Early Dialogues Research Articles

PNS262 EARLY DIALOGUE WITH NICE AND EUNETHTA: A UK PERSPECTIVE IN A POLITICALLY UNCERTAIN ERA

The National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) and the European Network for Health Technology Assessment (EUnetHTA), a network of HTA bodies, including the UK, offer manufacturers the opportunity to engage in early dialogue (ED) regarding specific evidence requirements for products in development. Recommendations inform evidence generation within and outside the clinical programme for future HTA product submissions. This review compares HTA ED processes offered by EUnetHTA and NICE, provides information on good quality interactions for manufacturers, and describes new service options introduced by NICE, including contingency plans should the UK leave the European Union (EU). A targeted review of literature and Internet-based sources identified the most recent information on ED processes provided by NICE and EUnetHTA. Both offer joint regulatory and HTA advice; this review focused on the HTA advice process. The EUnetHTA ED process involves the ED Working Party (EDWP) with agencies from France, Germany, Hungary, Italy, UK, Belgium, and The Netherlands; additional HTA bodies may participate in EDs as required. Manufacturers submit a briefing book with product and disease information, plus specific questions on clinical and economic issues for HTA. NICE employs a similar overall process and in April 2019 introduced different options, including an express service and choice of more limited expert review. EUnetHTA and NICE include the opportunity for face-to-face discussion plus written recommendations. NICE has published steps to ensure continuity of service if the UK leaves the EU. EUnetHTA and NICE ED services have similar process structures but differ in breadth of country feedback and flexibility of scope. The optimal time for seeking ED is preinitiation of main registration efficacy studies, aiding appropriate study design for HTA and regulatory review; alternatively, ED sought during study conduct informs the approach to economic analysis.

PCN296 OUT WITH THE OLD AND IN WITH THE NEW: THE EVOLUTION OF THE CANCER DRUGS FUND

The Cancer Drugs Fund (CDF), founded in 2011, has benefited a large number of cancer patients. However, the lack of clear criteria determining how and when drugs should exit the fund placed it under unsustainable financial pressure. In 2016, the CDF was revised to provide a more sustainable approach to fund promising new drugs and collect additional clinical data. Some treatments recommended for funding via the new CDF have now been re-assessed for routine commissioning. This research aims to highlight differences between the old and new CDF, identify the key reasons for CDF funding and assess outcomes of products that have been re-assessed for routine commissioning. Secondary analysis of NICE appraisal documents and primary research with NICE/CDF representatives. The revised CDF provides NICE the option to recommend treatments for use within the CDF; previously, it could only recommend ‘yes’, ‘no’ or ‘only in research’. This new option is used when NICE considers there to be plausible potential for drugs to satisfy criteria for routine commissioning, but where significant clinical uncertainty remains. Of the 34 drugs currently receiving CDF funding, immature overall survival and progression-free survival data are the main reasons for clinical uncertainty. Analysis of eight drugs that have entered routine commissioning found that providing additional data after two years, modification of the Patient Access Scheme or updated cost-effectiveness calculations support positive NICE recommendations for routine commissioning. The advantage of the new CDF is that promising new cancer drugs can be granted provisional status, allowing immediate access to patients. During the two-year funding period, manufacturers must appropriately collect and model clinical data to address uncertainty and ensure cost-effectiveness, through discounting if required. Early dialogue with NICE and NHS England will ensure appropriate trial design so that NICE is convinced that clinical uncertainty can be mitigated by further data collection.

Shaping the Conversation: Madeleine de Scudéry's Use of Genre in Her Rhetorical Dialogues

This essay argues that Madeleine de Scudéry's engagement with the early modern dialogue genre in Conversations sur Divers Sujets reflects and strengthens the conversational theory that scholars have pinpointed as an important feminist rhetorical strategy. By imagining and constructing the dialogue to function as a metadiscourse on the conversational theories that provide the speaking points of her characters, Scudéry enacts her rhetorical theory of sermo in addition to describing it. After an overview of varying forms of the dialogue genre in Renaissance Europe, a comparison between Scudéry's Conversations and Sir Thomas Elyot's The Defence of Good Women illuminates Scudéry's feminist construction of the genre and exemplifies her choice to use the dialogue to both perform and advance her theories on conversational practice.

PNS128 READY FOR PRIME TIME? HAVE EMA PRIME DESIGNATIONS SUPPORTED ACCELERATED REGULATORY APPROVAL AND PATIENT ACCESS?

