Product Development Decisions Research Articles

How Management Accountants Purposefully Create Cash Flow Forecasts in Capital Budgeting: A Field Study of Product Development Decisions*

ABSTRACTIn capital budgeting, management accountants may have their own agendas when they are creating cash flow forecasts and recommending particular capital investments. What are the mechanisms management accountants can use to influence cash flow forecasts in capital budgeting? This field study investigates how management accountants prepared cash flow forecasts for product development investment decisions at a car company. We describe in detail two instances of the technical design of new cars, the preparation of cash flow forecasts, and decisions on capital investment projects. When management accountants monetarily quantify various kinds of inputs, they not only make pragmatic choices as part of their normal work of dealing with complexity and uncertainty, but they also purposefully intervene in various ways to make their cash flow forecast support a particular capital investment. These interventions can be differentiated in terms of their nature (qualitative or quantitative) and timing (initiating or counteracting). This field study contributes a conceptualization and empirical evidence on accounting tactics in the context of capital budgeting.

Better methods, better data: landscaping the priorities for improving methodologies in vector control

This article addresses the evolving challenges in evaluating insecticide-based tools for vector control. In response to the emergence of insecticide resistance in major malaria vectors, novel chemistries and products are coming to market, and there is a need to review the available testing methodologies. Commonly used methods for evaluating insecticides, such as the World Health Organization (WHO) cone bioassay, are inadequate for the diverse range of tools now available. Innovation to Impact (I2I) has studied the variability in laboratory methods, with the aim of identifying key factors that contribute to variation and providing recommendations to tighten up protocols. The I2I Methods Landscape is a living document which presents a review of existing methods for evaluating vector control tools, with the scope currently extending to insecticide-treated nets (ITNs) and indoor residual sprays (IRS). The review reveals a lack of validation for many commonly used vector control methods, highlighting the need for improved protocols to enhance reliability and robustness of the data that is generated to make decisions in product development, evaluation, and implementation. A critical aspect highlighted by this work is the need for tailored methods to measure endpoints relevant to the diverse modes of action of novel insecticides. I2I envisage that the Methods Landscape will serve as a decision-making tool for researchers and product manufacturers in selecting appropriate methods, and a means to prioritise research and development. We call for collective efforts in the pro-active development, validation, and consistent implementation of suitable methods in vector control to produce the data needed to make robust decisions.

Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report.

This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.

Enabling novel paradigms: a biological questions-based approach to human chemical hazard and drug safety assessment.

Throughput needs, costs of time and resources, and concerns about the use of animals in hazard and safety assessment studies are fueling a growing interest in adopting new approach methodologies for use in product development and risk assessment. However, current efforts to define "next-generation risk assessment" vary considerably across commercial and regulatory sectors, and an a priori definition of the biological scope of data needed to assess hazards is generally lacking. We propose that the absence of clearly defined questions that can be answered during hazard assessment is the primary barrier to the generation of a paradigm flexible enough to be used across varying product development and approval decision contexts. Herein, we propose a biological questions-based approach (BQBA) for hazard and safety assessment to facilitate fit-for-purpose method selection and more efficient evidence-based decision-making. The key pillars of this novel approach are bioavailability, bioactivity, adversity, and susceptibility. This BQBA is compared with current hazard approaches and is applied in scenarios of varying pathobiological understanding and/or regulatory testing requirements. To further define the paradigm and key questions that allow better prediction and characterization of human health hazard, a multidisciplinary collaboration among stakeholder groups should be initiated.

Information needs and presentation in agile software development

Agile software companies applying the DevOps approach require collaboration and information sharing between practitioners in various roles to produce value. Adopting new development practices affects how practitioners collaborate, requiring companies to form a closer connection between business strategy and software development. However, the types of information management, sales, and development needed to plan, evaluate features, and reconcile their expectations with each other need to be clarified. To support practitioners in collaborating and realizing changes to their practices, we investigated what information is needed and how it should be represented to support different stakeholders in their tasks. Compared to earlier research, we adopted a holistic approach—by including practitioners throughout the development process—to better understand the information needs from a broader viewpoint. We conducted six workshops and 12 semi-structured interviews at three Finnish small and medium-sized enterprises from different software domains. Thematic analysis was used to identify information-related issues and information and visualization needs for daily tasks. Three themes were constructed as the result of our analysis. Visual information representation catalyzes stakeholder discussion, and supporting information exchange between stakeholder groups is vital for efficient collaboration in software product development. Additionally, user-centric data collection practices are needed to understand how software products are used and to support practitioners’ daily information needs. We also found that a passive way of representing information, such as a dashboard that would disturb practitioners only when attention is needed, was preferred for daily information needs. The software engineering community should consider reviewing the information needs of practitioners from a more holistic view to better understand how tooling support can benefit information exchange between stakeholder groups when making product development decisions and how those tools should be built to accommodate different stakeholder views.

A Model-Based Engineering Approach for Evaluating Software-Defined Radio Architecture

In product development, important specification and design decisions must be made at various stages of the lifecycle that include design, manufacturing, operations, and support. However, making these decisions becomes more complex when a multi-disciplinary team of stakeholders is involved in system-level or subsystem-level architecture and design decisions. Model-Based Engineering (MBE) approaches are enabling a digital thread of connected data and models. This work demonstrates a novel MBE approach that incorporates a model-based systems engineering (MBSE) method and a multi-criteria decision-making (MCDM) method to determine the best architecture solution that aligns with stakeholder needs and objectives over multiple domains. This approach demonstrates the connection of a system descriptive model, modeled using the systems modeling language (SysML), to underlying physics-based engineering models for the purpose of better predicting the technical performance of systems during the architecture development phase. This approach is demonstrated for a common aerospace communications application, a software-defined radio. This novel MBE approach supports digital transformation at organizations and allows for earlier design validation, enabling designers to test and select the best system architecture from many candidates and validate that the design meets stakeholder needs.

