Review of Surrogate Endpoint Validation Methodologies and Application In Solid Tumour Htas

VA L U E I N H E A LT H

in advanced stages of breast cancer.  Methods: We searched phase II and phase III clinical trials of advanced breast cancer registered in ClinilcalTrial.gov registry between October 2000 to September 2012, which was divided into two study periods (cohort A: October 2000 to September 2007 and cohort B: October 2007 to September 2012). The assessment of primary and secondary endpoints was conducted by two independent reviewers.  Results: In 398 phase II trials, there was a change in the most commonly used primary outcome measure from objective response rate in cohort A (60.6 %) to progression-free survival in cohort B (40.7 %). The trend was statistically significant with a decline in objective response rate selection (P <  0.001) and an increase in progression-free survival selection (P <  0.001). For 120 phase III trials, progression-free survival was the most frequently used primary outcome in both cohort groups (cohort A: 35.9 %; cohort B: 66.1 %; P <  0.001).  Conclusions: This was the first study to assess endpoint selection in advanced breast cancer clinical trials over a decade. For both phase II and III trials, progression-free survival was the most frequently used primary outcome in general. However, in phase II trials studies, increasing trend in progression-free survival use in substitution of objective response rate was observed. As selection of proper endpoints is important for the success of clinical trials, changing trends should be considered when deciding upon primary and secondary outcome measures for the assessment of drug efficacy and safety. PRM5 Cognitive assessments on portable devices: A comparison between phones and tablets Jansen J1, van de Loo A1, Garssen J2, Scholey A3, Tiplady B4, Verster J1 1Utrecht University, Utrecht, The Netherlands, 2Nutricia Research, Utrecht, The Netherlands, 3Swinburne University, Melbourne, Australia, 4University of Edinburgh, Edinburgh, UK

Objectives: Assessments of cognitive function are important endpoints in clinical research. It is often important to carry out such assessments in an everyday setting. In such cases, portability and ease of use are very important. Smaller devices are more portable, but screen size may become a limitation. The study examined whether a mobile test battery yields similar results on a mobile phone (6cm diagonal screen) and a tablet (18cm).  Methods: 39 healthy volunteers took part. aged 18 - 30 years, 20 female. The 20 minute test battery assessed attention, psychomotor functioning, memory, and comprehension. Tests were: Number Pairs, Arrow Flankers, Arrow Reaction Time, Memory Scanning, Shape Pair Learning; and Serial Sevens Subtraction. Outcome measures for each test were mean reaction time (RT) and percentage of errors (PE). The study used a two-period crossover design, with the two platforms in randomised order within a half-day session. Within each period, volunteers completed 5 practise assessments, then a final assessment that was used for the present analysis.  Results: Test scores were similar for the platforms. Differences between phone and tablet were all small, with effect sizes < 0.25, and there was no clear tendency for scores to differ overall between platforms. For RT scores, correlations between phone and tablet scores were in the range 0.54 – 0.82 (mean 0.71). For PE scores correlations were somewhat lower. One measure, Shape Pairs, showed a correlation of 0.14. Other PE scores were in the range 0.53 – 0.76 (overall mean 0.59).  Conclusions: Taken together, these results indicate that there is good agreement between phones and tablets. The six tests, which assess a broad range of functions, can be used across a range of screen sizes from 6 – 18 cm with equivalent results, allowing great flexibility in the choice of portable devices for everyday assessments of cognition. PRM6 Using Convergent Mixed Methods To Evaluate Treatment Risks and Benefits In Rare Disease: An Example From A Phase Ii Registration Trial In Metastatic Merkel Cell Carcinoma Bharmal M1, Guillemin I2, Marrel A2, Lambert J2, Arnould B2, Fatoumata F2, Hennessy M3, Dias-Barbosa C2 1Merck KGaA, Darmstadt, Germany, 2Mapi, Patient-Centered Outcomes, Lyon, France, 3EMD Serono, Billerica, MA, USA