To systematically evaluate all PRIME (PRIority MEdicines) designations to date and how these have translated into reimbursement and patient access. INTRODUCTION: In March 2016, the European Medicines Agency (EMA) launched the PRIME (PRIority MEdicines) scheme. PRIME enhances early dialogue and regulatory support for putative medicinal products that address severe unmet treatment needs. PRIME also enables EMA accelerated assessment (which reduces the assessment timeframe from 210 days to 150 days). The EMA website was screened and medicines with PRIME designation identified (as of 06-MAR-2019). For any with EC marketing authorisation (MA), the corresponding HTA assessments by NICE, SMC, G-BA and HAS were screened and their outcomes extracted. Since 2016, fifty therapies have received PRIME designations (2016: 15; 2017: 19; 2018: 14; 2019: 2). The most common therapy indications were in oncology (26%) and haematology (18%). 40% were submitted by SMEs. 20% no longer have PRIME designation (3 discontinued development, 5 submitted for EC MA, and 2 received EC MA: the CAR-T cell therapies: tisagenlecleucel [in ALL] and axicabtagene ciloleucel). All HTA bodies in scope had appraised both, 6/8 with positive outcomes (though 4/6 conditionally): NICE recommended both (for inclusion in the CDF), the SMC accepted tisagenlecleucel but not axicabtagene ciloleucel, G-BA reported that both offered a non-quantifiable additional benefit, and HAS deemed these offered an ASMR IV and III, respectively. The median delay from MA to positive HTA assessment was 5.2 months. Many therapies have received PRIME designation, but to date more have had their development discontinued than have received European MA. Nevertheless, the two EMA-approved therapies with PRIME designations have received broad reimbursement across several major markets, but these recommendations are frequently conditional and add additional delays to patient access. Better integration with payers may be necessary to ensure that accelerated regulatory approval programs translate into patent access.

Evaluating the "return on patient engagement initiatives" in medicines research and development: A literature review.

BackgroundShowing how engagement adds value for all stakeholders can be an effective motivator for broader implementation of patient engagement. However, it is unclear what methods can best be used to evaluate patient engagement. This paper is focused on ways to evaluate patient engagement at three decision‐making points in the medicines research and development process: research priority setting, clinical trial design and early dialogues with regulators and health technology assessment bodies.ObjectiveOur aim was to review the literature on monitoring and evaluation of patient engagement, with a focus on indicators and methods.Search strategy and inclusion criteriaWe undertook a scoping literature review using a systematic search, including academic and grey literature with a focus on evaluation approaches or outcomes associated with patient engagement. No date limits were applied other than a cut‐off of publications after July 2018.Data extraction and synthesisData were extracted from 91 publications, coded and thematically analysed.Main resultsA total of 18 benefits and 5 costs of patient engagement were identified, mapped with 28 possible indicators for their evaluation. Several quantitative and qualitative methods were found for the evaluation of benefits and costs of patient engagement.Discussion and conclusionsCurrently available indicators and methods are of some use in measuring impact but are not sufficient to understand the pathway to impact, nor whether interaction between researchers and patients leads to change. We suggest that the impacts of patient engagement can best be determined not by applying single indicators, but a coherent set of measures.

James Frederick Ferrier's Socratic Ethics

James Frederick Ferrier is probably best known for the idealism he presents in An Introduction to the Philosophy of Consciousness and Institutes of Metaphysic, in which Ferrier critiques and offers an alternative to Common Sense Realism – the dominant school of thought in Scotland in the 18thand early 19thcenturies – spearheaded by Thomas Reid and his followers. What has received significantly less attention in the literature, however, is Ferrier's 1866 Lectures on Greek Philosophy, which serves as an important point of connection between the moral philosophy that Ferrier develops in the Introduction and Institutes and what Ferrier takes to be the ethics that Socrates taught and according to which he lived. In this paper, I examine Plato's early dialogues in order to demonstrate that Ferrier's ethics should be understood as a descendent of Socratic ethics insofar as both Ferrier and Socrates endorse the view that individual freedom is only possible through a life of thought that transcends the particularities of sensation.

The Iterative Development of Medicines Through the European Medicine Agency's Adaptive Pathway Approach.

