Evaluating Endpoints and Changing Trends In Advanced Stages of Cancer Related Clinical Trials

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with these novel agents must be evaluated alongside the benefit provided. Health technology assessment (HTA) decisions in MS aim to generate policies that produce cost-effective symptomatic or disease-modifying benefit. The objective of this analysis was to update a 2014 study by evaluating recent HTA decisions and their rationales to identify trends in selected countries.  Methods: HTA surveillance was conducted for Australia, Canada, France, Germany, and the United Kingdom (UK) from January 1, 2012 to April 30, 2017 (64 months). MS-related HTAs were evaluated by indication, decision, and rationale for the decision. Decisions were categorized as favorable, unfavorable, mixed (both favorable and unfavorable), and neutral (deferral).  Results: 31 MS-related HTA decisions were published in the study timeframe for 9 unique products. Across studied nations, 14 (45%) decisions were favorable, 13 (42%) unfavorable, 3 (10%) mixed, and 1 (3%) neutral. The UK had the highest percentage of favorable decisions (5/5; 100%), followed by France (5/6, 83%), Australia (2/8, 25%), Canada (1/4, 25%) and Germany (1/8, 13%). Nearly all favorable decisions were for products indicated to treat relapsing-remitting MS (RRMS; 13/14, 93%), while other MS-related indications (walking improvement, spasticity / paralysis, clinically isolated syndrome) were mostly unfavorable (7/8, 88%). HTAs published during or after May 2014 represented half of the decisions examined and tended to be more favorable than studied assessments before this date (53% vs 38%, respectively).  Conclusions: Overall, there were a similar number of favorable and unfavorable decisions, reinforcing the need for manufacturers to develop strong data customized to the evidentiary requirements of each country. PND71 Assessment of Marketed and In-Development Products for Alzheimer’s Disease: What are the Strategic Value Drivers? Gautam R Optum Global Solutions, Noida, India

Objectives: The increasing Alzheimer’s disease (AD) population is a serious concern to governments and payers. The currently marketed products do not alter, nor affect the progression of AD, they only impact cognitive functions. The unmet treatment need in AD is significantly higher. The in-development products have yet to demonstrate their ability to modify the disease. This analysis aimed to assess the clinical, humanistic and economic value drivers for AD market.  Methods: The strategic value drivers were identified through a targeted literature search using electronic databases (e.g., PubMed, Embase), using disease terminology and clinical, humanistic and economic terms. Treatment guidelines were identified through PubMed and National Guideline Clearinghouse. The labels of marketed products were reviewed to identify the reported outcomes. ClinicalTrials.gov was reviewed to identify the in-development products and emerging therapies. Key review articles were also reviewed. Data were analyzed to draw insights.  Results: This analysis identified the following attributes as the most valuable drivers for AD market: Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE) scales score (Efficacy attributes); confusion and vomiting side-effects (Safety attributes); cerebrospinal fluid (CSF) amyloid-β 42 and amyloid positron emission tomography (PET) scans (Biomarkers); Quality of Life–Alzheimer’s Disease (QOL-AD) scale measure (Humanistic attribute); and direct cost, budgetimpact and cost-effectiveness analyses (Economic attributes).  Conclusions: For AD therapy, the most notable value drivers from the payer’s perspective would be efficacy and safety of the upcoming new products. The disease-modifying treatments, with less cost, less invasive diagnostics (e.g. blood test vs. spinal tap) and improving patient’s QOL would be considered as priority from payer’s perspective. Safety attributes can be addressed with the products having least adverse events and are more sensitive to those that have little to no impact. Other attributes such as biomarkers should demonstrate a positive impact on decreasing patient β -amyloid in the brain.

RESEARCH POSTER PRESENTATIONS - SESSION V

RESEARCH ON METHODS STUDIES

RESEARCH ON METHODS – Clinical Outcomes Methods PRM1 COMPARISON OF VARIOUS SEVERITY ASSESSMENT SCORING SYSTEMS IN PATIENTS WITH SEPSIS Badrinath K1, Shekhar M1, Moturu SL1, Kunhikatta V1, Thunga G1, Nileshwar KR2 1Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India, 2Kasturba Medical College, Manipal, Manipal University, Manipal, India

Objectives: To evaluate the predictive ability of six severity assessment scoring systems, namely, Acute Physiology and Chronic Health Evaluation (APACHE II), Rapid Emergency Medicine Score (REMS), Sequential Organ Failure Assessment (SOFA), Multiple Organ Dysfunction Score (MODS), Predisposition, Infection, Response and Organ Dysfunction (PIRO) and Mortality in Emergency Department Sepsis (MEDS) scores,  in patients with sepsis. Methods: A prospective cohort study, carried out in a south Indian tertiary care teaching hospital. Institutional ethics committee approval was obtained prior to the study. All patients diagnosed with sepsis according to guidelines the third International Consensus Definitions for Sepsis and Septic shock (Sepsis 3), who meets the inclusion and exclusion criteria were enrolled into the study. Patients were followed from the day of admission to till the day of discharge or death. Patient demographics, clinical characteristics, laboratory test data and comorbidities were recorded on the day of sepsis diagnosis. These parameters were used to calculate the severity scores and predicted mortality for each patient. ROC curve analysis was used to analyse the discriminative power (ability to differentiate between survivors and non-survivors) of various severity

scores.  Results: A total of 193 patients were included in the study. The mean age was 57.2±15.3 (mean±SD) years. Majority of the patients were male, 125 (64.76%). Overall mortality was 108 (55.9%). The calculated AUCs were 0.86 (95% CI: 0.80-0.90) for APACHE II, 0.81 (95% CI: 0.75-0.87) for REMS, 0.80 (95% CI: 0.74-0.86) for SOFA, 0.74 (95% CI: 0.67-0.80) for MODS, 0.78 (95% CI: 0.71-0.84) for PIRO and 0.77 (95% CI: 0.71-0.83) for MEDS. Sensitivity and specificity for APACHE II was 81.5 and 75.3 respectively.  Conclusions: In our study, APACHE II score proved to be the most superior of all the scores, as it considers not only the laboratory data but also chronic comorbidities and surgical status of the patient. PRM2 Could Embase Emtree Index Search Terms Be Focused To Reduce Numbers To Screen In Clinical Systematic Reviews? Cadwell K, Fox D, Jones G PHMR Ltd, London, UK