20 (2017) A399–A811

A731

Objectives: The use of surrogate endpoints in oncology trials may allow for a smaller sample size, a shorter study duration, and a more rapid time to market, if proven to be valid. We aimed to investigate the validation of surrogate endpoints in melanoma trials, and their use in health technology assessments (HTA).  Methods: We conducted a targeted literature review to identify studies assessing the validity of surrogate endpoints in melanoma, using the key words ‘surrogate endpoint’, ‘correlation’ ‘regression’ and ‘melanoma’. Searches were conducted on MEDLINE, EMBASE and Cochrane Library (2012-2017), ISPOR, ASCO and ESMO congresses (2012-2017), and HTA websites (NICE, SMC, HAS, PBAC, IQWIG and pCODR).  Results: Four metaanalyses and one phase III trial were identified that assessed the following surrogate measures for overall survival (OS): progression free survival (PFS), 1- and 2-year OS, recurrence-free-survival (RFS), early-tumour-response, time-to-progression (TTP), objective-response-rate (ORR) and disease-control-rate (DCR). Methods used for statistical validation included correlations between surrogate endpoints and OS (outcome level surrogacy, R), correlations between the treatment effects on surrogate endpoints and OS (trial level surrogacy, R2), and calculation of surrogate threshold effect (STE). Analysis of immunotherapies in metastatic melanoma suggests that 1-year OS may be an appropriate surrogate for OS (R2 =  0.75); however, no clear correlations were observed between DCR/ORR/PFS and OS (R2 = 0.03/0.03/0.19). TTP was more strongly correlated with OS than early-tumour-response to vemurafenib in metastatic melanoma (τ  =  0.655). Correlation between PFS and OS was reported for dacarbazine in metastatic melanoma (R = 0.71); however, IQWiG deemed the methodology insufficient for surrogate validation. Analysis of adjuvant treatment in resectable melanoma suggested that RFS could be an appropriate surrogate for OS (R2 = 0.91) and calculated an STE of 0.77.  Conclusions: Robust and appropriate methodologies are required in order to validate surrogate endpoints in melanoma for use in HTA. PRM8 Analysis of Effectiveness Criteria In Pharmacoeconomic Studies of Antimicrobial Therapeutic Agents Proposed for Inclusion In The Essential Drug List (RUSSIA) In 2014-2016 Kolbin A, Gomon Y Pavlov Medical University, St.Petersburg, Russian Federation

Objectives: To determine the proportion of hard and surrogate endpoints chosen as effectiveness criteria in pharmacoeconomic studies of antimicrobial therapeutic agents proposed for inclusion in the essential drug lists (Russia) in 20142016.  Methods: Analysis of pharmacoeconomic studies included in 30 antimicrobial pharmaceutical agents dossier proposed for inclusion in the essential drug list (Russia) in 2014-2016.  Results: 47 effectiveness criteria were analyzed. Hard endpoints were used in 42,5%. Two studies of antifungal agents used hard endpoints only. The proportion of hard endpoints used in research involving antibacterial agents was 53%. The least percentage of hard endpoints (26%) was used in antiviral agent research. Single study of an antiviral agent used the risk of development of resistant strains as an endpoint.  Conclusions: 1. Hard endpoints were chosen as effectiveness criteria in pharmacoeconomic studies of antimicrobial therapeutic agents only in 42,5% of endpoints. 2. The most percentage of hard endpoints (100%) was used in antifungal agent research.3. The least percentage of hard endpoints (26%) was used in antiviral agent research. 5. Gaps in data on the possible development of antimicrobial resistance and the speed of this process do not allow to predict direct and indirect costs of prescribing individual antimicrobial therapeutic agents. PRM9 Review of Surrogate Endpoint Validation Methodologies and Application In Solid Tumour Htas Hopkinson D1, Chadwick C1, Bibi M1, Bastian A2 1McCann Health, Macclesfield, UK, 2Incyte Corporation, Wilmington, DE, USA

