The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life‐span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade‐off, help de‐risk drug development, and lead to better outcomes for patients.

There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.

Background: The accountability for reasonableness (A4R) framework defines 4 conditions for legitimate healthcare coverage decision processes: Relevance, Publicity, Appeals, and Enforcement. The aim of this study was to reflect on how the diverse features of decision-making processes can be aligned with A4R conditions to guide decision-making towards legitimacy. Rare disease and regenerative therapies (RDRTs) pose special decision-making challenges and offer therefore a useful case study. Methods: Features operationalizing each A4R condition as well as three different approaches to address these features (cost-per-QALY-focused and multicriteria-based) were defined and organized into a matrix. Seven experts explored these features during a panel run under the Chatham House Rule and provided general and RDRT-specific recommendations. Responses were analyzed to identify converging and diverging recommendations. Results: Regarding Relevance, recommendations included supporting deliberation, stakeholder participation and grounding coverage decision criteria in normative and societal objectives. Thirteen of 17 proposed decision criteria were recommended by a majority of panelists. The usefulness of universal cost-effectiveness thresholds to inform allocative efficiency was challenged, particularly in the RDRT context. RDRTs raise specific issues that need to be considered; however, rarity should be viewed in relation to other aspects, such as disease severity and budget impact. Regarding Publicity, panelists recommended transparency about the values underlying a decision and value judgements used in selecting evidence. For Appeals, recommendations included a life-cycle approach with clear provisions for re-evaluations. For Enforcement, external quality reviews of decisions were recommended. Conclusion: Moving coverage decision-making processes towards enhanced legitimacy in general and in the RDRT context involves designing and refining approaches to support participation and deliberation, enhancing transparency, and allowing explicit consideration of multiple decision criteria that reflect normative and societal objectives.

Reflective multicriteria are useful to explore substantive values of HTAs, reflect how these values and their ethical underpinnings can be operationalized into criteria, and explore the ethical reasoning at the heart of the healthcare debate.

IntroductionWell- or moderately differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are often slow-growing, and some patients with unresectable, asymptomatic, non-functioning tumors may face the choice between watchful waiting (WW), or somatostatin analogues (SSA) to delay progression. We developed a comprehensive multi-criteria decision analysis (MCDA) framework to help patients and physicians clarify their values and preferences, consider each decision criterion, and support communication and shared decision-making.MethodsThe framework was adapted from a generic MCDA framework (EVIDEM) with patient and clinician input. During a workshop, patients and clinicians expressed their individual values and preferences (criteria weights) and, on the basis of two scenarios (treatment vs WW; SSA-1 [lanreotide] vs SSA-2 [octreotide]) with evidence from a literature review, expressed how consideration of each criterion would impact their decision in favor of either option (score), and shared their knowledge and insights verbally and in writing.ResultsThe framework included benefit-risk criteria and modulating factors, such as disease severity, quality of evidence, costs, and constraints. Overall and progression-free survival being most important, criteria weights ranged widely, highlighting variations in individual values and the need to share them. Scoring and considering each criterion prompted a rich exchange of perspectives and uncovered individual assumptions and interpretations. At the group level, type of benefit, disease severity, effectiveness, and quality of evidence favored treatment; cost aspects favored WW (scenario 1). For scenario 2, most criteria did not favor either option.ConclusionsPatients and clinicians consider many aspects in decision-making. The MCDA framework provided a common interpretive frame to structure this complexity, support individual reflection, and share perspectives.FundingIpsen Pharma.Electronic supplementary materialThe online version of this article (10.1007/s12325-017-0653-1) contains supplementary material, which is available to authorized users.