The development of novel regulatory tools such as adaptive clinical trial design and utilization of real-world evidence are topics of high interest. Recently, the European Medicines Agency (EMA) introduced the Adaptive Pathways (AP) that represents an innovative tool in healthcare systems allowing the early dialogue with multiple stakeholders on promising and innovative medicinal products in areas with an high unmet medical need. The innovative aspect in the AP is the early involvement of several stakeholders such as pharmaceutical industry, the Academia, Health Technology Assessment (HTA) bodies, and patient representatives bringing their real experience with the disease and their expectations about the treatment. AP is not a new licensing tool but an opportunity for a very early discussions, before starting the phase II studies, among all stakeholders, including regulators, companies, HTA bodies, and patient representatives on a new potential medicine in areas of high unmet medical need. The aim of this paper is to describe the evolution of the AP approach from the beginning of the pilot project to date, highlighting major advances, and achievement at European level.

Bridging communities in the field of nanomedicine

An early dialogue between nanomedicine developers and regulatory authorities are of utmost importance to anticipate quality and safety requirements for these innovative health products. In order to stimulate interactions between the various communities involved in a translation of nanomedicines to clinical applications, the European Commission's Joint Research Centre hosted a workshop titled “Bridging communities in the field of Nanomedicine” in Ispra/Italy on the 27th −28th September 2017. Experts from regulatory bodies, research institutions and industry came together to discuss the next generation of nanomedicines and their needs to obtain regulatory approval. The workshop participants came up with recommendations highlighting methodological gaps that should be addressed in ongoing projects addressing the regulatory science of nanomedicines. In addition, individual opinions of experts relevant to progress of the regulatory science in the field of nanomedicine were summarised in the format of a survey.

Patient Preference Studies During Early Drug Development: Aligning Stakeholders to Ensure Development Plans Meet Patient Needs.

Although patient preferences have been studied broadly for marketed products or around the time of submission to authorities and launch, patient preference studies have rarely been used during the early drug development phases. In this paper, we formulate three hypotheses supporting the use of patient preference studies in early product development: (1) integration of the patient perspective into the development process from phase 1 onwards will result in healthcare solutions with outcomes that best address patients' needs; (2) a structured process to build patient-based evidence involving partnerships between patients and other key stakeholders will improve alignment of development activities with the needs of patients; (3) quantitative patient preference research built on robust qualitative insights is necessary to strengthen development decisions in the interests of patients. To illustrate such a structured process, we describe qualitative insights research (social media analysis and online bulletin boards) and quantitative patient preference studies in dry eye disease and non-alcoholic steatohepatitis conducted during early product development by a pharmaceutical company to generate patient-based evidence. The outputs from such early patient preference studies are being used to inform patient reported outcome strategies, clinical development strategies, product design and delivery features, and form the basis for early dialog with regulators, health technology assessment (HTA) bodies and payers to ensure focus and alignment on patient-relevant endpoints. Furthermore, to discuss and theoretically substantiate our hypotheses, we review how different groups and organizations are working to embrace fully the patient perspective in product development and healthcare decision-making. The hypotheses are commensurate with the general trend toward patient-centered healthcare and the activities initiated by regulators, HTA agencies, and patient organizations. We advocate that all healthcare players should actively contribute to aligning on best practices concerning choice of methodologies and engage in multi-stakeholder dialog along the entire product development chain, to realize health technologies that best meet the needs of patients.

Omics of the early molecular dialogue between Frankia alni and Alnus glutinosa and the cellulase synton.

The early Frankia-Alnus symbiotic molecular exchanges were analyzed in detail by protein and RNA omics. For this, Frankia cells were placed in the presence of Alnus roots but separated by a dialysis membrane for 64 h. The bacterial cells were then harvested and analyzed by high-throughput proteomics and transcriptomics (RNA-seq). The most upregulated gene clusters were found to be the potassium transporter operon kdp and an ABC transporter operon of uncharacterized function. The most upregulated proteins were found to be acyl dehydrogenases and the potassium transporter Kdp. These suggest a preadaptation to the impending stresses linked to the penetration into isotonic host tissues and a possible rearrangement of the membrane. Another cluster among the 60 most upregulated ones that comprised two cellulases and a cellulose synthase was conserved among the Frankia and other actinobacteria such as Streptomyces. Cellulase activity was detected on CMC all along the length of the root but not away from it. Frankia alni ACN14a was found to be unable to respire or grow on glucose as sole carbon source. The cellulose synthase was found active at the tip of hyphae in response to Alnus root exudates, resulting in a calcofluor stained tip.

