Medical Product Development Research Articles

The Potential of Disease Progression Modeling to Advance Clinical Development and Decision Making.

While some model-informed drug development frameworks are well recognized as enabling clinical trials, the value of disease progression modeling (DPM) in impacting medical product development has yet to be fully realized. The Clinical Trials Transformation Initiative assembled a diverse project team from across the patient, academic, regulatory, and industry sectors of practice to advance the use of DPM for decision making in clinical trials and medical product development. This team conducted a scoping review to explore current applications of DPM and convened a multi-stakeholder expert meeting to discuss its value in medical product development. In this article, we present the scoping review and expert meeting output and propose key questions that medical product developers and regulators may use to inform clinical development strategy, appreciate the therapeutic context and endpoint selection, and optimize trial design with disease progression models. By expanding awareness of the unique value of DPM, this article does not aim to be technical in nature but rather aims to highlight the potential of DPM to improve the quality and efficiency of medical product development.

Linking for Impact: Enhancing Linked Data Infrastructure to Meet Clinical Trials Sector Needs

BackgroundAustralia possesses valuable population health data, yet its potential for advancing medical product development remains largely untapped. Transformative growth in the use of linked data in clinical trials will support Australia’s therapeutic development sector to be more responsive in the development of new therapeutics and the monitoring and surveillance of their safety and effectiveness. MethodsWe conducted interviews with clinical trialists and data linkage experts to understand the current state and awareness of linked data within the clinical trials sector, identify existing pain points in the linkage process, and explore opportunities for improving visibility and access for the clinical trials sector. Researchers represented all stages of the medical product development pipeline and had a diverse range of experience with linked data. ResultsInterviews revealed numerous barriers hindering the clinical trials sector from effectively using linked data, limiting its impact. Barriers included a lack of awareness, the complexity of the application and approval process, and lengthy delays in accessing data. Participants readily recognised several ways that linkage of real-world data could be applied to their work in clinical trials, with pre-recruitment data, measurements of primary and secondary endpoints, and health economic analysis being the most consistently noted use cases. ConclusionTo optimise the use of linked data to support clinical trials and medical product development in Australia, increased awareness among the therapeutic development sector regarding available real-world data and its potential is needed urgently. Lowering the barriers to accessing linked data will enhance health services and patient outcomes across Australia.

Linking for Impact: Enhancing Linked Data Infrastructure to Meet Clinical Trials Sector Needs

BackgroundAustralia possesses valuable population health data, yet its potential for advancing medical product development remains largely untapped. Transformative growth in the use of linked data in clinical trials will support Australia’s therapeutic development sector to be more responsive in the development of new therapeutics and the monitoring and surveillance of their safety and effectiveness. MethodsWe conducted interviews with clinical trialists and data linkage experts to understand the current state and awareness of linked data within the clinical trials sector, identify existing pain points in the linkage process, and explore opportunities for improving visibility and access for the clinical trials sector. Researchers represented all stages of the medical product development pipeline and had a diverse range of experience with linked data. ResultsInterviews revealed numerous barriers hindering the clinical trials sector from effectively using linked data, limiting its impact. Barriers included a lack of awareness, the complexity of the application and approval process, and lengthy delays in accessing data. Participants readily recognised several ways that linkage of real-world data could be applied to their work in clinical trials, with pre-recruitment data, measurements of primary and secondary endpoints, and health economic analysis being the most consistently noted use cases. ConclusionTo optimise the use of linked data to support clinical trials and medical product development in Australia, increased awareness among the therapeutic development sector regarding available real-world data and its potential is needed urgently. Lowering the barriers to accessing linked data will enhance health services and patient outcomes across Australia.

Artificial Intelligence in Military Medicine.

Artificial intelligence (AI) has garnered significant attention for its pivotal role in the national security and health care sectors. However, its utilization in military medicine remains relatively unexplored despite its immense potential. AI operates through evolving algorithms that process extensive datasets, continuously improving accuracy and emulating human learning processes. Generative AI, a type of machine learning, uses algorithms to generate new content, such as images, text, videos, audio, and computer code. These models employ deep learning to encode simplified representations of training data and generate new work resembling the original without being identical. Although many AI applications in military medicine are theoretical, the U.S. Military has implemented several initiatives, often without widespread awareness among its personnel. This article aims to shed light on two resilience initiatives spearheaded by the Joint Artificial Intelligence Center, which is now the Chief Digital and Artificial Intelligence Office. These initiatives aim to enhance commanders' dashboards for predicting troop behaviors and develop models to forecast troop suicidality. Additionally, it outlines 5 key AI applications within military medicine, including (1) clinical efficiency and routine decision-making support, (2) triage and clinical care algorithms for large-scale combat operations, (3) patient and resource movements in the medical common operating picture, (4) health monitoring and biosurveillance, and (5) medical product development. Even with its promising potential, AI brings forth inherent risks and limitations that require careful consideration and discussion. The article also advocates for a forward-thinking approach for the U.S. Military to effectively leverage AI in advancing military health and overall operational readiness.

FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time.

The Food and Drug Administration's (FDA's) breakthrough therapy designation (BTD) program was created to increase patient access to safe and effective therapies by supporting the efficient clinical development of qualifying, clinically meaningful therapies. Using a new data set of key development milestones for drugs approved between 2006 and 2020, including both BTD drugs and a set of comparator drugs identified by FDA experts, we estimated the BTD program's impact on time spent in late-stage clinical development, measured as the elapsed time between a drug's end-of-Phase-II meeting with regulators and its approval for marketing. Our analysis suggests that the BTD program lowers late-stage clinical development time by 30percent. Our findings provide insight into future regulatory and innovation policies aimed at driving efficiency in medical product development to ensure timely patient access to the most clinically meaningful therapies.

Key Opinion Leaders' Interviews to Inform the Future of Benefit-Risk Planning in the Medical Total Product Life Cycle of Global Pharmaceutical and Medical Device Organizations.

Key opinion leader (KOL) interviews were conducted by the Benefit-Risk Assessment Planning(BRAP) Taskforce to seek expert opinion mainly from industry and regulatory bodies, about the current status and future direction of benefit-risk assessment (BRA) planning in the lifecycle of medical product development. The findings from these interviews are intended to help communication concerning planning for BRA between industry and regulators and shape future guidance. Key opinion leader interviews consisted of 5 questions related to BRA planning, which were administered to volunteers (mainly clinicians and statisticians) within a pool of experienced pharmaceutical and medical device professionals representing academia, industry, regulatory agenciesand a patient group. The interviewees' responses to the 5 questions were summarized. To analyze the qualitative data, a Coding System was developed to label themes arising from the interviews. The key findings from the interviews were summarized into a Master Template. A quantitative analysis based on descriptive statistics was also conducted. Of the 27 interviewees, there were 11 professionals from regulatory agencies, 11 from industry, 4 from academia and 1 from a patient advocacy group. Key findings based on the comments provided by 48% of the interviewees indicated the need of incorporating BRA into other (e.g., existing) processes with the importance of alignment between processes being stressed in the comments provided by 59% of the interviewees. Commencing BRA early in the product lifecycle was emphasized in comments provided by 44% of the interviewees. Among other needs identified were an appropriate contextualization of benefits and risks (based on comments provided by 41% of interviewees) through adoption of an integrated approach with structured support by regulatory agencies and a need for understanding the audience with better communication of benefit-risk (BR) among all stakeholders (based on comments provided by 44% of the interviewees). Almost all comments provided by interviewees (96%) highlighted the importance of utilizing patient experience/preference to guide new product development and BRA. Comments provided by 74% of the interviewees expressed the need to understand patient tolerance for risk and trade-offs, with a majority (78%) of interviewees highlighting how to gather information, and 59% stressing the need for the selection and development of appropriate methodologies as important considerations for enhancing the quality and relevance of the data collected from patients. Interviewees indicated that BRA should commence early in the medical product development and inform decision-making throughout the product lifecycle. Better planning and integration of BRA into existing processes within industry would be valuable. The importance of incorporating the patient voice into BRA and medical product development was emphasized. Other key findings from the KOL interviews included a need for improved communication of BR information, and establishment of methodologies for performing BRA and soliciting patient input.

Adaptively leverage multiple real-world data sources for treatment effect estimation based on similarity

ABSTRACT The incorporation of real-world data (RWD) into medical product development and evaluation has exhibited consistent growth. However, there is no universally adopted method of how much information to borrow from external data. This paper proposes a study design methodology called Tree-based Monte Carlo (TMC) that dynamically integrates patients from various RWD sources to calculate the treatment effect based on the similarity between clinical trial and RWD. Initially, a propensity score is developed to gauge the resemblance between clinical trial data and each real-world dataset. Utilizing this similarity metric, we construct a hierarchical clustering tree that delineates varying degrees of similarity between each RWD source and the clinical trial data. Ultimately, a Gaussian process methodology is employed across this hierarchical clustering framework to synthesize the projected treatment effects of the external group. Simulation result shows that our clustering tree could successfully identify similarity. Data sources exhibiting greater similarity with clinical trial are accorded higher weights in treatment estimation process, while less congruent sources receive comparatively lower emphasis. Compared with another Bayesian method, meta-analytic predictive prior (MAP), our proposed method’s estimator is closer to the true value and has smaller bias.