IntroductionUnresectable, well-differentiated nonfunctioning gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be monitored (watchful waiting, WW) or treated with systemic therapy such as somatostatin analogues (SSAs) to delay progression. We applied a reflective multicriteria decision analysis (MCDA) shared-decision framework (previously developed for the USA) to explore what matters to Spanish patients and clinicians considering GEP-NET treatment options.MethodsThe EVIDEM-derived framework was updated and adapted to the Spanish context. During a Chatham House session, five patients and six physicians assigned criteria weights using hierarchical point allocation and direct rating scale (alternative analysis). Informed by synthesized evidence embedded in the framework, participants scored how each criterion favored SSA treatment (reference case lanreotide) or WW and shared insights and knowledge. Weights and scores were combined into value contributions (norm. weight × score/5), which were added across criteria to derive the relative benefit–risk balance (RBRB, scale − 1 to + 1). Exploratory comparisons to US study findings were performed.ResultsFocusing on intervention outcomes (effectiveness, patient-reported, and safety), the mean RBRB favored treatment over WW (+ 0.32 ± 0.24), with the largest contributions from progression-free survival (+ 0.11 ± SD 0.07), fatal adverse events (+ 0.06 ± SD 0.08), and impact on HRQoL (+ 0.04 ± SD 0.04). Consideration of modulating criteria (type of benefit, need, costs, evidence, and feasibility) increased the RBRB to + 0.50 ± 0.14, with type of therapeutic benefit (+ 0.10 ± SD 0.08) and quality of evidence (+ 0.08 ± SD 0.06) contributing most towards treatment. Alternative weighting yielded similar results. Results were broadly comparable to those derived from the US study.ConclusionThe multicriteria framework helped Spanish patients and clinicians identify and express what matters to them. The approach is transferable across decision-making contexts.FundingIPSEN Pharma.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0745-6) contains supplementary material, which is available to authorized users.

A385Objectives: PAH-SYMPACT ® is a patient reported outcome (PRO) instrument developed based on interviews with patients with pulmonary arterial hypertension (PAH) and following the FDA's PRO guidance. Its psychometric characteristics are being evaluated using data from the phase IIIb PAH SYMPHONY study. After item reduction, the final instrument consists of 11 symptom items across 2 domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across 2 domains (physical impact and cognitive/emotional impacts). The objective of this analysis was to evaluate the psychometric properties of the PAH-SYMPACT< sup> ®< /sup> domain scores. MethOds: In SYMPHONY, patients completed generic and disease-specific questionnaires, while clinicians provided assessment of severity and changes in symptomatology. Internal consistency and test-retest reliability, knowngroup and construct validity and sensitivity to change were evaluated. Instrument performance based on oxygen use was also assessed. Results: Data from 278 patients (79% female, mean age 60 years) were included in the analysis. 59% of patients were in WHO functional class III, 41% were on background therapy with a phosphodiesterase type-5 inhibitor and 34% used oxygen therapy at any given time. Individual item scores did not differ based on oxygen use. For all 4 domains, internal consistency reliability was very good (Cronbach's alpha > 0.80) and test-retest reliability (assessed in stable patients) was high (intra-class correlation coefficient 0.84-0.94). Correlations with CAMPHOR and SF-36 were moderate-to-high with correlations slightly lower in the cardiovascular domain than the cardiopulmonary domain. The instrument differentiated well between patients with different disease severity levels. Domain scores were sensitive to changes in clinician-and patientreported disease severity levels. cOnclusiOns: The PAH-SYMPACT ® performed well -with good psychometric properties. The domain scores were reproducible, differentiated between patients of different severity, correlated with other instruments measuring similar constructs, and were sensitive to change. This PRO has the potential to become an important outcome measure in PAH.

reduced by at least $22 million under the new law. Reducing the corporate tax rate from 35% to 21% reduces the value of all tax credits, unless a business sustains a loss. Reducing the Orphan Drug Credit by half reduces the tax shelter provided by this specific credit, and reduces the incentive of companies to invest in orphan drugs. The corporate tax rate reduction should also result in an increased investment from companies, but this investment will be in all aspects of the company to maximize profit. It is likely that research investments would be made in other disease areas, which have larger markets and greater potential profits[1]-a large disease like diabetes has nearly 17 times the expected profits of a typical orphan disease. Conclusion: A profitable company may reduce its investments into orphan drug research to maximize profits due to the reduction in the orphan tax credit, despite the apparent advantages orphan drugs have, as orphan drug markets are much smaller. [1]Bio.org.