Early History of Micro and Meso Dialogue between Muslims and Non-Muslims in Australia

Interfaith dialogue has been touted as a means to solve many of the religious divisions that have arisen in an increasingly global and multi-faith society. In Australia, now a multi-cultural and multi faith society, a range of organisations exist to facilitate this dialogue, most coming in to existence after the 1960’s This paper will review the early dialogue between Muslims and non-Muslims as portrayed in the public record. It covers pre and post-Colonial Australia, up until the 1950’s. As inter-faith dialogue becomes more important in an increasingly global society, it will examine the effect that micro and meso level dialogue has influenced social harmony at some levels. By examining the public record and the narratives surrounding the Macassans, Afghans and other early Muslims, this paper will firstly argue that micro and meso dialogue prior to the 1950s’ between Muslims immigrants and non-Muslims made a contribution to the social harmony in Australia. Secondly, despite many attempts by Muslims, meso level dialogue was often ineffective and sometimes failed for a variety of reasons. Additionally, it will point to the need for further research in order to paint a complete picture of the levels of dialogue between Muslims and others throughout Australian history.

Supporting Implementation of the Arctic Science Agreement

The Arctic Science Agreement entered into force on 23 May 2018 with the Kingdom of Denmark as the depositary is now the third binding legal agreement among all eight Arctic states since 2011, arising with shared leadership from the United States and Russian Federation as co-chairs of the three preceding task forces. The Arctic Science Agreement recognizes the “excellent existing scientific cooperation already under way in many organizations” with the International Arctic Science Committee (IASC) as well as IASSA, UArctic and indigenous knowledge institutions among many others. However, as suggested in a November 2017 policy forum published in the journal Science: “effective implementation of the agreement will require its associated networks (including IASC, UArctic, IASSA, and partner organizations) to help strengthen research and education across borders.” Objective of this panel dialogue is to consider how the scientific community can best assist to achieve effective implementation of the Artic Science Agreement, with strategies such as: • Creation of a communication network with researchers that would aid government officials with their implementation of the Arctic Science Agreement; • Application of an information campaign to alert the broader Arctic research community about the Arctic Science Agreement; or • Development of case studies that might the trigger applications of the Arctic Science Agreement, such as with the Multidisciplinary Drifting Observatory for the Study of Arctic Climate – MOSAiC – project starting in 2019 with more than 120 M Euros across the international consortium. This session also builds on earlier dialogues, including with the International Science Initiative in the Russia Arctic (ISIRA) in Moscow (November 2017) and in Davos (June 2018) as well as in the Ambassadorial Panel on Arctic Science Diplomacy at the 2018 UArctic Congress last month in Oulu, leading into the 2nd Arctic Science Ministerial next week. The Arctic Science Agreement has the potential to be international, interdisciplinary and inclusive (aspiring to be holistic), bridging the natural sciences and social sciences as well as indigenous knowledge with their different methodologies, all of which reveal patterns and trends that are the bases for informed decision-making – integrating questions, data, evidence and options with science as the ‘study of change.’ Importantly, the Arctic Science Agreement reflects a common interest to enhance scientific cooperation even when diplomatic channels among nations are unstable, recognizing first "the importance of maintaining peace, stability, and constructive cooperation in the Arctic.” Such science diplomacy underlies decisions about governance mechanisms and built infrastructure that require close coupling to achieve progress with sustainable development, which is recognized as a ‘common Arctic issue’ by the eight Arctic states and six Indigenous peoples organizations in the Ottawa Declaration that established the Arctic Council in 1996. Translating the general language of the Arctic Science Agreement into enhanced action, however, requires continuous collaboration among diplomatic and scientific communities. This panel is at the early stages of this journey. Each of the panellists will provide 3-minute opening remarks with their written versions to be compiled in a publication of Science Diplomacy Action as a legacy of this dialogue. Following these opening interventions, there will be interactions among the panelists followed by their exchanges with the audience. The Arctic Science Agreement is a special step into OUR COMMON FUTURE with hope and inspiration across generations. It now gives me great pleasure to introduce the panelists in the order of their presentations.