Data-driven product optimization capabilities to enhance sustainability and environmental compliance in a marine manufacturing context

This paper investigates concerns related to product data and digital data flow when aiming to automate company processes. Accurate data is necessary to create value by enabling improved decision-making in product development, including sustainability capabilities. The case analyzed is an engineer-to-order (ETO) company operating in a low-volume marine manufacturing context. A participatory research approach is used to study two projects that are part of the company’s digital business transformation, aiming to digitalize information and autogenerate downstream processes. Building on the strengths promised by digitalization requires precise and extensive product and process information. An important facilitation capability is to create a digital thread from design to finished product, including product documentation. This is necessary to establish capabilities both to autogenerate appropriate compliance reporting as part of the product development process and to conduct virtual testing and validation before the physical equipment is acquired, resulting in a manufacturing process that is ‘right first time’. In addition, data capabilities guide and enable sound-decision making for improved sustainable practices in the early phase of product development. It is found that the data quality required to utilize tools within the context of Industry 4.0 demands changes to existing product design practices and focus on the three pillars harmonization, integration and automation of data and systems.

Overview of FDA guidelines for patient engagement in medical product development and regulatory decision making

About 10 years ago, the FDA launched an initiative to expand the role of patients in informing regulators and sponsors about the most serious consequences of the disease and the main treatment goals that can lead to desired medical outcomes. This initiative has grown into four guidance that aim.

FRAMEWORK FOR COMPARISON OF PRODUCT CARBON FOOTPRINTS OF DIFFERENT MANUFACTURING SCENARIOS

AbstractThe Product Carbon Footprint (PCF) has been established over the last few years as a new control variable in product design to quantify the sustainable impact of a product. However, the calculation of the PCF is subject to numerous uncertainties and assumptions, which are no longer represented in the stand-alone value. The uncertainties and assumptions arise at different stages of the calculation of the PCF and consequently create a multidimensional problem, which means that the PCF does not provide a trustworthy basis for comparing different production scenarios. To face this multidimensional issue, in this paper, a methodology for categorization of the different issues and, therefore, of the final PCF is presented. Through this methodology, which is divided into five levels mainly based on the origin, the quality, and the uncertainty of the data, an assessment can be made as to whether the values of the PCFs are comparable in different scenarios. The methodology can therefore help to improve decisions in product development with regard to environmental sustainability.

IN SEARCH FOR SHARED CHARACTERISTICS OF PHYSICAL AND VIRTUAL PROTOTYPES

AbstractPrototyping is essential for knowledge acquisition and, thus, for informed decision-making in product development. The gold standard is still the use of physical prototypes. However, with the increase in computing capacity, it is becoming easier also to use virtual prototypes.The selection of prototyping approaches often starts with the distinction between physical and virtual prototypes and therefore excluding a broad range of possibilities early on.This paper explains why a selection of prototypes based on the distinction between physical and virtual is not necessarily the best solution and suggests a selection approach based on characteristics which offer the possibility to avoid this limitation. Therefore the characteristics of physical prototypes commonly used in literature are analysed and reduced to a generally valid selection. Examples of virtual prototypes are selected and analysed regarding their characteristics. All elaborated characteristics are then tested for their applicability to the examples of virtual prototypes.

Uncovering Insights for New Car Recommendations with Sequence Pattern Mining on Mobile Applications

This study employs sequential pattern mining to analyze browsing behaviors and aid mobile app service providers in effectively promoting and recommending new products. We collected browsing history data from 66,004 mobile app users for new car info in Taiwan, totaling 1,263,614 records over two months. By utilizing sequence pattern mining, we identified frequent browsing sequences on the app that can indicate subsequence product interests and suggest new items to potential customers. The proposed method can improve the user experience for mobile app users and facilitate the development of the potential market for advertising. The study highlights the effectiveness of sequence pattern mining in recommending new products to car app users, benefiting small app vendors, improving user experience, and informing product development decisions in the automobile industry. Furthermore, the findings emphasize the importance of considering the sequential relationships between events or items in pattern mining, particularly in mobile app development. In conclusion, the proposed approach offers a cost-effective solution for small app vendors to recommend new products and improve the overall user experience, providing valuable insights for the automobile industry.

Integrating Prospective Scenarios in Life Cycle Engineering: Case Study of Lightweight Structures

Lightweight design is a common approach to reduce energy demand in the use stage of vehicles. The production of lightweight materials is usually associated with an increase in energy demand, so the environmental impacts of lightweight structures need to be assessed holistically using a life cycle assessment. To estimate the life cycle environmental impacts of a product in its developmental stage, for example, by life cycle engineering, future changes in relevant influencing factors must be considered. Prospective life cycle assessment provides methods for integrating future scenarios into life cycle assessment studies. However, approaches for integrating prospective life cycle assessment into product development are limited. The objective of this work is to provide the methodological foundation for integrating future scenarios of relevant influencing factors in the development of lightweight structures. The applicability of the novel methodology is demonstrated by a case study of a structural component in a steel, aluminium, and hybrid design. The results show that appropriate decarbonisation measures can reduce the life cycle greenhouse gas emissions by up to 95 percent until 2050. We also found that shifts in the environmentally optimal design are possible in future scenarios. Therefore, the methodology and data provided contribute to improved decision-making in product development.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Quantitative methods and modeling (QMM) are rapidly demonstrating their potential to support generic drug development and assessment. This commentary is based on the public input from the Generic Drug User Fee Amendments (GDUFA) Science and Research Initiative Public Workshop held in May 2022, which recognized the implementation of model-integrated evidence (MIE) as a high research priority for the next 5 years. On May 9 and 10, 2022, the US Food and Drug Administration (FDA) hosted the Fiscal Year (FY) 2022 Generic Drug Science and Research Initiative Public Workshop as a commitment under the Generic Drug User Fee Amendments of 2017 (GDUFA II). The workshop provided updates on current science and research initiatives and solicited public input on the prioritization of scientific issues impacting generic product development and approval that will shape the next 5 years of the GDUFA science and research program (known as GDUFA III, 2022–2027). This commentary will focus on QMM, which was highlighted as one of the key research priorities in this workshop. GDUFA science and research have focused on QMM as one of the two key drivers of innovation for generic drugs along with in vitro product characterization.1 The annual science and research initiative public workshops, including this year's, have included a session dedicated to discussing research needs and priorities for QMM. Quantitative models can support product development and regulatory decisions where bioequivalence (BE) is challenging to demonstrate or assess because the empirical evidence for BE may be impractical to sufficiently demonstrate BE. This integration of evidence from empirical tests or studies and computational models has been referred to as model-integrated evidence (MIE).2 At the workshop, MIE was one of key topics of the opening session titled “The Next Five Years of the Generic Product Science and Research Program.” The session explored generic industry perspectives about the challenges impacting generic product development that are the most critical to address by GDUFA research initiatives during the next 5 years. Some of the key product development challenges and BE issues were associated with complex products, such as orally inhaled drug products (OIDPs) and long-acting injectable, implantable, and insertable products (collectively, LAI products). Industry representatives' feedback also highlighted complex BE issues in other product areas, including noncomplex generics. In general, for the GDUFA science and research program, industry has utmost interest in prioritizing research that helps address the current challenges generic drug developers are facing. For MIE, industry is particularly interested in MIE implementation, precedents set through access to MIE case studies for regulatory purposes, and detailed guidance (e.g., recommendations in the product-specific guidances) for those challenging areas. As indicated by Figure 1, articles included in this special issue contain the summaries of the two most recent modeling focused public workshops organized by the FDA in collaboration with the Center for Research on Complex Generics (CRCG), engaging multiple stakeholders, including generic industry, academia, and government,3, 4 as well as this FDA public workshop. We believe the progress we have seen in MIE is attributable to the FDA's continuous investment in research and dissemination of outcomes advancing QMM in collaboration with experts in academia and other stakeholders as well as industry's efforts to leverage and adopt innovative QMM approaches in their development programs. The significant shift in the scope of industry's MIE feedback from development to implementation is consistent with the recent increase in submission of modeling and simulation-based alternative BE approaches to the FDA in abbreviated new drug applications (ANDAs) and pre-ANDA interactions. The increase is particularly notable for pre-ANDA interactions during the past 3 years mirroring industry's strong interest and recognition of the potential MIE can bring to generic drug development programs and regulation submissions (Figure 2). The interactions were mainly for complex products, such as LAIs and OIDPs, whereas some noncomplex drug products were also included, such as certain oral drug products for oncology/rare disease drug products. These submissions generally leveraged GDUFA research outcomes, both the FDA internal and external research progresses and outcomes. Notably, the FDA and industry are collaboratively advancing the field and establishing the ecosystem for the application of QMM to aid the development of generic drug products. According to the interviews the CRCG conducted with the generic drug industry, industry is strongly interested in applying MIE approaches as an alternative to conventional end point BE studies for inhalation and LAI products to their product development programs. Industry is looking for guidance in the implementation and validation of MIE in their submissions to the FDA and indicates the most effective way may be through publications of case studies of MIE for complex generics approvals. Such cases are expected to spur the adoption of modeling into practice in product development and regulatory submissions. The perspectives shared by multiple industry representatives were consistent with the CRCG interview. Another feedback was on enhancing communications. Specifically, detailed MIE case studies representing the FDA's current thinking and expectations on MIE for regulatory applications, can be effectively disseminated through organizing workshops and other communication means, in addition to scientific publications. We note that the FDA is dedicated to actively publishing the progresses and case examples of MIE from the GDUFA research and there are several publications in the complex products including orally inhaled, long-acting injectable/implant, and dermal products.5-8 In addition, we believe that this special issue will provide a useful summary of the most recent development and discussion around the application of MIE to generic drug product development and assessment. The annual GDUFA science and research reports are another resource to check out the progress in MIE, which include a summary of research activities, research highlights, comprehensive lists of new, ongoing, and completed grants and contracts, and outcomes generated from the GDUFA-funded science and research program in each fiscal year. In-depth industry feedback on implementing QMM approaches for specific products including OIDPS, LAIs, and orally administered products can be found in the Supplementary Material. Overall, industry recognizes: (i) the benefits that standardizing MIE approaches for both complex and noncomplex generics would bring them; (ii) the value of using population pharmacokinetic (PK) and physiologically-based pharmacokinetic (PBPK) modeling to replace or reduce in vivo BE studies; and (iii) the need for model validation and verification for regulatory assurance in such MIE applications. With regard to industry's desire for guidance/criteria for model validation and verification, the two specific FDA workshops discussed best practices and practical implementations of MIE (see detailed summaries in this special issue). In the modeling focused FDA/CRCG and FDA GDUFAII workshops, the concept of model-master file and its application to facilitate generic drug development, regulatory submission, and assessment, was introduced by the Office of Generic Drugs at the FDA. The aim of this concept is to provide a framework for communication of regulatory acceptable modeling practices allowing for increased confidence in industry use of QMM. Harmonization with other agencies, such as the European Medical Agency, for modeling and simulation for BE were also commented to be helpful. Other noteworthy comments include that as generic drug field is maturing, MIE may become a routine alternative to BE studies in support of product life cycle management such as post-approval changes. In general, PBPK modeling has already been recommended for biopharmaceutical applications and been increasingly applied for supporting bioequivalence assessment.9 In addition, industry suggested that the innovative approaches that the Agency used specifically to address the unexpected challenges in BE during coronavirus disease 2019 (COVID-19) may be applied broadly with further research. Finally, the value of artificial intelligence (AI) and machine learning (ML), potentially combined with real-world evidence/data, in advancing the development of complex generics has been well-recognized by industry, regulatory agency, and other stakeholders, thus the need for further research has been emphasized. Specifically, AI and ML may demonstrate their utility in optimizing the program design and reduce study duration; in utilizing public domain information (e.g., drug labeling) to facilitate unique study designs for complex generic drug product or exploratory studies on related compounds in support of generic development. In addition, Industry's feedback was focused on research that can help establish the framework and potential regulatory pathway of translating such data-driven technologies into regulatory submissions. We also note that ML/AI technologies have been applied as part of MIE, for example, these technologies can support the model building process contributing to standardization of MIE processes for BE.10 The challenges shared by Industry are consistent with what the FDA has regarded as opportunities for MIE. FDA's GDUFA research programs in QMM have made significant investment and generated useful outcomes over the past few years. Industry recognizes the value of MIE to address challenges in generic drug development and assessment and strongly supports the FDA's investment on research that can facilitate and accelerate MIE implementation. The FDA is committed to continue further advancing this area and included facilitating the utility of MIE to support demonstrations of BE as one of the priority areas for the next 5 years of the GDUFA Science and Research Program. Overall, it is evident that both the FDA and industry are collaboratively establishing an MIE ecosystem in generic drug development and assessment. No funding was received for this work. The opinions expressed in this paper are those of the authors and should not be interpreted as the position of the US Food and Drug Administration. The authors declared no competing interests for this work. Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Selected Developments in Biotechnology Law and the Biotechnology Industry