Objectives: Embase is one of the most commonly searched bibliographic databases when undertaking systematic reviews of healthcare interventions. Using a combination of text searching and index searching is accepted best practice when designing Embase search strategies. As the number of Emtree index terms assigned to each Embase record has increased over time, there has been a corresponding increase in overall search result numbers and, therefore, the size of the workload for reviewers. The objective of this research was to investigate whether focusing Emtree indexing terms using the ‘restrict to focus’ function, so that only those articles where the index term is key to that article are retrieved, could reduce the number of records for screening without loss of included studies.  Methods: Embase searches conducted in three selected clinical reviews undertaken by the review team were retrospectively compared with searches in which the Emtree terms were focused. The records retrieved by the focused Emtree searches were checked to see what proportion of included studies identified by the original unfocused search strategy were retrieved. The subjects of reviews investigated were treatments for invasive fungal infections, type 2 diabetes mellitus, and acute lymphoblastic leukaemia.  Results: The data collected was analysed to identify total results with and without focusing Emtree terms, and to calculate the yield of included records. The focused searches retrieved 100% of the included papers in each review but results retrieved to screen were reduced by up to 30%.  Conclusions: Focusing Emtree terms can potentially reduce screening burden in clinical systematic reviews without lowering retrieval of relevant records. Reducing the number of results in Embase searches without a loss of sensitivity could improve efficiency by reducing time spent and costs when undertaking systematic reviews. PRM3 A Real World Evidence (RWE) Approach To Characterising An Ultra-Rare Disease (URD) Cohort of Metastatic Uveal Melanoma (MUM) Patients Within National Health Service England (NHSE) Schwenkglenks M1, Alamgir G2, Cheng C3, Adams EJ3, Toward T4 1European Center of Pharmaceutical Medicine - University of Basel, Basel, Switzerland, 2Health iQ Ltd, London, UK, 3Aquarius Population Health Limited, London, UK, 4Immunocore Limited, Abingdon, UK

Objectives: In Europe, primary UM is reported to affect 2-8 Caucasians/million population annually. ~90% of tumours involve the choroid, with the remainder confined to iris and ciliary body. Despite radical intra-ocular intervention(s), ~50% of patients develop metastatic disease, predominately in the liver. In the absence of therapeutic options, median time-to-progression and overall survival is ~2-3 and ~7-12 months, respectively. To inform a real-world understanding of mUM standard of care (SoC) treatment pathways, this study aimed to i) identify a cohort of mUM patients within the NHSE monopsony using the Hospital Episodes Statistics (HES) database; ii) compare the cohort characteristics and observations against clinical literature.  Methods: A mUM patient cohort were identified within HES (observational period: Apr2012-Jun2016, follow-up until Jan2017). Eligible patients had no cancer ICD-10 codes prior to their first inpatient admission for UM (C693 or C694); and at least another cancer code in the same or subsequent admission(s), indicating metastasis. Patients with C699 or D31 codes for their first inpatient admission (indicating unspecified or benign disease) and C693 or C694 in subsequent admissions were permitted if they had a subsequent C787 code (liver metastasis).  Results: Consistent with total NHSE epidemiological estimates, 450 mUM patients were identified in HES. Cohort characteristics: Mean age [65 years, range 0-97]; female [49%]; primary tumour involvement: choroid [n= 391,87%] Vs. ciliary body [n= 55,12%]; reported enucleation [n= 177,39%]; “Liver” as first metastatic site [n= 212,47%]; The most frequent sites of metastases in the cohort were: liver [n= 255,57%], lung [n= 115,26%], skin/soft tissue [n= 82,18%], bone [n= 63,14%] and lymph nodes [n= 31,7%].  Conclusions: The cohort characteristics were consistent with published mUM literature. Only the overall involvement of liver metastases appeared discrepant to that reported [~90%] in literature. This may be explained by a limited observation and follow-up period in our cohort. This RWE methodology provides supportive insight into SoC treatment pathways for URDs such as mUM. PRM4 Evaluating Endpoints and Changing Trends In Advanced Stages of Cancer Related Clinical Trials Kim H1, Lee J1, Song SY2, Kim E3 1Department of Pharmaceutical Industry Management, The Graduate School, Chung-Ang University, Seoul, Korea, Republic of (South), 2Chung-Ang University College of Pharmacy, Seoul, Korea, Republic of (South), 3Evidence-Based Research and Clinical Research Lab., Department of Health, Social and Clinical Pharmacy, College of Pharmacy, Chung-Ang University, Seoul, Korea, Republic of (South)

Objectives: Properly selected endpoints are essential for clinical trials aimed at developing new drugs. This study uses ClinicalTrail.gov registry as data source in evaluating the use of endpoints and changing trends in phase II and phase III trials



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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

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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