The Confluence of Accelerated Regulatory and Health Technology Assessment Access Pathways

There is a growing interest in aligning accelerated regulatory pathways with flexible access and reimbursement pathways to expedite the equitable availability of high-quality, safe, and effective medicines that provide a value-based approach to meeting society's most important healthcare needs. The Centre for Innovation in Regulatory Science (CIRS) identified key issues regarding the confluence of regulatory and health technology assessment processes from discussions and presentations given by international regulators, health technology assessment bodies, payers, patient representatives, and multinational pharmaceutical company representatives on this topic at CIRS workshops held in 2014 and 2017 that focused on the commonalties and differences across these pathways. Recent publications have also been highlighted. The barriers to and opportunities for aligning stakeholder expectations and needs were investigated and recommendations provided. Early dialogue among the stakeholders is the process that will likely provide the greatest return on investment of time and effort to identify, develop, review, and recommend important new medicines, especially those that address an unmet medical need.

OP132 What Future For Drugs After An Early Dialogue Procedure?

IntroductionThe French health technology assessment (HTA) body, Haute Autorité de la Santé (HAS), started to provide early advice on evidence generation plans to pharmaceutical manufacturers in 2010. It became an official mission in 2016. Requests are eligible when the product has a new mechanism of action, if there is an unmet or partially met medical need in the claimed indication and when the pivotal study has not yet started. This analysis aims to provide a first overview of clinical developments for which pharmaceutical companies sought an early dialogue with HAS.MethodsFor each product that went through an early dialogue procedure with HAS, information regarding the clinical development was collected on pharmaceuticals companies’ pipelines, clinicaltrials.gov, the website of the European Medicine Agency (EMA) and HAS's internal database.ResultsBy the end of 2018, HAS has performed 84 early dialogues of which 53 were conducted in collaboration with the EMA and/or others European HTA bodies. They were mainly focused on phase III trials. Following early dialogue, the clinical study for which the company sought advice was not yet implemented in 25 cases. When the clinical trial was effectively launched, results were negative in 10 cases, positive in 11 cases and the study was still ongoing for 29 products. In nine cases, the clinical development was officially withdrawn or suspended before the initiation of the trial. Overall, only eight medicinal products were appraised by HAS, they all obtained a clinical added value score.ConclusionsThe success rate of clinical development for products that underwent an early dialogue procedure tends to be higher than data from literature, although it is likely to decrease in follow-up analysis. This could be partially explained by HAS's eligibility criteria that restrict early dialogues to promising products and by the scientific recommendations provided to pharmaceuticals companies.

Kamtekar, Rachana. Plato’s Moral Psychology: Intellectualism, the Divided Soul, and the Desire for the Good. Oxford: Oxford University Press, 2018. Pp. 240. $55.00 (cloth).

Kamtekar, Rachana. <i>Plato’s Moral Psychology: Intellectualism, the Divided Soul, and the Desire for the Good</i>. Oxford: Oxford University Press, 2018. Pp. 240. $55.00 (cloth).

VP06 HTA And Health Industry: Key Aspect Of Their Relationships

IntroductionConclusions and recommendations of health technology assessment (HTA) reports have an impact on all relevant actors involved in the health system (health authorities, administrators, health professionals, patients, citizens and industry). The involvement of all those relevant stakeholders in the HTA process facilitates making valid and informed decisions and an efficient allocation of resources. Improving communication, participation and transparency among all agents will lead to more efficient evaluation and decision-making processes.MethodsTo review key aspects of the relations between HTA agencies and health industries, two process were carried out: a narrative review of literature searched in Medline, PubMed, Embase, CINAHL and WOS (2007-2017) and a review of websites of international HTA agencies. References and webs with information on the framework, objectives, methodologies, impact or results of the relationships were included.ResultsA total of 1961 references were located and forty-five were selected. From the synthesis of the selected references the following key aspects of the relationships between HTA and industry were identified: (i) the importance of early dialogues with industry to align HTA objectives with the generation of evidence; (ii) challenges of the bias in the evidence produced by industry; (iii) difficulties in industry engagement in HTA processes; and (iv) industry interest in HTA. The review of six agency websites provided information on industry involvement in strategic activities, early dialogues, provision of documentation, management of industry clarifications, review of the report/allegations and other forms of relationship.ConclusionsBoth the review of the literature and the contents of the web pages of international agencies with experience in relations with industry show that the interest is in the creation of collaborative frameworks between regulatory authorities that decide on authorization and price and reimbursement and HTA agencies, while both try to maintain an early, transparent and systematic interaction with the healthcare industry.

