, awareness and knowledge of common environmental risk factors for infertility in a multiethnic sample of young adults. METHODS: Semistructured interviews were carried out with 40 university undergraduate students (16 men and 24 women) in Ottawa, Canada, followed by qualitative analysis of interview transcripts to identify major themes. RESULTS: The following broad themes described participants' risk perceptions about infertility and (1) environmental contaminants: knowledge gaps, media reports and negative perception of chemicals; (2) STIs: superficial understanding of their role in infertility, general awareness, associations with sexual behaviours and knowledge gaps; and (3) lifestyle: protective benefits of healthy lifestyle, dose or exposure effects for smoking and alcohol, and knowledge gaps. Students demonstrated a superficial understanding of environmental risks, at times relying on media reports and anecdotal information to support their beliefs. CONCLUSIONS: This next generation of potential infertility patients exhibits a general understanding of environmental risks to infertility; however, young adults are overly optimistic that healthy lifestyle behaviours will safeguard future fertility. STIs represent the most significant modifiable risk factors for this age group; a message that can be supported by sexual and reproductive health education and promotion with greater emphasis on the long-term outcomes of STIs, including infertility.