Biotechnology Law ReportVol. 42, No. 1 News BriefsFree AccessSelected Developments in Biotechnology Law and the Biotechnology IndustryBy Steven J. ZweigBy Steven J. ZweigSteven J. Zweig is the Managing Editor of Biotechnology Law Report.Search for more papers by this authorPublished Online:15 Feb 2023https://doi.org/10.1089/blr.2023.29299.sjzAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail WHITE HOUSE REQUESTS PUBLIC INPUT ON BIOTECHNOLOGY AND BIOMANUFACTURINGBy the time you read this News in Brief, the Biden White House's Office of Science and Technology Policy (OSTP) will have received and be considering public comments on how biotechnology and biomanufacturing can help the nation reach “goals that were previously out of reach” as well as regarding “what steps can be taken to ensure we have the right research ecosystem, workforce, data, domestic biomanufacturing capacity, and other components to support a strong bioeconomy.” The Administration had launched a US $2 billion biotechnology and biomanufacturing initiative in mid-September 2022, with the goal of “lower[ing] prices, creat[ing] good jobs, strengthen[ing] supply chains, improv[ing] health outcomes, and reduc[ing] carbon emissions.” The OSTP called for public comments about this initiative, which comments were due by January 20, 2023.SAUDI ARABIA HOSTS SECOND RIYADH GLOBAL MEDICAL BIOTECHNOLOGY SUMMITJanuary 25, 2023, Saudi Arabia will host a two-day medical biotechnology summit in its capital city of Riyadh. The summit, which takes place under the aegis of Crown Prince Mohammed bin Salman, is part of the Kingdom's Vision 2030 national development agenda, which seeks to diversify the petrostate's economy beyond oil: petroleum currently accounts for nearly half (42%) of gross domestic product (GDP) and a stunning 87% of the government's budget.1 While the nation has been doing well economically based on strong oil prices,2 such a reliance on a single industry sector creates an obvious vulnerability: a decline in demand for oil or in oil prices, or an increase in the cost of oil extraction or production, would be devasting. Hence the interest in diversification, with biotechnology seen as a particularly promising industry. The goal of the summit, which brings together stakeholders from industry and academia, is to create a “Riyadh Declaration for Biotechnology” to help transform Saudi Arabia into a global biotech hub and establish global partnerships.BELATED BUT WELCOME APPROVAL FROM CHINA FOR GM CROPSChina recently approved importation of eight genetically modified (GM) crops; this permits, among other things, the importation of GM alfalfa for the first time in a decade. The long-overdue approval was welcomed by seed manufacturers: China's extremely slow approval process not only impacted sales directly to China but also has a ripple effect elsewhere because as China is one of the world's largest agricultural markets, what is—or is not—approved for sale to China has an outsize impact on the allocation of product development and production.3The approvals are only for importation of GM crops as animal feed; China's enormously cautious approach to GM technology still does not permit GM food crops for humans. But the approvals nonetheless are “a positive step towards resolving the longstanding challenges biotechnology developers face in obtaining import approvals in China,” according to the Biotechnology Innovation Organization (BIO) in Washington, the world's largest biotech trade association. China's approval makes possible larger-scale plantings of the approved crops in areas—such as several western U.S. states—which supply export markets and the U.S. government has in fact hailed the approvals as good news for U.S. farmers.Hopefully, these approvals are but the harbingers of more frequent or rapid approvals: China had promised to speed access to its markets under the Phase 1 trade deal it entered into in 2020 with the Biden Administration. Speeding market access can function as a goodwill gesture to offset problems in China-United States caused by clashing geopolitical ambitions.In addition to U.S. agriculture—and the seed companies which supply it—other winners from the recent round of approvals include Brazil (GM sugar cane approved) and domestic Chinese developers of GM crops.U.S. BIOENERGY FUNDING OPPORTUNITIES TO COMEThe U.S. Department of Energy (DOE) intends to issue two funding opportunity announcements (FOAs) for the production of biofuels and bioproducts in early 2023. The planned FOAs are (at least at presently) titled, respectively, “Reducing Agricultural Carbon Intensity and Protecting Algal Crops (RACIPAC)” and “2023 Conversion R&D.” Their intention is to foster sustainable use of domestic biomass (including waste) to produce biofuels and other bioproducts, supporting the Biden Administration's dual related goals of increasing the percentage of energy needs met by clean energy while reducing emissions.The RACIAPC FOA is aimed at reducing the agricultural carbon footprint with “smart” agricultural practices for low-carbon-intensity feedstock and the protection of algae crops. The 2023 Conversion R&D FOA seeks to support technologies for the conversion of domestic lignocellulosic biomass4 and waste resources into biofuels and bioproducts to, again, reduce the carbon footprint. Both FOAs are in the service of meeting the “Sustainable Aviation Fuel Grand Challenge”5 of reducing aviation emissions by a fifth by 2030 and having 100% of U.S. domestic aviation fueled by sustainable aviation fuel by no later than 2050.BIONTECH MOVES TO INVALIDATE CUREVAC MRNA VACCINE TECHNOLOGYBioNTech has brought a motion in the German Patent Court to invalidate a competitor's (CureVac's) 2010 patent for mRNA vaccination technology. The January 2023 motion is a response to CureVac's 2022 patent lawsuit by CureVac. In its motion, BioNTech argues that CureVac's patent should never have been granted because its subject matter is not based on an inventive step. The CureVac lawsuit to which the motion is a response was one in which CureVac sought “fair compensation” from BioNTech and two of its subsidiaries for alleged infringement of CureVac's intellectual property rights—a claim which BioNTech vociferously denies, asserting that its work was original and that “We will vigorously defend it against all allegations of patent infringement.”1 https://www.cia.gov/the-world-factbook/countries/saudi-arabia/#economy2 https://www.imf.org/en/News/Articles/2022/08/09/CF-Saudi-Arabia-to-grow-at-fastest-pace3 By way of analogy: the author used to work in K-12 educational publishing, where he learned that Texas educational standards influence school books sold in all 50 states: as the largest centralized U.S. educational market (California decentralizes textbook purchasing decisions to a much greater degree than Texas), school books have to take cognizance of Texas standards since if you can't sell to Texas, the book may not be worth publishing. For another example, consider the fact that California, as the U.S.'s largest car market, influences auto safety, emissions, and gas mileage standards for cars sold in all 50 states. Any large market in any industry segment influences product development and production decisions outside that market.4 Basically, material from woody plants.5 https://www.energy.gov/eere/bioenergy/sustainable-aviation-fuel-grand-challengeFiguresReferencesRelatedDetails Volume 42Issue 1Feb 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:By Steven J. Zweig.Selected Developments in Biotechnology Law and the Biotechnology Industry.Biotechnology Law Report.Feb 2023.1-2.http://doi.org/10.1089/blr.2023.29299.sjzPublished in Volume: 42 Issue 1: February 15, 2023Online Ahead of Print:February 2, 2023PDF download

Exploring the Essence of Continuous Experimentation

Context: Today's software industry is faced with rapidly changing requirements and high expectations from customers and users. Agile software development with a focus on rapid and frequent product deployment to end-users calls for equally continuous feedback acquisition, guiding software design and supporting evidencebased product development decisions. For keeping pace and succeeding on the highly competitive software market it is essential for companies to quickly and reliably evaluate their ideas based on real usage experiences in a natural context. This can be enabled using Continuous Experimentation (CE) - an approach to close the feedback cycle and tightly integrate the empirical evaluation of new features into the software development process. Objectives: With this project I aim at creating an understanding of CE as practiced and theorised today. Furthermore, my goal is to identify the smallest set of prerequisites for successfully implementing systematic experimentation practices into companies' software development process. I want to find solutions for companies to adopt CE as most suitable to their product stage, process maturity, and available resources; and enable organisations to systematically run experiments for data-driven decision-making. Methods: In addition to a currently on-going multivocal literature review, the project will involve empirical studies following a design science approach. Starting with a practitioner survey or interview, and a pilot case study for finding both, the typical hurdles encountered and the minimum requirements needed to apply CE in any company, the project will transition into an iterative multiple-case study, where proposed solutions are to be evaluated. Conclusions: The proposed doctoral research project will contribute to an increased understanding of systematic experimentation practices in different organisational settings, and strives for providing actionable solutions for enabling more flexible software development which can quickly react to feedback gained through experimentation, as well as an evaluation of these suggested solutions. Especially, this project aims at the creation of an easy-to-adopt approach called light-weight CE, which allows also companies with few resources or projects involving an earlystage product to benefit from the advantages of CE.

Development of Celiac Disease Therapeutics: The Sixth Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics Workshop

The Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics VI Workshop, held on July 22, 2021, provided a forum for patients and representatives from academia, industry, patient advocacy groups, and Food and Drug Administration to discuss drug development for celiac disease (CeD). The workshop focused on the approach of histologic assessments in clinical trials, considerations for pediatric drug development, and the use of a gluten challenge (GC) in clinical trials. Given that no histologic scoring system is widely accepted for use in clinical trials at this time, early-phase clinical trials should ideally explore a variety of histologic scales and assess the histologic findings of CeD as individual measures to inform future trials. When planning pediatric drug development in CeD, appropriate use of extrapolation of efficacy data from adequate, well-controlled studies in adults could facilitate timely access to safe and effective therapies for pediatric patients. Identification of a fit-for-purpose pediatric clinical outcome assessment could further advance pediatric drug development. Histologic responses to the GC depend on exposure, dose, and duration; short exposures do not appear to cause long-term consequences. However, the GC should be incorporated into clinical trials in a thoughtful manner to generate interpretable results and ensure patient safety. Ongoing collaboration between all stakeholders will facilitate the development of safe and effective therapeutics for CeD. The Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics VI Workshop, held on July 22, 2021, provided a forum for patients and representatives from academia, industry, patient advocacy groups, and Food and Drug Administration to discuss drug development for celiac disease (CeD). The workshop focused on the approach of histologic assessments in clinical trials, considerations for pediatric drug development, and the use of a gluten challenge (GC) in clinical trials. Given that no histologic scoring system is widely accepted for use in clinical trials at this time, early-phase clinical trials should ideally explore a variety of histologic scales and assess the histologic findings of CeD as individual measures to inform future trials. When planning pediatric drug development in CeD, appropriate use of extrapolation of efficacy data from adequate, well-controlled studies in adults could facilitate timely access to safe and effective therapies for pediatric patients. Identification of a fit-for-purpose pediatric clinical outcome assessment could further advance pediatric drug development. Histologic responses to the GC depend on exposure, dose, and duration; short exposures do not appear to cause long-term consequences. However, the GC should be incorporated into clinical trials in a thoughtful manner to generate interpretable results and ensure patient safety. Ongoing collaboration between all stakeholders will facilitate the development of safe and effective therapeutics for CeD. Celiac disease (CeD) is a chronic disorder caused by an immune reaction to ingested gluten that primarily affects the small intestine and produces a variety of gastrointestinal and extraintestinal symptoms. A gluten-free diet (GFD) is currently the only treatment. Although strict compliance with a GFD is effective for many patients, maintaining the diet and avoiding inadvertent gluten exposure can be challenging. Therefore, an unmet need exists for pharmacologic therapies for CeD. The Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics VI (GREAT VI) workshop on CeD was held on July 22, 2021, sponsored by the Food and Drug Administration (FDA) in collaboration with the American College of Gastroenterology, the American Gastroenterological Association, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. The workshop was attended by stakeholders from academia, clinical practice, industry, FDA, patients, and patient advocacy groups. Herein are summarized the topics covered in the workshop. Details regarding the presentations can be found at http://www.fda.gov/drugs/news-events-human-drugs/gastroenterology-regulatory-endpoints-and-advancement-therapeutics-vi-great-vi-workshop-celiac. Dr Benjamin Lebwohl reviewed approaches to monitoring the underlying disease using histologic assessments in clinical practice for adults. Clinicians often rely on a combination of factors when assessing the response to a GFD, including improvement in clinical symptoms, serologies, and histology. Symptoms and serology are not reliable predictors of persistent villous atrophy in CeD.1Sharkey L.M. Corbett G. Currie E. et al.Optimising delivery of care in coeliac disease - comparison of the benefits of repeat biopsy and serological follow-up.Aliment Pharmacol Ther. 2013; 38: 1278-1291Crossref PubMed Scopus (82) Google Scholar,2Silvester J.A. Kurada S. Szwajcer A. et al.Tests for serum transglutaminase and endomysial antibodies do not detect most patients with celiac disease and persistent villous atrophy on gluten-free diets: a meta-analysis.Gastroenterology. 2017; 153: 689-701.e1Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Although the role of follow-up biopsy in the management of CeD in clinical practice remains uncertain, there appear to be untoward consequences of persistent villous atrophy. A follow-up biopsy may help determine the response to a GFD, and whether ongoing symptoms are due to gluten exposure or other factors (eg, functional gastrointestinal disorders), because persistent villous atrophy suggests ongoing gluten exposure. The American College of Gastroenterology clinical guidelines state that obtaining a follow-up biopsy is reasonable in adults after 2 years of starting a GFD to assess healing.3Rubio-Tapia A. Hill I.D. Kelly C.P. et al.ACG clinical guidelines: diagnosis and management of celiac disease.Am J Gastroenterol. 2013; 108 (quiz 677): 656-676Crossref PubMed Scopus (1153) Google Scholar Age appears to be an important predictor of intestinal healing, and children are more likely to heal, and heal more rapidly, than adults.4Lebwohl B. Murray J.A. Rubio-Tapia A. et al.Predictors of persistent villous atrophy in coeliac disease: a population-based study.Aliment Pharmacol Ther. 2014; 39: 488-495Crossref PubMed Scopus (79) Google Scholar Adults with CeD may take a year or longer for the underlying inflammation to resolve on a GFD. Patients are often characterized in clinical practice as healed or not healed; however, there is a continuum of response that could be evaluated using the distinguishing histologic features of CeD. Dr Jocelyn Silvester shared several considerations for using histologic assessments in clinical practice to monitor pediatric patients with CeD. Assessing mucosal recovery is not routinely performed in pediatric patients on a GFD; however, a follow-up biopsy may be useful for patients with new or ongoing symptoms, persistently elevated serology, or comorbidities assessed by routine follow-up biopsies (eg, eosinophilic esophagitis).5Leonard M.M. Weir D.C. DeGroote M. et al.Value of IgA tTG in predicting mucosal recovery in children with celiac disease on a gluten-free diet.J Pediatr Gastroenterol Nutr. 2017; 64: 286-291Crossref PubMed Scopus (49) Google Scholar Defining histologic improvement in clinical trials can be challenging because pediatric patients do not routinely undergo repeat biopsies, and the reporting of histology in clinical practice tends to be less rigorous than that in clinical trials. Dr Marie Robert provided a pathologist’s perspective on histologic assessment in CeD. Several different classification systems (eg, Marsh-Oberhuber, Corazza and Vilanaci, Ensari) are used to assess the underlying disease state in CeD; however, no system is widely accepted for use in clinical trials at this time. Ideally, clinical trials should collect histologic data in a variety of ways to maximize the scientific gain. Because intraepithelial lymphocyte recovery may lag behind normalization of villi, the villous architecture could be dissociated from intraepithelial lymphocyte counts. Standardizing the approach to histologic scoring and tissue handling, including biopsy location and number and fixation and orientation of samples, is important for clinical trials. Using centralized laboratories may reduce variability. Panelists discussed that performing follow-up biopsies to evaluate histologic improvement in patients with an active disease may be reasonable after 6–12 months of treatment in a trial (and in another 1–2 years to assess for more-complete healing); however, evaluating histologic changes after a shorter time may be practical after a gluten challenge. There was consensus on the importance of relying on well-oriented samples and a standardized process for histologic scoring. The clinicians on the panel appreciated the importance of therapies that can improve both patient symptoms and the underlying intestinal damage. Additionally, patients may be willing to undergo endoscopies in clinical trials if they understand how the data may inform the results of the trial and advance the science; education is part of the role of trial investigators. FDA described that appropriate use of extrapolation of efficacy data to a pediatric population from adequate, well-controlled studies in adults can promote timely access to safe and effective therapies for pediatric patients. The ability to extrapolate is based on the quality, quantity, and relevance of the adult efficacy data to the target pediatric population and whether the available data support the assumptions of similarities in the disease and treatment response between the 2 populations. The degree of confidence in the assumptions dictates what additional pediatric data are needed. Planning for pediatric trials early helps to ensure that certain design elements are incorporated into the adult program to facilitate extrapolation of efficacy for the pediatric program. Dr Maureen Leonard presented the clinical manifestations, natural history, and unmet needs of pediatric CeD. Pediatric manifestations of CeD include short stature, delayed puberty, dental enamel defects, and behavioral changes.6Jericho H. Sansotta N. Guandalini S. Extraintestinal manifestations of celiac disease: effectiveness of the gluten-free diet.J Pediatr Gastroenterol Nutr. 2017; 65: 75-79Crossref PubMed Scopus (82) Google Scholar,7Nurminen S. Kivelä L. Huhtala H. et al.Extraintestinal manifestations were common in children with coeliac disease and were more prevalent in patients with more severe clinical and histological presentation.Acta Paediatr. 