«Сократический вопрос»: cтарые проблемы и новые тенденции

The article deals with new approaches to the solution of the so-called “Socratic question” associated with the search for a “historical” Socrates in different sources. The author outlines the history of the issue starting with Schleiermacher and his distinction between the images of Socrates in Plato and Xenophon. It is shown how, at the beginning of the 20th century, a consensus on the authenticity of Plato’s Socrates was reached (Robin, Taylor, Burnet, Maier), and then a sceptical view on the possibility itself to ever solve the “Socratic question” developed (Gigon). Vlastos’ position, which became influential in the late 20th century, is considered: he believed that Socrates of early Platonic dialogues is “historical”, while Socrates of the middle dialogues is a fiction of Plato’s. The second part of the article provides a brief overview of the six editions devoted to Socrates in 2006–2018, and the conclusion is made that there is an obvious trend towards a return to the sceptical position of Gigon in regard to the “Socratic question”.

PP150 Bevan Health Technology Exemplars: Early Dialogue To Systematize HTA

IntroductionWales has ambitious health, wealth, and innovation policies and a clear goal to use the economic muscle of the Welsh National Health Service (NHS) to support its strong life sciences sector. Health Technology Wales (HTW) has a clear remit to appraise technologies over the span of their lifecycle from innovation to obsolescence. HTW is collaborating with the Bevan Commission through their national Health Technology Exemplars (HTEs), which partners NHS and industry stakeholders to strengthen innovation within the Welsh health system.MethodsHealth technology assessment (HTA) methods were used to produce topic exploration reports for assessing the evidence underpinning applicant innovations. A “Dragons’ Den” expert panel was convened to select the successful HTEs.ResultsFourteen Bevan HTEs were awarded funds, which were matched by industry partners. Application of HTA methods resulted in more critical consideration of technology value propositions, including: developing pull models of innovation focused on delivering health technology solutions for current problems facing NHS Wales; supporting early dialogue between the NHS and industry partners around demonstrating evidence of improved patient outcomes; and focusing on transformative rather than incremental innovation. The most promising innovations will progress to rapid HTA, where the evidence generated will be used to develop guidance for NHS Wales.ConclusionsHTA methods were productively deployed at the innovation phase of the technology lifecycle to support evidence-informed allocation of scarce innovation resources. In this way, HTW is working with key stakeholders to identify and offer early support to the most promising innovations, with the aim of expediting their adoption and realizing health benefits for patients as quickly as possible. The Bevan Commission has partnered with HTW to routinely build in HTA and evidence considerations in its future innovation calls and competitions. Thus, HTW has established a “feeder” pipeline for assessing bottom-up service-led innovations and encouraging evidence consideration throughout the lifecycle of innovative technologies.

Global Regulatory Landscape.

Continuous manufacturing (CM) of pharmaceuticals is a rapidly growing approach in the production of active pharmaceutical ingredients and finished products. The European Medicines Agency, the US Food and Drug Administration, and the Pharmaceuticals and Medical Devices Agency have independently stated their support for the introduction of CM and provided opportunities for early dialog between industries and regulatory agencies. This paper describes the current regulatory landscape and the regulatory harmonization.

Adaptive designs in clinical trials: from scientific advice to marketing authorisation to the European Medicine Agency

BackgroundIn recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials.MethodsUsing the internal EMA MAA database, the AdisInsight database and related trial registries, we analysed how many of these 59 trials actually started, the completion status, results, the time to trial start, the adaptive elements finally implemented after SA, their possible influence on the success of the trial and corresponding product approval.ResultsOverall 31 trials out of 59 (53%) were retrieved. Thirty of them (97%) have been started and 23 (74%) concluded. Nine of these trials (39% out of 23) demonstrated a significant treatment effect on their primary endpoint and 4 (17% out of 23) supported a marketing authorisation (MA). An additional two trials were stopped using pre-defined criteria for futility, efficiently identifying trials on which further resources should not be spent. Median time to trial start after SA letter was given by EMA was 5 months. In the investigated trial registries, at least 18 trial (58% of 31 retrieved trials) designs were implemented with adaptive elements, which were predominantly dose selection, sample size reassessment (SSR) and stopping for futility (SFF). Among the 11 completed trials including adaptive elements, 6 demonstrated a significant treatment effect on their primary endpoint (55%).ConclusionsAdaptive designs are now well established in the drug development landscape. If properly pre-planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated.