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.

Use of big data for drug development and for public and personal health and care.

The use of data analytics across the entire healthcare value chain, from drug discovery and development through epidemiology to informed clinical decision for patients or policy making for public health, has seen an explosion in the recent years. The increase in quantity and variety of data available together with the improvement of storing capabilities and analytical tools offer numerous possibilities to all stakeholders (manufacturers, regulators, payers, healthcare providers, decision makers, researchers) but most importantly, it has the potential to improve general health outcomes if we learn how to exploit it in the right way. This article looks at the different sources of data and the importance of unstructured data. It goes on to summarize current and potential future uses in drug discovery, development, and monitoring as well as in public and personal healthcare; including examples of good practice and recent developments. Finally, we discuss the main practical and ethical challenges to unravel the full potential of big data in healthcare and conclude that all stakeholders need to work together towards the common goal of making sense of the available data for the common good.

Personalized Medicine: What's in it for Rare Diseases?

Personalised Medicine has become a reality over the last years. The emergence of 'omics' and big data has started revolutionizing healthcare. New 'omics' technologies lead to a better molecular characterization of diseases and a new understanding of the complexity of diseases. The approach of PM is already successfully applied in different healthcare areas such as oncology, cardiology, nutrition and for rare diseases. However, health systems across the EU are often still promoting the 'one-size fits all' approach, even if it is known that patients do greatly vary in their molecular characteristics and response to drugs and other interventions. To make use of the full potentials of PM in the next years ahead several challenges need to be addressed such as the integration of big data, patient empowerment, translation of basic to clinical research, bringing the innovation to the market and shaping sustainable healthcare systems.

Unlocking the full potential of digital endpoints for decision making: a novel modular evidence concept enabling re-use and advancing collaboration.

INTRODUCTION: Over the last decade increasing examples indicate opportunities to measure patient functioning and its relevance for clinical and regulatory decision making via endpoints collected through digital health technologies. More recently, we have seen such measures support primary study endpoints and enable smaller trials. The field is advancing fast: validation requirements have been proposed in the literature and regulators are releasing new guidances to review these endpoints. Pharmaceutical companies are embracing collaborations to develop them and working with academia and patient organizations in their development. However, the road to validation and regulatory acceptance is lengthy. The full value of digital endpoints cannot be unlocked until better collaboration and modular evidence frameworks are developed enabling re-use of evidence and repurposing of digital endpoints. AREAS COVERED: This paper proposes a solution by presenting a novel modular evidence framework -the Digital Evidence Ecosystem and Protocols (DEEP)- enabling repurposing of measurement solutions, re-use of evidence, application of standards and also facilitates collaboration with health technology assessment bodies. EXPERT OPINION: The integration of digital endpoints in healthcare, essential for personalized and remote care, requires harmonization and transparency. The proposed novel stack model offers a modular approach, fostering collaboration and expediting the adoption in patient care.

Why Language Matters in Digital Endpoint Development: Harmonized Terminology as a Key Prerequisite for Evidence Generation.

Background: Developments in the field of digital measures and digitally derived endpoints demand greater attention on globally aligned approaches to enhance digital measure acceptance by regulatory authorities and health technology assessment (HTA) bodies for decision-making. In order to maximize the value of digital measures in global drug development programs and to ensure study teams and regulators are referring to the same items, greater alignment of concepts, definitions, and terminology is required. This is a fast-moving complex field; every day brings new technologies, algorithms, and possibilities. A common language is particularly important when working in multifunctional teams to ensure that there is a clear understanding of what is meant and understood. Summary: In the paper, the EFPIA digital endpoint joint subgroup reviews the challenges facing teams working to advance digital endpoints, where different terms are used to describe the same things, where common terms such as "monitoring" have significantly different meaning for different regulatory agencies, where the preface "e" to denote electronic is still used in some contexts, but the term "digital" is used in other, and where there is significant confusion as to what is understood by "raw" when it comes to data derived from digital health technologies. Key Message: The EFPIA subgroup is calling for an aligned lexicon. Alignment provides a more predictable path for development, validation, and use of the tools and measures used to collect digital endpoints supporting standardization and consistency in this new field of research, with the goal of increasing regulatory and payer harmonization and acceptance.

