Modeling impact of inflation reduction act price negotiations on new drug pipeline considering differential contributions of large and small biopharmaceutical companies.

BACKGROUND/AIMS: Provisions of the Inflation Reduction Act mandating drug price negotiation by the Centers for Medicare & Medicaid Services have been criticized as a threat to pharmaceutical innovation. This study models potential impacts of the Inflation Reduction Act on drug approvals based on the differential contributions of large pharmaceutical companies and smaller biotechnology firms to clinical trials and the availability of capital. METHODS: This study examined research and development expense, revenue, and new investment (sale of common and preferred stock) by public biopharmaceutical companies and sponsorship of phased clinical trials in ClinicalTrials.gov. Financial data were incorporated in a model that estimates the number of drugs in each phase and approvals from reported phase-specific costs and transition rates, proportional sponsorship of trials by companies of different size, projected reductions in research and development spending based on company size, and three scenarios by which large companies may allocate reductions in research and development spending among clinical phases: (1) research and development proportionally reduced across phases; (2) research and development disproportionally reduced in phases 2-3; and (3) research and development disproportionately reduced in phases 1-2. RESULTS: Financial data were examined for 1378 public biopharmaceutical companies (2000-2018). Research and development expense was associated with revenue for 79 large companies with market capitalization ≥$7 billion with a 10% reduction in revenue reducing research and development expense by 8.4%. For 1299 smaller companies with market capitalization <$7 billion, research and development was associated with new investment, but not revenue. Smaller companies sponsored 55.2% of phase 1, 55.6% of phase 2, and 49.8% of phase 3 trials in ClinicalTrials.gov 2013-2018. In a model of clinical development that apportions clinical trials between large and smaller companies and determines the number of trials based on research and development resources, 400 drugs entering development produced 47.3 approvals (11.83% rate). A 10% reduction in revenue, reflecting the upper boundary of observed changes 2000-2018, with (1) proportional reduction across phases 1-3 produced 45.1 approvals (4.61% reduction); (2) disproportional reduction of phases 2-3 produced 42.8 approvals (9.55% reduction); and (3) disproportional reduction of phases 1-2 produced 46.9 approvals (0.95% reduction). CONCLUSION: This work suggests that the drug price negotiation provisions of the Inflation Reduction Act could have little or no impact on the number of drug approvals. While large pharmaceutical companies may reduce research and development spending, continued research and development by smaller companies and strategic allocation of research and development resources by large companies may mitigate any negative effects of the Inflation Reduction Act.

From Innovator Result-driven to Multi-actor Impact-oriented Public-Private Partnerships: Integrating the Patient Perspective.

Public-Private Partnerships (PPPs) have been crucial in medicine research and development (R&D) for decades. Initially, PPPs involved private and academic innovators working in bilateral collaborations to advance pharmaceutical innovation. Later, a precompetitive open innovation environment was created, where multiple public and private innovators collaborated on mutual interests. The entry of regulators and patient interest organizations into PPPs has triggered a third shift from an innovator result-driven to a multi-actor impact-oriented partnership model. Using the second Innovative Medicines Initiative program (IMI2) as an example, this chapter focuses on the increasing roles of patient interest organizations in PPPs in roughly the last decade.Most IMI2 partnerships focused on raising awareness and sharing information tailored to patient needs (listener role) and inviting patients to share their experiences and needs (co-thinker role). Many partnerships also integrated the patient perspective by implementing patient advisory bodies (advisor role) or including patients as equal partners in steering the project (partner role). Notably, partnerships like EUPATI and PARADIGM showed that patient interest organizations can lead initiatives, especially those aiming at advancing patient engagement across the medicine R&D lifecycle (decision-maker role). While the overall impact of patient involvement in the IMI2 program is still being assessed, it has exposed many innovators and regulators to the patient perspective and created a community of patient experts with access to tools and guidelines for meaningful involvement.The PPP model continues to evolve, shifting from a treatment-only to a comprehensive diagnosis, treatment, and monitoring approach by incorporating digital and medical technology actors. This development, alongside continued patient and public integration could revolutionize the R&D and accessibility of new treatments and diagnostics.

A prediction model based on artificial intelligence techniques for disintegration time and hardness of fast disintegrating tablets in pre-formulation tests.

BACKGROUND: The pharmaceutical industry is continually striving to innovate drug development and formulation processes. Orally disintegrating tablets (ODTs) have gained popularity due to their quick release and patient-friendly characteristics. The choice of excipients in tablet formulations plays a critical role in ensuring product quality, highlighting its importance in tablet creation. The traditional trial-and-error approach to this process is both expensive and time-intensive. To tackle these obstacles, we introduce a fresh approach leveraging machine learning and deep learning methods to automate and enhance pre-formulation drug design. METHODS: We collected a comprehensive dataset of 1983 formulations, including excipient names, quantities, active ingredient details, and various physicochemical attributes. Our study focused on predicting two critical control test parameters: tablet disintegration time and hardness. We compared a range of models like deep learning, artificial neural networks, support vector machines, decision trees, multiple linear regression, and random forests. RESULTS: A 12-layer deep neural network, as a form of deep learning, surpassed alternative techniques by achieving 73% accuracy for disintegration time and 99% for tablet hardness. This success underscores its efficacy in predicting complex pharmaceutical factors. Such an approach streamlines the drug formulation process, reducing iterations and material consumption. CONCLUSIONS: Our findings highlight the deep learning potential in pharmaceutical formulations, particularly for tablet hardness prediction. Future work should focus on enlarging the dataset to improve model effectiveness and extend its application in pharmaceutical product development and assessment.

Localizing pharmaceuticals manufacturing and its impact on drug security in Saudi Arabia.

Local production of pharmaceuticals plays a vital role in maintaining resilience of national healthcare systems, especially when it comes to facilitating access to needed medicines and decreasing exposure to imports and international supply chains. Pharma is a research-intensive industry and the systemic lack of governance and support to R&D activities in this sector, among other host of related issues such as unsupportive regulatory regimes and human resources capacity limitations, is one of the major impediments to the diversifying of locally produced pharmaceuticals portfolio. In this review, an overview of the current pharmaceutical production system in Saudi Arabia, its major challenges, and proposed remedies to address them will be highlighted.

The Health Impact Fund: making the case for engagement with pharmaceutical laboratories in Brazil, Russia, India, and China.

Despite progress in global health, the general disease burden still disproportionately falls on low- and middle-income countries. The health needs of these countries' populations are unmet because there is a shortage in drug research and development, as well as a lack of access to essential drugs. This health disparity is especially problematic for diseases associated with poverty, namely neglected tropical diseases and microbial infections. Currently, the pharmaceutical landscape focuses on innovations determined by profit margins and intellectual property protection. To expand drug accessibility and catalyze research and development for neglected diseases, a team of researchers proposed the Health Impact Fund as a potential solution. However, the fund is predominantly considering partnerships with pharmaceutical giants in high-income countries. This commentary explores the limitations and benefits in partnering with pharmaceutical companies based in Brazil, Russia, India, and China (BRIC), with the goal of expanding the Health Impact Fund's vision to incorporate long-term, local partnerships. Identified limitations to a BRIC country partnership include lower levels of drug development expertise compared to their high-income pharmaceutical counterparts, and whether the Health Impact Fund and the participating stakeholders have the financial capability to assist in bringing a new drug to market. However, potential benefits include the creation of new incentives to fuel competitive local innovation, more equitable routes to drug discovery and development, and a product pipeline that could involve stakeholders in lower- and middle-income countries. Our commentary explores how partnership with pharmaceutical firms in BRIC countries might be advantageous for all: The Health Impact Fund, pharmaceutical companies in BRIC economies, and stakeholders in low- and middle- income countries.

Incentives to promote the US pharmaceutical innovation: empirical research based on the case of Epogen.

OBJECTIVE: This study aims at emphasizing the significant impact of the incentives to promote the United States (US) pharmaceutical innovation. METHODS: We carried out a retrospective single-case study. We analyzed the innovation process of Epogen: basic research, applied research, regulatory, and marketing. RESULTS: Incentives and policies of pharmaceutical innovation significantly facilitates the entire life cycle of Epogen. The transfer of patent presented by the Bayh-Dole Act allowed Amgen to purchase the research results of Epogen. Relying on the intellectual property mechanisms and financing incentives, Amgen raised the funds needed for Epogen in applied research. Special review shortened the regulatory of Epogen. Epogen obtained orphan drug designation twice and 8 years of market exclusivity. Tax deduction and research funding provided direct economic compensation. The patent system enabled Epogen to obtain 32 years of patent protection (1983-2015). Monopoly pricing was a significant determinant to increase the sales of Epogen through pricing strategies. CONCLUSION: We pointed out that Amgen has developed the successful innovation of Epogen taking advantages of the incentives. Effective and flexible incentives and policies are essential to support the entire life cycle of new drugs, ultimately forming a sustainable driver for the long-run pharmaceutical innovation.