2019; 108: 681-687Crossref PubMed Scopus (20) Google Scholar Initiation of a GFD is the treatment irrespective of the presentation at diagnosis, disease duration, symptoms, or age. There are distinct challenges as patients progress through childhood with less parental control of their diet, necessitating alternative treatment options. FDA shared the regulatory perspective on assessing clinical benefits in pediatric trials. Clinical benefit is defined as a favorable effect of a treatment on a meaningful aspect of how a patient feels, functions, or survives. Clinical outcome assessments (COAs), such as patient-reported outcomes, are used to assess how a patient feels or functions.8FDAGuidance for industry; patient-reported outcome measures: use in medical product development to support labeling claims.2009https://www.fda.gov/regulatory-information/search-fda-guidance-documents/Date accessed: December 2, 2023Google Scholar,9FDAPatient-focused drug development guidance series for enhancing the incorporation of the patient's voice in medical product development and regulatory decision making.2020Google Scholar COAs should be well-defined and reliable in their specific context of use (“fit-for-purpose”) to support regulatory decision-making. Evidence should be provided to support content validity, measurement properties, and interpretation of meaningful changes. Interpreting meaningful changes in COA scores involves using quantitative anchor-based scoring methods and qualitative evidence (eg, results of exit interviews with patients or caregivers). A patient diagnosed with CeD at 11 years of age provided his perspective on living with CeD. He experienced abdominal pain, nausea, vomiting, and diarrhea. Fortunately, strict adherence to a GFD relieved his symptoms; however, the potential for inadvertent gluten exposure hampers social activities, including traveling and eating outside of the home. The possibility of new therapies to complement a GFD brings hope. Panelists generally considered symptoms between the adult and pediatric CeD populations to be similar, but not identical, and discussed that since CeD in the 2 populations has a common pathogenesis, the potential drug targets could be the same. Advances toward identifying a fit-for-purpose COA for pediatric CeD could move pediatric drug development forward. Dr Joseph Murray provided an overview on using a prescribed gluten challenge in clinical practice, primarily as part of the initial diagnosis in patients on a GFD, and contraindications to performing a gluten challenge (eg, history of anaphylaxis to wheat or gluten, severe neurologic manifestations of CeD).3Rubio-Tapia A. Hill I.D. Kelly C.P. et al.ACG clinical guidelines: diagnosis and management of celiac disease.Am J Gastroenterol. 2013; 108 (quiz 677): 656-676Crossref PubMed Scopus (1153) Google Scholar,10Leffler D. Schuppan D. Pallav K. et al.Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.Gut. 2013; 62: 996-1004Crossref PubMed Scopus (167) Google Scholar The histologic changes due to gluten exposure likely depend on the dose and duration of exposure. In clinical practice, the follow-up of patients with CeD is based on general expectations that symptoms tend to resolve in 1–3 months and serology levels fall substantially in about 6 months and are often negative at 1 year.3Rubio-Tapia A. Hill I.D. Kelly C.P. et al.ACG clinical guidelines: diagnosis and management of celiac disease.Am J Gastroenterol. 2013; 108 (quiz 677): 656-676Crossref PubMed Scopus (1153) Google Scholar,11Murray J.A. Watson T. Clearman B. et al.Effect of a gluten-free diet on gastrointestinal symptoms in celiac disease.Am J Clin Nutr. 2004; 79: 669-673Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar Repeat biopsy after 1–2 years may be performed in adults but is not mandatory in all patients doing well on a GFD without an increased risk of complications. Dr Jason Tye-Din summarized the dose and duration of gluten exposure that elicit clinical signs and symptoms and changes in histology based on several published studies of varying design on the effects of gluten challenge in CeD.10Leffler D. Schuppan D. Pallav K. et al.Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.Gut. 2013; 62: 996-1004Crossref PubMed Scopus (167) Google Scholar,12Kelly C.P. Murray J.A. Leffler D.A. et al.TAK-101 Nanoparticles induce gluten-specific tolerance in celiac disease: a randomized, double-blind, placebo-controlled study.Gastroenterology. 2021; 161: 66-80.e8Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 13Lähdeaho M.L. Mäki M. Laurila K. et al.Small-bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease.BMC Gastroenterol. 2011; 11: 129Crossref PubMed Scopus (57) Google Scholar, 14Leonard M.M. Silvester J.A. Leffler D. et al.Evaluating responses to gluten challenge: a randomized, double-blind, 2-dose gluten challenge trial.Gastroenterology. 2021; 160: 720-733.e8Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 15Sarna V.K. Skodje G.I. Reims H.M. et al.HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge.Gut. 2018; 67: 1606-1613Crossref PubMed Scopus (47) Google Scholar, 16Taavela J. Viiri K. Popp A. et al.Histological, immunohistochemical and mRNA gene expression responses in coeliac disease patients challenged with gluten using PAXgene fixed paraffin-embedded duodenal biopsies.BMC Gastroenterol. 2019; 19: 189Crossref PubMed Scopus (15) Google Scholar Histologic changes in the ratio of villous height to crypt depth appear to occur on a continuum from healing to injury. Understanding the baseline disease activity is important, including how the baseline status will be factored into the trial design. Additionally, symptoms are not always caused by gluten (eg, functional gastrointestinal disorders occur frequently in patients with CeD and symptoms can be triggered by nongluten components of food).17Roncoroni L. Bascuñán K.A. Doneda L. et al.Correction: Roncoroni, L. et al. A low FODMAP gluten-free diet improves functional gastrointestinal disorders and overall mental health of celiac disease patients: a randomized controlled trial.Nutrients. 2018; 10 (Nutrients 2019;11): 1023Crossref PubMed Scopus (33) Google Scholar Moreover, symptoms that patients expect to have from gluten exposure may not be the symptoms that they experience during a gluten challenge. Therefore, the patient-reported outcome measures should be designed to capture the symptoms that are driven by gluten exposure. A standardized approach to the gluten challenge is needed to minimize heterogeneity and yield interpretable results to advance drug development. Dr Daniel Leffler provided the industry perspective on the role of gluten challenges in clinical trials. While gluten exposure causes symptoms, elevations in celiac serologies, and histologic changes, a short exposure should not increase the risk of long-term complications, or cause permanent intestinal damage or ongoing symptoms after the trial is complete. Gluten challenges are used in proof-of-concept and dose-finding studies assessing therapeutic protection against gluten-induced disease activation. Simulated inadvertent gluten exposure can be used to reduce trial effects, wherein some patients may adhere more strictly to a GFD during a trial. Operational challenges for studies utilizing gluten include (1) slower enrollment due to concerns with gluten exposure; (2) potential for missed gluten doses that may confound the results; (3) dropouts due to gluten-related symptoms; and (4) lack of standardization of gluten amount and form. When and how to use gluten in trials warrants careful consideration. During the discussion, panelists discussed that introducing gluten, whether in the context of a formal challenge or as intermittent exposure, could increase the likelihood of demonstrating efficacy in certain circumstances. Patient hesitancy to enroll in clinical trials with gluten challenges could be addressed through improved education on the purpose of the gluten challenge and benefits and risks of trial participation. Panelists also highlighted the importance of differentiating gluten-driven symptoms from those that arise from other causes. It can be challenging to differentiate symptoms that are gluten-driven from those due to ongoing enteropathy in patients with CeD, as patients with total villous atrophy may experience symptoms from other foods. There remains a need for pharmacologic therapies to treat CeD. Prospective collection of data on various outcome measures that assess different histologic features of CeD in clinical trials may advance the field. Pediatric patients with CeD generally have similar symptoms to adult patients; however, intestinal inflammation may improve earlier and possibly more completely than adults. There are other unique pediatric considerations that should be factored into designing clinical trials. Although extrapolation of efficacy from adult data may be possible, the extent to which pediatric trials can rely on adult efficacy data warrants further discussion. When necessary, a gluten challenge should be incorporated to produce interpretable results that cannot be obtained by other means and designed to ensure patient safety. Ongoing collaboration among academia, industry, patients, and regulatory agencies is critical to move the field forward. The authors thank Drs Benjamin Lebwohl, Jessica Lee, and Julie Beitz for reviewing the manuscript and Monika Deshpande for drafting the manuscript. The authors acknowledge the workshop planners representing the following organizations: the American College of Gastroenterology, American Gastroenterological Association, and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

Mechanistic modeling of drug products applied to the skin: A workshop summary report.

The development of a generic drug product involves demonstrating that there is no significant difference in the rate and extent to which the active ingredient becomes available at the site of action, relative to the reference listed drug product. This remains challenging for many locally acting topical dermatological products because measuring the concentration of the active ingredient at the site of action in the skin may not be straightforward, and, in most instances, there are no established relationships between skin and plasma pharmacokinetic profiles. In recent years, the Office of Generic Drugs of the US Food and Drug Administration (FDA) established scientific research programs with the goal of enhancing patient access to high quality, affordable topical dermatological generics. A key strategy of these research programs was to leverage modeling and simulation methodologies that accelerate the development of these generics by facilitating alternative bioequivalence approaches for dermatological drug products. This report summarizes relevant insights and discussions from a 2021 FDA public workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," which illustrated how mechanistic modeling and simulation approaches can be utilized (and have been used) to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA.

Study protocol for a phase 1/2, single-centre, double-blind, double-dummy, randomized, active-controlled, age de-escalation trial to assess the safety, tolerability and immunogenicity of a measles and rubella vaccine delivered by a microneedle patch in healthy adults (18 to 40 years), measles and rubella vaccine-primed toddlers (15 to 18 months) and measles and rubella vaccine-naïve infants (9 to 10 months) in The Gambia [Measles and Rubella Vaccine Microneedle Patch Phase 1/2 Age De-escalation Trial]

BackgroundNew strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants.MethodsThis is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18–40 years] followed by 120 toddlers [15–18 months] and 120 infants [9–10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee.DiscussionThis trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination.Trial registrationPan-African Clinical Trials Registry 202008836432905. ClinicalTrials.govNCT04394689

Physiologically‐Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations

Physiologically-based pharmacokinetic (PBPK) modeling and simulation provides mechanism-based predictions of the pharmacokinetics of an active ingredient following its administration in humans. Dermal PBPK models describe the skin permeation and disposition of the active ingredient following the application of a dermatological product on the skin of virtual healthy and diseased human subjects. These models take into account information on product quality attributes, physicochemical properties of the active ingredient and skin (patho)physiology, and their interplay with each other. Regulatory and product development decision makers can leverage these quantitative tools to identify factors impacting local and systemic exposure. In the realm of generic drug products, the number of US Food and Drug Administratioin (FDA) interactions that use dermal PBPK modeling to support alternative bioequivalence (BE) approaches is increasing. In this report, we share scientific considerations on the development, verification and validation (V&V), and application of PBPK models within the context of a virtual BE assessment for dermatological drug products. We discuss the challenges associated with model V&V for these drug products stemming from the fact that target-site active ingredient concentrations are typically not measurable. Additionally, there are no established relationships between local and systemic PK profiles, when the latter are quantifiable. To that end, we detail a multilevel model V&V approach involving validation for the model of the drug product of interest coupled with the overall assessment of the modeling platform in use while leveraging in vitro and in vivo data related to local and systemic bioavailability.

Art Of Designing A Novel Drug Formulation With Patient In Mind

Patients, ultimately consumer in traditional means, and health care systems will not accept new drug that fail to conform to consumer preferences or fail to deliver expected results in real world use because it will lead to increase the lack of patient adherence and that will ultimately cost to Pharmaceutical Industries. If research driven pharmaceutical industries still remain unengaged with patients during the Novel Drug Formulation development, then they are at risk of misinterpreting the need of patient that ultimately likely to have significant financial ramifications. Therefore, developing a therapy that ensure improvement in the lives of patients and their adherence to the therapy should be first rooted through a firm understanding of all aspects of the challenges faced by patients in their daily lives, during treatment, their needs and trade-offs they are willing to make to gain relief prior to conceptualisation of product design, research prioritization, product development, trial design, regulatory approval, access, reimbursement, and treatment decisions.