Assessing the net financial benefits of employing digital endpoints in clinical trials.

In the last few decades, developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints and the US clinical trials registry, ClinicalTrials.gov. The benefit metrics are changes in trial phase duration and enrollment associated with the use of digital endpoints. The cost metric was obtained from an industry survey of the costs of including digital endpoints in clinical trials. We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess financial value. The value measure is the increment in eNPV that occurs when digital endpoints are employed. We also calculated a return on investment (ROI) as the ratio of the estimated increment in eNPV to the mean digital endpoint implementation cost. For phase II trials, the increase in eNPV varied from $2.2 million to $3.3 million, with ROIs between 32% and 48% per indication. The net benefits were substantially higher for phase III trials, with the increase in eNPV varying from $27 million to $40 million, with ROIs that were four to six times the investment. The use of digital endpoints in clinical trials can provide substantial extra value to sponsors developing new drugs, with high ROIs.

Comparison of the Latin America Regulation Landscape and International Reference Health Authorities to Hasten Drug Registration and Clinical Research Applications.

INTRODUCTION: Promptly providing new drugs to fulfill unmet medical needs requires changes in drug development and registration processes. Health Authorities (HAs) considered as reference due to their experience and acknowledgement (Food and Drug Administration [FDA] among others) already consider innovative clinical trial (CT) designs and flexible approval procedures, but Latin America (LATAM) regulations are still far. A comparison was performed to identify gaps. MATERIALS AND METHODS: CT requirements for drug Marketing Authorization Application (MAA) and CT approval regulations were compared between LATAM and reference HAs (FDA/European Medicines Agency [EMA]/Health-Canada/Swissmedic/Therapeutic Goods Administration [TGA]/Pharmaceuticals and Medical Devices Agency [PMDA]), as of August 2022. Procedure included reference HAs regulations review, item selection, identification in LATAM regulations, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (ICH-E6[R2]/ICH-E8[R1]) implementation revision. RESULTS: For MAA, specific application requirements or ICH guideline M4(R4) on common technical document (CTD) adoption are generally stated, and phase-I/III performance is mandatory (explicitly/implicitly). Faster patient access procedures are infrequent: Priority-drug programs, conditional authorizations, or expedited procedures are scarce or non-existent. Regulatory reliance procedures are adopted through different pathways. Regarding CT approval, innovative/complex CT designs are not prohibited but usually omitted. Some countries implemented adapted CT conducting during the COVID-19 pandemic. Early scientific advice meetings (HA-sponsor) are occasionally considered. Most countries are not formally ICH-joined. CONCLUSIONS: LATAM regulations must adapt to new regulatory standards (FDA/EMA/ICH) through implementation of frequent updates, reliance/expedited procedures, early HA-sponsor interactions, innovative/complex CTs, mandatory phase-III reaching elimination, and decentralized elements for CT conducting.

Modified study designs to expand treatment options in personalised oncology: a multistakeholder view.

Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology.

Reverse Engineering of Digital Measures: Inviting Patients to the Conversation.

Background: Digital measures offer an unparalleled opportunity to create a more holistic picture of how people who are patients behave in their real-world environments, thereby establishing a better connection between patients, caregivers, and the clinical evidence used to drive drug development and disease management. Reaching this vision will require achieving a new level of co-creation between the stakeholders who design, develop, use, and make decisions using evidence from digital measures. Summary: In September 2022, the second in a series of meetings hosted by the Swiss Federal Institute of Technology in Zürich, the Foundation for the National Institutes of Health Biomarkers Consortium, and sponsored by Wellcome Trust, entitled "Reverse Engineering of Digital Measures," was held in Zurich, Switzerland, with a broad range of stakeholders sharing their experience across four case studies to examine how patient centricity is essential in shaping development and validation of digital evidence generation tools. Key Messages: In this paper, we discuss progress and the remaining barriers to widespread use of digital measures for evidence generation in clinical development and care delivery. We also present key discussion points and takeaways in order to continue discourse and provide a basis for dissemination and outreach to the wider community and other stakeholders. The work presented here shows us a blueprint for how and why the patient voice can be thoughtfully integrated into digital measure development and that continued multistakeholder engagement is critical for further progress.