Unpacking the effects of adverse regulatory events: Evidence from pharmaceutical relabeling.

We provide causal evidence that regulation induced product shocks significantly impact aggregate demand and firm performance in pharmaceutical markets. Event study results suggest an average loss between $569 million and $882 million. Affected products lose, on average, $186 million over their remaining effective patent life. This leaves a loss of between $383 million and $696 million attributable to declines in future innovation. Our findings complement research that shows drugs receiving expedited review are more likely to suffer from regulation induced product shocks. Thus, it appears we may be trading off quicker access to drugs today for less innovation tomorrow. Results remain robust to variation across types of relabeling, market sizes, and levels of competition.

The endless frontier? The recent increase of R&D productivity in pharmaceuticals.

BACKGROUND: Studies on the early 2000s documented increasing attrition rates and duration of clinical trials, leading to a representation of a "productivity crisis" in pharmaceutical research and development (R&D). In this paper, we produce a new set of analyses for the last decade and report a recent increase of R&D productivity within the industry. METHODS: We use an extensive data set on the development history of more than 50,000 projects between 1990 and 2017, which we integrate with data on sales, patents, and anagraphical information on each institution involved. We devise an indicator to quantify the novelty of each project, based on its set of mechanisms of action. RESULTS: First, we investigate how R&D projects are allocated across therapeutic areas and find a polarization towards high uncertainty/high potential reward indications, with a strong focus on oncology. Second, we find that attrition rates have been decreasing at all stages of clinical research in recent years. In parallel, for each phase, we observe a significant reduction of time required to identify projects to be discontinued. Moreover, our analysis shows that more recent successful R&D projects are increasingly based on novel mechanisms of action and target novel indications, which are characterized by relatively small patient populations. Third, we find that the number of R&D projects on advanced therapies is also growing. Finally, we investigate the relative contribution to productivity variations of different types of institutions along the drug development process, with a specific focus on the distinction between the roles of Originators and Developers of R&D projects. We document that in the last decade Originator-Developer collaborations in which biotech companies act as Developers have been growing in importance. Moreover, we show that biotechnology companies have reached levels of productivity in project development that are equivalent to those of large pharmaceutical companies. CONCLUSIONS: Our study reports on the state of R&D productivity in the bio-pharmaceutical industry, finding several signals of an improving performance, with R&D projects becoming more targeted and novel in terms of indications and mechanisms of action.

Research funding and price negotiation for new drugs.

This paper analyzes the negotiation process, which leads to basic research funding and price setting for new drugs in regulated health insurance markets. Its results bring answers to the following questions: Should basic research be privately funded, publicly funded, or produced by an independent lab? Under which conditions is public integration of basic research efficient? How do pharmaceutical prices respond to different organizations of basic research? We show that efficiency and prices are higher when basic research is integrated in the firm that commercializes the drug as compared with independent basic research. In both organizations, the higher the negotiation power of the research labs relative to the one of the public health authority is, the higher the prices and the efficiency are. We thereby confirm the traditional trade-off between price containment and dynamic efficiency. We identify one important exception to this trade-off. Indeed, public integration of basic research can result in lowest prices and highest efficiency, as compared with the other possible organizations, in particular when basic and applied research are highly complementary.

Disease burden metrics and the innovations of leading pharmaceutical companies: a global and regional comparative study.

BACKGROUND: The recent innovation activities of global top-tier pharmaceutical companies in accordance with global and regional health concerns were investigated in order to identify their innovations contributing to population health. METHODS: "Innovation activity" was defined as the number of drugs for which R&D activities have been reported within the last three years. Such activities were measured by collecting the data on drug developments and classifying them by developer company, phase of development, therapeutic use, and the country in which the development conducted. Subsequently, we examined and compared the correlations between the global innovation activities of the top 20 pharmaceutical companies and the disease burden measured in disability-adjusted life years (DALYs) by income level and region. In addition, this study analyzed the association between country-specific innovations and DALYs in the corresponding countries. RESULTS: At a global level, the innovation activities were not associated with global DALYs. However, when analyzed by income level, the innovation activities were associated with DALYs in high income and upper middle income countries while it was not associated with DALYs in low middle income and low income countries. In terms of region, correlations were found between the innovation activities and DALYs in the European region, the Americas, and the Western Pacific region whereas such correlations were not found in the African, Eastern Mediterranean, and South-East Asian regions. Similar to the analyses by income level and region, correlations between country-specific innovations and DALYs were only found in high income or high GDP countries. In addition, an empirical analysis of several cases including Canada, Germany, South Korea, and the United Kingdom revealed that pharmaceutical innovation is more closely related to market size than disease burden. CONCLUSIONS: This study identified that discrepancies between pharmaceutical innovation and public health needs, i.e., disease burden values, have persisted until recently. To alleviate this imbalance, both public and private sectors should not only fulfill their respective roles and responsibilities regarding these issues, but also make strategic and collaborative efforts such as Product Development Partnerships (PDPs) directed toward public health improvement.

Does global drug innovation correspond to burden of disease? The neglected diseases in developed and developing countries.

Although it is commonly argued that there is a mismatch between drug innovation and disease burden, there is little evidence on the magnitude and direction of such disparities. In this paper, we measure inequality in innovation, by comparing research and development activity with population health and gross domestic product data across 493 therapeutic indications to globally measure: (a) drug innovation, (b) disease burden, and (c) market size. We use concentration curves and indices to assess inequality at two levels: (a) broad disease groups and (b) disease subcategories for both 1990 and 2010. For some top burden disease subcategories (i.e., cardiovascular and circulatory diseases, neoplasms, and musculoskeletal disorders), innovation is disproportionately concentrated in diseases with high disease burden and large market size, whereas for others (i.e., mental and behavioral disorders, neonatal disorders, and neglected tropical diseases) innovation is disproportionately concentrated in low burden diseases. These inequalities persisted over time, suggesting inertia in pharmaceutical research and development in tackling the global health challenges. Our results confirm quantitatively assertions about the mismatch between disease burden and pharmaceutical innovation in both developed and developing countries and highlight the disease areas for which morbidity and mortality remain unaddressed.

Challenges and potential solutions to the evaluation, monitoring, and regulation of surgical innovations.

BACKGROUND: As it may be argued that many surgical interventions provide obvious patient benefits, formal, staged assessment of the efficacy and safety of surgical procedures has historically been and remains uncommon. The majority of innovative surgical procedures have therefore often been developed based on anatomical and pathophysiological principles in an attempt to better manage clinical problems. MAIN BODY: In this manuscript, we sought to review and contrast the models for pharmaceutical and surgical innovation in North America, including their stages of development and methods of evaluation, monitoring, and regulation. We also aimed to review the present structure of academic surgery, the role of methodological experts and funding in conducting surgical research, and the current system of regulation of innovative surgical procedures. Finally, we highlight the influence that evidence and surgical history, education, training, and culture have on elective and emergency surgical decision-making. The above discussion is used to support the argument that the model used for assessment of innovative pharmaceuticals cannot be applied to that for evaluating surgical innovations. It is also used to support our position that although the evaluation and monitoring of innovative surgical procedures requires a rigorous, fit-for-purpose, and formal system of assessment to protect patient safety and prevent unexpected adverse health outcomes, it will only succeed if it is supported and championed by surgical practice leaders and respects surgical history, education, training, and culture. CONCLUSION: We conclude the above debate by providing a recommended approach to the evaluation, monitoring, and regulation of surgical innovations, which we hope may be used as a guide for all stakeholders involved in interpreting and/or conducting future surgical research.

Cost-Effectiveness and Dynamic Efficiency: Does the Solution Lie Within?

The majority of the current systems spread across the world require the value of pharmaceuticals to be demonstrated with an acceptable degree of certainty before a technology is funded. Often involving the notion of cost-effectiveness, one of the key characteristics of such assessments tends to be the consideration of efficiency as a static outcome; with a strong emphasis on current health gains but a disregard for the impact of decision making on the potential health value over time. In this article, we argue that current systems using cost-effectiveness thresholds may provide an incomplete indicator of value. We defend the idea that funding decisions should also be informed by dynamic efficiency considerations and reflect both the current and the future value of achieving a certain level of effectiveness in a specific disease area. We further lay down the foundations for the implementation of such a value assessment framework.

