Use Of Pragmatic Clinical Trials To Support Drug Launch

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include the ones with P&R process completed and have been reimbursed. These drugs are part of a monthly updated database (currently 145 drugs) aiming to track the process over the time. For each analysed drug standard checkpoints were identified to measure timings of each single approval steps.  Results: Up to May 2017, 47 reimbursed drugs have been categorized in: innovative (7), orphan (10), innovative and orphan (2), oncological (9) and other approved drugs (28). The analysis shows an average time between Start and OJ publication of 332 days (min 43 max 959), of which 143 due to CTS-CPR assessment. Other checkpoints reveals an average total administrative delay of 190 days (56% of total time). Timing is significantly reduced in all steps for innovative drugs (247 days) while results longer for oncological drugs (383 days), particularly the CTS assessment. Orphan drugs have shorter opening procedures, but longer assessments. The remaining 28 drugs have longer openings and faster CTS assessments.  Conclusions: Despite a relevant speed up in the approval process in the last 2 years compared to previous publications (247,5 days in 2013-2015 vs. 205 days in 2015-2017 for CTS assessment of oncological drugs), the subanalysis by category reveals a variety of pathways, impacting on approval timings. The analysis also reveals that the majority of the overall timing is linked to administrative steps. PHP47 Gene-Therapy, The Way Forward In Europe – The Payer Perspective Poschen C, Schmitz S, Krishnan A Partners4Access, LONDON, UK

Objectives: Gene-therapy is a novel treatment area that includes stem-cell and genetic products and procedures. Perception of gene-therapy; its use, its value, and appropriate price varies between stakeholders. This research will support the understanding of payers’ perceptions, on the last three gene-therapy launches (alipogene tiparvovec, talimogene laherparepvec, autologous CD34+ enriched-cell-fraction), withdrawal of alipogene tiparvovec and understand ways to incorporate genetherapy into healthcare budgets.  Methods: Secondary research was conducted using systematic literature review (PRISMA methodology) aiming to understand the gene-therapy environment in key markets - Germany, Italy, and the UK. The review included publicly available documents of HTA evaluations and scientific articles. The review served as a base for an online survey of payers in the three countries. An online survey of six payers was conducted; consisting of multiple choice and open-ended questions on their respective country’s experience and readiness for gene-therapy.  Results: While payers considered the opportunity of gene-therapy as positive, only one payer rated their (Italian) health-system as ready for genetherapy. Major concerns were insufficiently robust clinical programmes (50%), lack of predictability (80%), lack of experience (100%), and high anticipated prices (100%). One payer (Germany) expects non-curing gene-therapy to be equivalent in cost to a standard drug therapy with similar effects. Payers expect gene-therapy to be curative, and industry needs to effectively demonstrate this. All respondents confirmed a dialogue between industry and payers is needed to agree how to provide satisfactory evidence of value.  Conclusions: The findings are in line with the previously identified literature. Work remains to be done to increase payers’ understanding of genetherapy, its curative and/or symptom relieving potential to effectively prepare for future launches. Optimal evidence and amenable funding will be the key areas for industry to address to ensure gene-therapies are successfully launched in Europe. PHP48 Orphan Drugs In The Uk, Do They Meet The Nice Highly Specialised Technology Threshold? Weinstein N, Martin M, Campbell R inVentiv Health, London, UK

Objectives: Orphan Medicinal Products (OMPs) for rare diseases undergo health technology appraisals (HTA) by the National Institute for Health and Care Excellence (NICE). Drugs for ‘very rare’ conditions undergo further extensive Highly Specialized Technology (HST) reviews, to establish the overall magnitude of their therapeutic benefits, cost effectiveness, and budget impact. On April 1, 2017, NICE published an incremental cost-effectiveness ratio (ICER) threshold for OMPs set at £100,000 per quality-adjusted-life-year (QALY) gained, in addition to a QALY weighting dependent on the QALY gain offered by the new treatment. The objective of this analysis was to investigate the OMPs previously recommended by NICE and assess to what extent they meet this new guidance.  Methods: Currently, 96 drugs possess European Medicines Agency (EMA) orphan designation and market authorization. This list has been reviewed to establish which OMPs have acquired NICE recommendations. All publicly available ICER data were collated from NICE consultation, appraisal and committee papers between January 2007 and June 2017.  Results: As of June 2017, a total of 33 EMA authorized OMPs have undergone a standard HTA appraisal, while 7 have been reviewed via the HST process. Of those appraised, 27 ICER’s have been published. NICE recommended 27 OMPs; twelve of these involved Patient Access Schemes (PAS) of which three (therapeutic areas: pulmonary and musculoskeletal/ nervous system) had ICERs greater than the £100,000 threshold. The majority of the products approved before April 2017 involved a PAS, making it unclear to which level the ICER was reduced to allow for the product to receive a positive opinion from NICE.  Conclusions: Considering the pubically available information, the majority of OMP drugs recommended before April 2017, fell within the threshold of £100,000. For the exceptions, applying the new guidelines on the QALY weighting resulted in ICERs unlikely to fall within the thresholds adjusted for therapeutic benefit. PHP49 Nice’s New Budget Impact Threshold – What Proportion Of Drugs Is This Likely To Affect? Macaulay R, Shaw S, Dave K, Tang M PAREXEL International, London, UK

Objectives: Since 2006, the National Institute of Health and Care Excellence (NICE) have issued guidance on whether new health technologies should be adopted by the National Health Service (NHS) in England and Wales. The cost-effectiveness

of a new technology expressed as the incremental cost per Quality Adjusted Life Year gained is a key appraisal criterion. However, recent affordability challenges in reimbursing some new innovations resulted in NICE introducing an additional annual budget impact threshold of £20 million in April 2017. If a new therapy was anticipated to exceed this threshold during any of its first 3 years on the market, it would need to enter a second process of price negotiation before it can be made available on the NHS. This research aims to evaluate the proportion of technologies likely to be impacted by this new process.  Methods: NICE single technology appraisal Resource Impact reports were screened (15/04/2012-31/05/2017) to extract the number of patients and annual budget impact. For technologies with a patient access scheme, the budget impact data are considered commercial in confidence. In such cases, the cost per patient was extracted from the corresponding Scottish Medicines Consortium report.  Results: Of 133 appraisals screened, annual budget impact data was calculated for 51 technologies. The mean and median annual budget impact was £33,422,815 and £6,599,808 in year 1, £47,623,183 and £10,659,825 in year 2, and £70,730,456 and £14,886,400 in year 3, respectively. The anticipated budget impact exceeded the annual £20 million threshold within the first 3 years in 43% (22/51) of appraisals.  Conclusions: The new budget impact threshold introduced by NICE is likely to impact a substantial proportion of appraisals. The precise consequences of this second round of price negotiations are not yet clear but this additional reimbursement hurdle will likely negatively impact market access for innovative new therapies. PHP50 Price Life Cycle Management Of Orphan Drugs In France Lebreton C1, Avot D2, Morand F1, Laigle V3, Troubat A1 1QuintilesIMS, Paris La Defense, France, 2MSD France, Courbevoie, France, 3MSD Vaccins, Lyon, France

Objectives: The objective of this analysis is to describe economic regulation of orphan drugs[1]in France and identify key criteria influencing price life cycle management.  Methods: We reviewed literature published from 2006 to 2016 to comprehensively research any decision or regulation informing orphan drug market access management in France. Then, we screened all non-oncologic orphan drugs launched on the French market since 2006 (n= 32) and analyzed their pricing history by categorizing each price cut based on rationale (n= 33). Finally we clustered products based on HAS evaluation (SMR, ASMR, target population), years since launch and turnover/ sales volume since 2010 extracted from QuintilesIMS MIDAS® database (drugs dispensing at retail pharmacies).  Results: Two major regulation components appear specific to orphan drugs in France: exemption from safeguard clause (conditional to turnover < 30M€ ) and opportunity to reach a cost per patient-year up to 50K€ . Pricing analysis showed that the first price-cut occurred on average 5.1 years [0,2; 11,3] after launch, mean decrease was -8% [-2,25%; -25,45%] and did not seem to be linked with turnover level. Extension of indication led to price-cuts in most of cases (75%) in 1 to 1.5 years following HTA opinion publication, correlated with an increase of target population. Most price cuts were attributed to number of years on the market since launch. Neither SMR or ASMR level nor any other HTA evaluation components seem to be strongly correlated to price life cycle management.  Conclusions: Orphan drug price life cycle does not differ as much as one would expect from general regulation, apart from 5 years price stability sometimes granted regardless of ASMR level. Extension of indication generally led to a price cut regardless of orphan status of new indication or ASMR level. [1] (excluding oncology orphan drugs) PHP51 Avoiding A Market For Lemons With Pharmaceuticals: How RiskSharing Mechanisms Can Improve Allocation Brammli-Greenberg S1, Daniels E2, Yaari I2 1University of Haifa, Haifa, Israel, 2Myers-JDC-Brookdale Institute, Jerusalem, Israel

Objectives: To analyze a potential market failure in the interaction between pharmaceutical companies and consumers, which is relevant to key ethical, financial and social objectives, and to explore the feasibility of a risk-sharing mechanism to reduce system-wide inefficiency.  Methods: We reviewed trends in pharmaceutical spending across OECD countries and analyze the process of accepting new drugs into the Israeli Health Services Basket (HSB). We constructed two theoretical models to explain a sub-optimal allocation of pharmaceuticals in the economy. The first method uses a dynamic pricing game framework, while the second method uses a constraint theory scheme.  Results: The economic analysis revealed several insights regarding market players’ behavior: extensive uncertainty drives pharmaceutical companies to overstate prices, while it drives health plans to overestimate the number of potential users. The empirical analysis revealed a national pharmaceutical expenditure increase in Israel, reflected by a 4 to 10 percent yearly change in nominal expenditure since 2010, and inadequate pharmaceutical care, revealed by a 2016 national survey in Israel. The survey showed that 10 percent of low income and 9 percent chronically ill households forwent prescribed drugs due to costs involved, compared to only 5 percent of the overall population. The combined analysis showed that each model does allow for an introduction of risk-sharing mechanisms that increase efficiency and overall welfare.  Conclusions: By reducing uncertainty and mitigating the effects of asymmetric information between pharmaceutical companies and consumers, risk-sharing mechanisms can allow for better clinical outcomes, improved population well-being, and more efficient economic allocation. Further analysis could quantify preferences and benefits, optimizing a risk-sharing mechanism in Israel and other health-care systems. PHP52 Use Of Pragmatic Clinical Trials To Support Drug Launch Rémuzat C1, Kloc K2, Toumi M3 1Creativ-Ceutical, Paris, France, 2Creativ-Ceutical, Krakow, Poland, 3Aix-Marseille University, Marseille, France

Objectives: Pragmatic clinical trials (PCTs) are currently an important topic of interest in drug development. Increasing external validity of trials, PCTs have the



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potential to close the gap between internal validity of explanatory trials and real-life practice. The objective of this study was to assess the current use of PCTs to support drug launch.  Methods: Peer-reviewed articles on PCTs were searched in Medline/ Embase through Ovid. In addition, search of the EUnetHTA and EU Commission websites was performed, supplemented by Google search of grey literature.  Results: PCTs are currently on the rise; however, their use to support drug launch is uncommon. PCTs have several limitations, i.e., 1) methodological/analytical issues inherent to the potential risk of bias of more flexible designs, 2) operational issues with coordinating the recruitment of large patient populations from different settings, 3) concerns of regulatory and ethical nature, e.g. securing rights and interests of participants while remaining pragmatically flexible, 4) substantial costs incurred to conduct large PCTs. In the United States, PCTs are currently mainly promoted through public sector funding, while their potential use by regulators and payers is still uncertain. Before PCTs can be used for decision-making, academic experience (e.g. from the National Institutes of Health Health Care Systems Research Collaboratory, the National Patient-Centered Clinical Research Network, the Clinical Trials Transformation Initiative) with these trials should broaden. In Europe, PCTs are usually considered by decision-makers as complementing (but not replacing) standard randomised clinical trials. Evidence from PCTs seems more acceptable for drugs with a known benefit/risk profiles, while less acceptable for drugs with novel mechanisms of action.  Conclusions: PCTs are currently underused for initial drug regulatory/reimbursement dossier filing. Currently, multi-stakeholder initiatives are undertaken to enhance pragmatism in clinical trials and reduce decisionmaking uncertainty through developing tools, guidelines, and research on new trial designs and statistical methodologies. PHP53 A Typology-Based Decisional Framework To Support Market Access And Reimbursement Decisions For Personalised Medicines Govaerts L1, Geldof T1, Simoens S1, Huys I1, Van Dyck W2 Leuven, Leuven, Belgium, 2Vlerick Business School, Brussels, Belgium

1KU

Objectives: New co-development approaches in personalised medicine challenge current decisional frameworks of health-technology access and reimbursement procedures. We aim to conceptualize an efficient typology-based decisional framework which takes into account the development and market access synchronism between therapeutic (Tx) and diagnostic (Dx) components of personalized medicines.  Methods: Following systematic literature review, a focus group discussion study was conducted with Belgian personalised medicine industry stakeholders; BeMedTech (Dx-component), Pharma.be (Tx-component), and the Belgian health payer (INAMI). The discussions resulted in Tx-Dx cases to be used to support the personalized medicine access and reimbursement decision-making.  Results: A Tx-Dx typology-based decision support framework was derived and agreed upon by the stakeholders for implementation in the Belgian healthcare system. Within the personalised medicine industry, different strategic development approaches were unfolded for either in vitro diagnostics and therapeutics. The proposed Tx-Dx co-development and market access typology takes into account the synchronism of the strategic development approaches and translates them into access and reimbursement pathways to be used by assessment committees. In the framework, we distinguish different access and reimbursement pathways based on personalized medicine development strategies; (1) The co-development of an innovative therapeutic and companion diagnostic combination (e.g. Vemurafenib and BRAF-case), (2) the novel therapeutic development on a targeted patient population characterized by an already marketed diagnostic (e.g. Olaparib and BRCA-case). (3) The novel diagnostic development on a patient subpopulation within an already marketed therapeutic treatment (e.g. Cetuximab and KRAS/NRAS-case) and (4) the development of an innovative improved diagnostic on an already marketed diagnostic stratification technology [e.g. Immunohistochemistry products and Fluorescence in situ hybridization products-case].  Conclusions: The proposed typology-based decisional framework might allow for a more efficient and effective assessment and budget impact analysis of personalised medicine products. Accepted for guiding decisions in the Belgian healthcare system, the framework can function as a conceptual basis for other agencies outside Belgium. PHP54 Relaxing Rules For Pharmaceuticals And Benefit Coverage Expansion In Korea: The Impact On The Pharmaceutical Expenditure Oh R, Na Y HIRA (Health Insurance Review & Assessment Service), Wonju-si, Gangwon-do, Korea, Republic of (South)

Objectives: Korea has gradually extended the benefit coverage of National Health Insurance. For pharmaceuticals, reimbursement restriction that limits use on disease or patient for approved indication is to manage new medicines or oncology treatments. Strengthening benefit for serious diseases has been forwarded by reimbursing new drugs and relieving the restrictions. This study aims to investigate the effects of the coverage expansion on the pharmaceutical expenditure trends.  Methods: The National Health Insurance Claims data for year 2015 and 2016 was used. We analyzed the increase of total pharmaceutical expenditure by dividing it into 1) newly reimbursed drugs in the year 2015~2016, 2) drugs which have alleviated the reimbursement restrictions during 2015~2016, and 3) the residual which has not changed their reimbursement area.  Results: Korea’s national drug expenditure has been increased by 118 million dollars (9.8%) during 2015 and 2016. The expenditure of the newly reimbursed drugs accounted for 20.7% of the total pharmaceutical increase. The drugs reimbursed in the year 2015 and 2016 have contributed 12.0% and 8.7% respectively. The drugs which have lifted the reimbursement restriction between 2015 and 2016 have contributed to the 23.1% of the total increase of expenditure. Anti-tumor drugs accounted for 30% among them expanded on use. The increase of the expenditure due to the residuals which have remained the reimbursement conditions accounted for 56.2% of the total increase. As an individual product, Herceptin(trastzumab) treating breast cancer showed the

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largest increase.  Conclusions: Korea’s new government is likely to drive force to expand the national health insurance coverage. It is not inconclusive whether relaxing pharmaceutical restriction contributes to the goal of the benefit extension plan policy yet. We examined only short term effect and presented the estimates maximizing the effect on expenditure rather than optimizing. PHP55 Early Acess But Then What? The Uk Early Access To Medicines Scheme Three Year Report Card Macaulay R PAREXEL International, London, UK

Objectives: In April 2014 the UK Medicines and Healthcare products Regulatory Agency (MHRA) launched the Early Access to Medicines Scheme (EAMS) to enable patients with severe, life-threatening diseases without adequate treatment options to access medicines prior to their marketing authorization. EAMS is a voluntary scheme whereby the medicine is provided free of charge by the manufacturer. EAMS comprises two key steps: (i) Promising Innovation Medicine (PIM) designation and (ii) EAMS scientific opinion. We aimed to systematically evaluate all EAMS appraisals to date.  Methods: Publically-available EAMS documentation was screened from the MHRA website (to 08/06/2017).  Results: Of 50 PIM designation applications, 68% were granted; 16% refused; 4% withdrawn, with 12% pending. Only 40% (20/50) of medicines granted PIM status had applied for an EAMS scientific opinion, 75% (15/20) of which were awarded. 73% (11/15) of awarded opinions were in oncology. 82% (9/11) oncology agents were for anti-PD-1/L1 therapies: nivolumab, pembrolizumab and atezolizumab. Only 1/15 was from a small-/medium-size enterprise (SME). 73% (11/15) awarded opinions had expired when EU marketing authorization was granted. Medicines were available under EAMS for an average of 93 days (range: 18–327). In the mean of 441 days (range: 128–720) since these EAMS opinions had expired, only 6/11 had been NICE-appraised (all recommended) and 8/11 SMC-appraised (75% accepted/restricted) at an average delay of 202 and 270 days post-EAMS expiry, respectively.  Conclusions: Over the past three years, EAMS has enabled medicines for nine drugs across fifteen indications (mostly within oncology) to be made available to patients with severe unmet prior to marketing authorization. However, this was for an average time period of only three months and was followed by an average delay of over six months until NICE/SMC appraisal completion. Reforming EAMS to ensure patients can continue to access therapies post-marketing authorisation until a NICE/SMC appraisal should be considered. PHP56 Identification Of Important Criteria For Drug Reimbursement Decision-Making And Their Relative Importance Funagoshi M, Murasawa H, Shimozuma K Ritsumeikan University, Kusatsu, Japan

Objectives: In healthcare technology assessment for reimbursement decisions, it is important to consider multiple aspects and public preferences. We aimed to identify important decision-making criteria for reimbursement of drugs to treat life-threatening diseases and to reveal their relative importance for the general public (GP) and healthcare professionals (HCPs) comprising physicians and pharmacists.  Methods: We selected some decision-making criteria for drug reimbursement from a literature review and conducted a two-step online cross-sectional survey. In the first step, participants were asked to rate each criterion on a 7-point scale. The criteria with high ratings were selected based on means for each group. In the second step, the same participants were asked to allocate 100 points among these criteria to measure their relative importance.  Results: The first survey was completed by 719 participants (GP: 499, HCPs: 220) and 8 criteria were selected: out-of-pocket cost (Mean= 5.73 [GP], 5.47 [HCPs]), adverse event (5.66, 5.74), symptom relief (5.61, 5.79), cost effectiveness (5.57, 5.73), productivity loss (5.54, 5.39), life expectancy (5.41, 5.55), significant innovation (5.30, 5.49), and budget impact (5.29, 5.36). There were 613 respondents to the second survey (GP: 421, HCPs: 192). The most important criterion among the GP was symptom relief (relative importance= 16.2 vs. 15.6), but the difference with HCPs was not significant. Similarly, no significant differences were found in budget impact (9.7, 8.7) and life expectancy (8.8, 10.5). The criteria in which there were significant differences were out-of-pocket cost (15.2, 9.7), productivity loss (12.7, 10.0), adverse event (11.8, 9.3), significant innovation (11.3, 16.2), and cost effectiveness (14.2, 20.1).  Conclusions: This study shows the relative importance of reimbursement decision-making criteria both for the GP and HCPs. These findings will provide valuable insight for an appropriate method for drug reimbursement decisions. PHP57 Review Of The Reimbursement Environment For Advanced Therapeutic Medicinal Products (AtmpS) In The Uk Hughes T, Harries M, Sattar S MAP BioPharma Limited, Cambridge, UK

Objectives: To review current processes for reimbursement of ATMPs in the UK and consider mechanisms to improve patient access to these therapies.  Methods: Structured desk research was conducted to assess the health technology assessment (HTA) status and reimbursement of products classified by the European Medicines Agency (EMA) as ATMPs in the UK. A review of decision drivers and consideration of potential policy solutions to support wider access was undertaken.  Results: Appraisal processes in the UK are no different for ATMPs than non-ATMPs. The only determinant of which reimbursement process applies to an ATMP is the size of the eligible patient population. Eight ATMPs have received marketing authorisation in Europe, seven launched commercially, but four were subsequently withdrawn from the market due to low uptake. Imlygic was recommended for restricted use by NICE with a patient access scheme, ChrondoCelect was not recommended by NHS England and Strimvelis is scheduled for a NICE Highly Specialised Technology appraisal. Provenge was not recommended by NICE and the company has subsequently withdrawn marketing authorisation. Scottish Medicines Consortium has