Objectives: Demonstrating treatment benefits for rare diseases within clinical trials is challenging. Mixed methods research (MMR) offers to overcome these challenges by combining quantitative and qualitative approaches, thus providing a better understanding of the available data. A convergent mixed methods design in the context of Merkel cell carcinoma, a rare type of skin cancer, during the JAVELIN Merkel 200 trial (NCT02155647) Part A, was used. We aimed to assess the concordance between a patient’s assessment of their own cancer health versus the objective measure of RECIST.  Methods: Nine of 88 patients from the trial were interviewed at baseline prior to receiving the study treatment avelumab, and at 13 weeks and 25 weeks after first avelumab administration. Key concepts of interest (COIs) identified from the baseline interviews were physical functioning, fatigue/energy, and pain. Patient perceptions of overall change in their cancer-related health status since starting study treatment was also recorded. During qualitative analysis, at each time-point, each COI was assigned a category describing the trend in change (e.g. newly emerged, no change/stable, improved, worsened, ceased/disappeared). In parallel, patients’ tumour status was determined by the overall response status, as per the clinical trial protocol.  Results: A high concordance between patient-reported qualitative data and tumour status was observed. All eight patients who responded to treatment perceived an improvement in their disease, while the single patient whose tumour progressed perceived no improvement in the COIs since starting the treatment.  Conclusions: Embedding qualitative research in clinical trials is an innovative approach for characterization of treatment benefit meaningful to patients. This application of MMR can support clinician-reported outcomes to provide a more comprehensive picture of perceived benefits of treatment in rare diseases.

Objectives: There are currently no universally accepted surrogate endpoints for overall survival in trials of solid tumours. We aimed to conduct a literature review of methods that have been utilised to validate surrogate endpoints, and assess how these methods have been applied in health technology assessments (HTA).  Methods: Using the key words ‘surrogate endpoint’, ‘correlation’ and ‘regression’, searches of MEDLINE, EMBASE, Cochrane Library, ISPOR, ASCO and ESMO (2012-2017) were conducted to identify studies reporting methodologies for validating surrogate endpoints. A number of national HTA agencies (NICE, SMC, HAS, PBAC, IQWIG and pCODR) were also searched to investigate the use and critique of these methods, with a focus on solid tumours.  Results: The foremost methodologies for surrogate validation reported in the literature include multi-trial approaches (meta-analytic analyses, informatics theoretic approach and surrogate threshold effect [STE]) and causal inference (causal association and principal stratification). Of the six HTA agencies investigated, only IQWiG and PBAC suggest preferred methodologies for the validation of surrogate endpoints, citing meta-analytic analyses and STE. A search for solid tumour HTAs examining the validity of surrogate endpoints returned eight results. Negative decisions were reported for axitinib in kidney cancer (PBAC), dabrafenib in melanoma (IQWiG), palbocliclib in breast cancer (IQWiG), and pertuzumab in breast cancer (SMC and pCODR). Positive decisions were reported for imatinib in GIST (PBAC), pertuzumab in breast cancer (NICE) and vandetanib in thyroid cancer (pCODR), despite a lack of statistical evidence for surrogate validation. Reasons for rejection of surrogate endpoints included lack of appropriate and robust methodology, inclusion of non-comparable treatments, regimens or endpoints, exclusion of relevant trials, and lack of relevant sensitivity analyses.  Conclusions: There is currently no clear consensus on how to validate surrogate endpoints. The design of appropriate and robust methodologies will be required to validate surrogate endpoints for use in solid tumour HTAs.

PRM7 Validation of Surrogate Endpoints In Melanoma Therapies and Use In HTA

PRM10 Impact of Drug Related Problems on Blood Pressure Control In Patients With Hypertension In Indonesian Primary Health Care

Hopkinson D1, Chadwick C1, Bibi M1, Bastian A2 1McCann Health, Macclesfield, UK, 2Incyte Corporation, Wilmington, DE, USA

Rahmawati F, Andayani TM, Wijayanti L, Lefiani L Universitas Gadjah Mada, Yogyakarta, Indonesia