ReRouting biomedical innovation: observations from a mapping of the alternative research and development (R&D) landscape.

In recent years, the world has witnessed the tragic outcomes of multiple global health crises. From Ebola to high prices to antibiotic resistance, these events highlight the fundamental constraints of the current biomedical research and development (R&D) system in responding to patient needs globally.To mitigate this lack of responsiveness, over 100 self-identified "alternative" R&D initiatives, have emerged in the past 15 years. To begin to make sense of this panoply of initiatives working to overcome the constraints of the current system, UAEM began an extensive, though not comprehensive, mapping of the alternative biomedical R&D landscape. We developed a two phase approach: (1) an investigation, via the RE:Route Mapping, of both existing and proposed initiatives that claim to offer an alternative approach to R&D, and (2) evaluation of those initiatives to determine which are in fact achieving increased access to and innovation in medicines. Through phase 1, the RE:Route Mapping, we examined 81 initiatives that claim to redress the inequity perpetuated by the current system via one of five commonly recognized mechanisms necessary for truly alternative R&D.Preliminary analysis of phase 1 provides the following conclusions: 1. No initiative presents a completely alternative model of biomedical R&D. 2. The majority of initiatives focus on developing incentives for drug discovery. 3. The majority of initiatives focus on rare diseases or diseases of the poor and marginalized. 4. There is an increasing emphasis on the use of push, pull, pool, collaboration and open mechanisms alongside the concept of delinkage in alternative R&D. 5. There is a trend towards public funding and launching of initiatives by the Global South. Given the RE:Route Mapping's inevitable limitations and the assumptions made in its methodology, it is not intended to be the final word on a constantly evolving and complex field; however, its findings are significant. The Mapping's value lies in its timely and unique insight into the importance of ongoing efforts to develop a new global framework for biomedical R&D. As we progress to phase 2, an evaluation tool for initiatives focused on identifying which approaches have truly achieved increased innovation and access for patients, we aim to demonstrate that there are a handful of initiatives which represent some, but not all, of the building blocks for a new approach to R&D.Through this mapping and our forthcoming evaluation, UAEM aims to initiate an evidence-based conversation around a truly alternative biomedical R&D model that serves people rather than profits.

R&D productivity rides again?

A recent analysis of R&D productivity suggests that there are grounds for 'cautious optimism' that the industry 'turned the corner' in 2008 and is 'on the comeback trail'. We believe that this analysis is flawed and most probably wrong. We present an alternative analysis of these same data to suggest that the industry is not yet 'out of the woods' and suggest that many of the systemic issues affecting pharmaceutical R&D productivity are still being resolved.

Hangover free! The social and material trajectories of PartySmart.

This paper presents three embedded episodes in the life of a polyherbal drug indicated as a preventative measure for hangovers. Invented and marketed in 2005 by a leading ayurvedic pharmaceutical company in India, PartySmart is a reformulated compound based on ayurvedic, biomedical and phytochemical sources. This creative process has involved multiple translations, resulting in hybrid pharmacological models, including, for instance, ayurvedic post-digestive tastes and biomedical effects on enzymatic activities. These modes of therapeutic action are conceptualizations of an active drug-- i.e., a digested and metabolized drug. A problem arises, however, in the fact that the ingestion of this drug is linked to alcohol consumption in a country where it is widely considered in negative terms. For this reason, PartySmart was seen as an ambivalent presence in the firm's catalogue and thus a series of interventions aiming to uphold the image of this drug transformed both its social inscription and its materiality. This transformation also took a different, global trajectory as the drug gradually developed as a transnational pharmaceutical commodity and became a new object in new latitudes. By focusing on the social and material dimensions of this drug in these contexts, this paper calls upon science studies to expand the scope of pharmaceutical anthropology. It brings together various layers of analysis to offer new perspectives on contemporary herbal formulations as they traverse material cultures, medical epistemologies, sociopolitical borders, legal environments and social practices.

Pharmaceutical innovation collaboration, evaluation, and matching.

This paper theoretically studies pharmaceutical innovation collaborations, where heterogeneous firms compete for heterogeneous academics. At an interim stage, the firm evaluates the project, which allows it to monitor academics and decide whether to terminate the project to avoid the loss from a future failure. This paper explores the contract, project termination strategy, and collaboration matching. The firm's innovation strategy (exploitations or explorations) determines the evaluation structure, which may affect the market equilibrium. By considering different innovation strategies, this paper shows that in each case, the equilibrium matching is unique (either positive or negative assortative). Consequently, the chosen innovation strategy plays a pivotal role in shaping equilibrium matching outcomes. These findings provide theoretical insights into pharma-academic alliances, shed light on the observed positive or negative assortative properties in the market, and advocate for the consideration of innovation strategies and evaluation structures in future research endeavors. Moreover, this paper also provides several empirical and policy implications.

Quantifying public and private investment in European biopharmaceutical research and development.

Robust biopharmaceutical research and development (R&D) ecosystems require investment from both the public and private sectors. In Europe, there is an interest in growing biopharmaceutical R&D given its contribution to public health and the economy, which requires an understanding of current public and private investment. In addition, recent European draft legislation has focused on the public sector's contributions to biopharmaceutical R&D to inform pharmaceutical prices. However, there is little empirical evidence on the specifics of public and private funding for medicine R&D in Europe. This paper performs aggregative data collection to quantify 2019 investment in biopharmaceutical R&D by the public and private sectors in 6 countries: Belgium, France, Germany, Norway, Poland, and the United Kingdom. We find that, across these countries, the private sector accounts for just under two-thirds of investment. We contrast results to those obtained using high-level R&D indicators from the Organization for Economic Co-operation and Development (OECD) and contextualize differences. We then provide 2013-2019 estimates for Belgium, France, Germany, and the United Kingdom (countries with data to support such analysis), and show that total spending grew over those years, although proportions attributable to each sector remained stable. These findings should provide further evidence for debates on policies to effectively grow the biopharmaceutical R&D sector.

Pharmaceutical innovativeness index: methodological approach for assessing the value of medicines - a case study of oncology drugs.

BACKGROUND: We propose a framework to assess the value of pharmaceutical innovations, with explicit clinical and methodological parameters, based on the therapeutic value and health needs. RESEARCH DESIGN AND METHODS: The study was based on the adaptation of health technology assessment methods documented in the literature, which was applied to a sample of oncological drugs. Difficulties and issues during the application of those tools were identified and addressed to develop a new framework with new and revised domains and clear classification criterion for each domain. Scores were assigned to each level and domain according to their relevance to generate the final score of innovativeness. RESULTS: The Pharmaceutical Innovation Index (PII) includes four domains, two related to clinical and social dimensions - Therapeutic Need and Added Therapeutic Value - and other two about methodological features - Study Design and Quality (risk of bias). The scores combined after assigned to each domain results Index of the Innovativeness of the medicines represents the degree of pharmaceutical innovation. CONCLUSION: This work proposes a transparent methodology with well-defined criteria and script; the algorithm developed with authors' weightings and criteria may be switched to best adjust to other applications, perspective or clinical indications, while keeping the transparency and objectiveness.

Lessons learned from the Canadian Fabry Disease Initiative for future risk-sharing and managed access agreements for pharmaceutical and advanced therapies in Canada.

Risk sharing agreements (RSAs) and managed access agreements have emerged as tools to overcome evidentiary uncertainty and contain costs of pharmaceuticals; however, Canada has relatively little experience with these health policy instruments. This article describes one of the few examples of national RSAs. Enzyme replacement therapies (ERT) were introduced in Canada to treat Fabry disease in the early 2000s through an RSA. Based on qualitative interviews with key participating actors, this article explains how this RSA ensured continuity of treatment for patients already on ERT, and collected robust real-world evidence to secure treatment for future Fabry patients. We show the importance of partnerships, collaborations, and active patient communities in establishing RSAs, as well as the critical role of robust registries for the collection, storage, and use of that real-world data. In doing so, this paper points to reasons that explain the relative dearth of RSAs in Canada, which can be resource (both human and finance) intensive and are difficult to broker in a federalist health system. Through these findings, policy lessons are developed concerning the need for technological and governance platforms on how RSA in Canada can be more effectively supported going forward in a broader move towards "social pharmaceutical innovation".