The COVID-19 pandemic as a catalyst for innovation: a regulatory framework to assess fit-for-purpose innovative approaches in clinical research.

The COVID-19 pandemic has had a devastating impact on individuals and multiple aspects of our society including healthcare and clinical research. The silver lining is that the pandemic also served as a catalyst for wider adoption of innovative approaches in clinical research, notably the use of mobile or remote services, and digital technologies. Regulators, clinical study investigators, clinical study participants, sponsors, and other stakeholders collaborated to adopt measures that ensured safe participation in clinical studies whilst maintaining study integrity. In this article, we propose a regulatory framework for assessing fit-for-purpose innovative approaches in clinical research based on Roche/Genentech's experience during the COVID-19 pandemic with the aim to inform and encourage broader implementation of patient-centric and sustainable innovation in clinical research. Our goal is to contribute to ongoing discussions on introducing innovative approaches in clinical trials and eventually the development of globally harmonised guidelines.

Developing a Novel Measurement of Sleep in Rheumatoid Arthritis: Study Proposal for Approach and Considerations.

The development of novel digital endpoints (NDEs) using digital health technologies (DHTs) may provide opportunities to transform drug development. It requires a multidisciplinary, multi-study approach with strategic planning and a regulatory-guided pathway to achieve regulatory and clinical acceptance. Many NDEs have been explored; however, success has been limited. To advance industry use of NDEs to support drug development, we outline a theoretical, methodological study as a use-case proposal to describe the process and considerations when developing and obtaining regulatory acceptance for an NDE to assess sleep in patients with rheumatoid arthritis (RA). RA patients often suffer joint pain, fatigue, and sleep disturbances (SDs). Although many researchers have investigated the mobility of joint functions using wearable technologies, the research of SD in RA has been limited due to the availability of suitable technologies. We proposed measuring the improvement of sleep as the novel endpoint for an anti-TNF therapy and described the meaningfulness of the measure, considerations of tool selection, and the design of clinical validation. The recommendations from the FDA patient-focused drug development guidance, the Clinical Trials Transformation Initiative (CTTI) pathway for developing novel endpoints from DHTs, and the V3 framework developed by the Digital Medicine Society (DiMe) have been incorporated in the proposal. Regulatory strategy and engagement pathways are also discussed.

HIV-1 exploits importin 7 to maximize nuclear import of its DNA genome.

BACKGROUND: Nuclear import of the HIV-1 reverse transcription complex (RTC) is critical for infection of non dividing cells, and importin 7 (imp7) has been implicated in this process. To further characterize the function of imp7 in HIV-1 replication we generated cell lines stably depleted for imp7 and used them in conjunction with infection, cellular fractionation and pull-down assays. RESULTS: Imp7 depletion impaired HIV-1 infection but did not significantly affect HIV-2, simian immunodeficiency virus (SIVmac), or equine infectious anemia virus (EIAV). The lentiviral dependence on imp7 closely correlated with binding of the respective integrase proteins to imp7. HIV-1 RTC associated with nuclei of infected cells with remarkable speed and knock down of imp7 reduced HIV-1 DNA nuclear accumulation, delaying infection. Using an HIV-1 mutant deficient for reverse transcription, we found that viral RNA accumulated within nuclei of infected cells, indicating that reverse transcription is not absolutely required for nuclear import. Depletion of imp7 impacted on HIV-1 DNA but not RNA nuclear import and also inhibited DNA transfection efficiency. CONCLUSION: Although imp7 may not be essential for HIV-1 infection, our results suggest that imp7 facilitates nuclear trafficking of DNA and that HIV-1 exploits imp7 to maximize nuclear import of its DNA genome. Lentiviruses other than HIV-1 may have evolved to use alternative nuclear import receptors to the same end.

Early Patient Access to Medicines: Health Technology Assessment Bodies Need to Catch Up with New Marketing Authorization Methods.

National and international medicines agencies have developed innovative methods to expedite promising new medicines to the market and facilitate early patient access. Some of these approval pathways are the conditional approval and the adaptive pathways by the European Medicines Agency (EMA); the Promising Innovative Medicine (PIM) designation and the Early Access to Medicines Scheme (EAMS) by the Medicines and Healthcare Products Regulatory Agency (MHRA), as well as the Fast Track, Breakthrough or Accelerated Approval methods by the Food and Drug Administration (FDA). However, at least in Europe, these methods cannot achieve the goal of improving timely access for patients to new medicines on their own; the reimbursement process also has to become adaptive and flexible. In the past 2 years, the effective access (national patient access) to newly approved oncology drugs ranged from 1 to 30 months, with an extremely high variability between European countries. The goal of early patient access in Europe can only be achieved if the national health technology assessment bodies, such as NICE (ENG), HAS (FR), G-BA (DE) or AIFA (IT), provide harmonized, transparent, flexible, conditional and adaptive methods that adopt the level of evidence accepted by the medicines agencies. The efforts from medicines agencies are welcome but will be in vain if health technology assessments do not follow with similar initiatives, and the European 'postcode' lottery will continue.

Test Pricing and Reimbursement in Genomic Medicine: Towards a General Strategy.

This paper aims to provide an overview of the rationale and basic principles guiding the governance of genomic testing services, to clarify their objectives, and allocate and define responsibilities among stakeholders in a health-care system, with a special focus on the EU countries. Particular attention is paid to issues pertaining to pricing and reimbursement policies, the availability of essential genomic tests which differs between various countries owing to differences in disease prevalence and public health relevance, the prescribing and use of genomic testing services according to existing or new guidelines, budgetary and fiscal control, the balance between price and access to innovative testing, monitoring and evaluation for cost-effectiveness and safety, and the development of research capacity. We conclude that addressing the specific items put forward in this article will help to create a robust policy in relation to pricing and reimbursement in genomic medicine. This will contribute to an effective and sustainable health-care system and will prove beneficial to the economy at large.

Integrating Personalized Medicine in the Canadian Environment: Efforts Facilitating Oncology Clinical Research.

There is currently a rapid evolution of clinical practices based on the introduction of patient stratification and molecular diagnosis that is likely to improve health outcomes. Building on a strong research base, complemented by strong support from clinicians and health authorities, the oncology field is at the forefront of this evolution. Yet, clinical research is still facing many challenges that need to be addressed in order to conduct necessary studies and effectively translate medical breakthroughs based on personalized medicine into standards of care. Leveraging its universal health care system and on resources developed to support oncology clinical research, Canada is well positioned to join the international efforts deployed to address these challenges. Available resources include a broad range of structures and funding mechanisms, ranging from direct clinical trial support to post-marketing surveillance. Here, we propose a clinical model for the introduction of innovation for precision medicine in oncology that starts with patients' and clinicians' unmet needs to initiate a cycle of discovery, validation, translation and sustainability development.

Available Tools to Facilitate Early Patient Access to Medicines in the EU and the USA: Analysis of Conditional Approvals and the Implications for Personalized Medicine.

Scientific knowledge and our understanding of the human body and diseases have limited any possible treatment tailoring to each patient. The technological advances enabling the integration of various data sets (e.g. '-omics', microbiome, epigenetics and environmental exposure) have facilitated a greater understanding of the human body, the molecular basis of disease and all the factors influencing disease onset, progression and response to treatment, thereby ushering in the era of personalized medicine. We evaluate the regulatory approaches available to facilitate early patient access to efficacious and safe compounds in the EU and the USA in order to make more informed recommendations in the future as to the gaps in regulations for early patient access. An in-depth analysis of conditional approvals (EU) and accelerated approvals (USA) is performed based on the publicly available information (European public assessment reports and a summary review of products approved under both programmes). The types of product, indications, time to approval and type of evidence submitted were analysed. Between 2007 and early 2015, 17 products were conditionally approved in the EU and 25 in the USA, most of them in the area of oncology and based on evidence from phase II clinical trial data. Early approval of promising products based on data from early phases of development is already possible in the EU and the USA. Some of the improvements could entail implementing a rolling assessment of evidence in Europe and extending the scope of early dialogues.

Clinical Trials, Data Protection and Patient Empowerment in the Era of the New EU Regulations.

Cancer clinical trials and, in general, cancer clinical research by definition need a multi-modality approach. It is not enough to discover and register new drugs. To get cancer under control requires us to perform complex clinical studies that integrate drugs, companion diagnostics, new or improved surgical procedures and new radiotherapy approaches as well as, most importantly, to integrate all available information. This includes biological material and, of increasing importance, large amounts of data using big data technologies. To personalise treatment, genetic data are more and more frequently used. Therefore, the general approach is holistic. Legislators, on the other hand, work in a silo mentality; the needs of clinical research are poorly understood, and legislation focuses on either health care or the commercialisation of a product, and not on clinical research. In the last 2 years the EU has drafted several major regulations touching on clinical trials, in vitro diagnostics, medical devices and data protection, all of which will impact clinical research, although the silo mentality makes the overall framework inconsistent and potentially highly damaging to the EU's capacity to make rapid progress in the field of personalised medicine.

Working towards personalization in medicine: main obstacles to reaching this vision from today's perspective.

Rapid advances in 'omics' sciences and technologies have elevated the relevance of personalized medicine. This article reviews the current advances in the application of personalized medicine, outlines and summarizes the key areas that still need to be addressed and gives recommendations in this direction. Eighteen relevant high-level reports on personalized medicine were reviewed in order to identify the gaps and needs that are present for the implementation of personalized medicine. We identify 12 key areas that represent the main obstacles on the road towards the personalization of medicine and divide these 12 key areas into four domains, namely: scientific research and stakeholder collaboration; translational tools; regulations and systematic early dialog with regulators; and uptake into healthcare systems. All of the evaluated reports agree on the imperative need for intensive collaboration among all stakeholders with early active participation and changes in the current healthcare infrastructure.

An index of barriers for the implementation of personalised medicine and pharmacogenomics in Europe.

BACKGROUND: Personalised medicine (PM) is an innovative way to produce better patient outcomes by using an individualised or stratified approach to disease and treatment rather than a collective treatment approach for patients. Despite its tangible advantages, the complex process to translate PM into the member states and European healthcare systems has delayed its uptake. The aim of this study is to identify relevant barriers represented by an index to summarise challenging areas for the implementation of PM in Europe. METHODS: A systematic literature review was conducted, and a gaps-and-needs assessment together with a strengths-weaknesses-opportunities-and-threats analysis were applied to review strategic reports and conduct interviews with key stakeholders. Furthermore, surveys were sent out to representatives of stakeholder groups. The index was constructed based on the priorisation of relevant factors by stakeholders. RESULTS: A need for stakeholder-agreed standards at all levels of implementation of PM exists, from validating biomarkers to definitions of 'informed consent'. The barriers to implement PM are identified in 7 areas, namely, stakeholder involvement, standardisation, interoperable infrastructure, European-level policy making, funding, data and research, and healthcare systems. CONCLUSIONS: Challenges in the above-mentioned areas can and must be successfully tackled if we are to create a healthier Europe through PM. In order to create an environment in which PM can thrive for the patients' best outcomes, there is an urgent need for systematic actions to remove as many barriers as possible.