International Comparison of Qualification Process for Medical Product Development Tools

IntroductionQualification of medical product evaluation tools is underway in the United States, Europe, and Japan to reflect the advancements in the basic science of medical products. In Europe and the U.S., Guidance of Guidances (GoG) policies that clarify regulators’processes, tasks, and methods of sponsor involvement are adopted to issue tool guidance. However, in Japan, a non-GoG type policy focusing on supporting the research and development for tools without defining a tool guidance-making process has been adopted.MethodsIn this study, an analytical framework for the lifecycle of development tools was constructed, including pre- and post-tool qualification processes, to compare the two above-mentioned approaches. For this study, Japanese cases were selected as experimental cases, whereas Western cases served as controls. The progress of tool qualification and composition of deliverables were analyzed.Results and ConclusionsIt was indicated that in the GoG type policy, in which processes are defined, and involvement methods are clarified, tool qualification can progress more smoothly than in a non-GoG type policy. This policy indicates that deliverables may have a consistent composition. Contrastingly, GoG-type policies alone present challenges in connecting upstream tools for R&D support.

Tepid Uptake of Digital Health Technologies in Clinical Trials by Pharmaceutical and Medical Device Firms.

Digital health technologies (DHTs) can enable more patient-centric therapeutic development by generating evidence that captures how patients feel and function, enabling decentralized trial designs that increase participant inclusivity and convenience, and collecting and structuring patient-generated data for regulators to use in approval decisions alongside traditional clinical outcomes. Although a growing body of evidence has documented increasing use of DHTs in clinical trials overall, the use of DHTs in clinical trials supporting medical product development is unclear; here, we quantify the use of DHTs in clinical trials sponsored by pharmaceutical and medical device firms. Despite interest from pharmaceutical and medical device manufacturers in DHTs, we find tepid uptake of DHTs in trials by these sponsor types over time. Further, to date, these sponsors have most frequently used conventional, hardware-based technologies that have been available for many years (e.g., Holter monitors and glucose meters) rather than newer activity monitors, mobile apps, and other online-based tools that are frequently used by non-industry sponsors. Considering the recent and evolving nature of regulatory guidance around DHT use in clinical trials, our findings suggest that organizations pursuing product development still appear hesitant to incorporate DHTs in trials that provide the most critical evidence for regulatory review and impact how new products are used. This suggests there are likely additional opportunities for sponsors of regulated trials to incorporate (more) DHTs and patient-centric endpoints into product development clinical trials. However, additional regulatory clarity and efforts to reduce operational barriers may be needed in order to more fully capture these opportunities.

Nutrient composition analysis and practical functional application of Morchella esculenta

Morels ranks first among the world’s four famous bacteria.Morels is a kind of rare edible and medicinal fungi that can be cultivated artificially in recent years. It has a variety of nutrients, has rich cultural deposits and a long history in Europe and China, and has high value in edible and medicinal health care. Morels is widely distributed, the growth environment conditions are harsh, the number is relatively rare, the individual is small, the price is higher, and there is a higher status in fungi, with the shape like the belly named. At present, the development and utilization of morels has not reached to a good level. This paper expounds the nutritional composition, edible value and medicinal value of mochella as a whole to further deepen people’s cognition and understanding of mochella. And summarizes the development status and existing problems of mochella industry, in order to provide more theoretical reference for mochella in medical care and product development.

Easing the data sharing burden: perspectives and principles to successfully leverage AD data repositories, infrastructures and functionality

AbstractCritical Path Institute (C‐Path) is a nonprofit organization that brings together patient groups, academic institutions, the pharmaceutical industry and regulatory agencies from around the world to improve public health. C‐Path provides the legal, scientific, and regulatory infrastructure to generate a unique neutral environment for medical product development, supported by more than a decade of experience in data standards development, platform development and hosting, patient‐level data privacy stewardship, data platform security, and controlled access methodology. The Critical Path for Alzheimer’s Disease (CPAD) is a pre‐competitive consortium that aims to promote, support, and manage a diverse source and format of data and facilitate knowledge sharing from the Alzheimer disease (AD) drug development community. The CPAD database currently contains 65 clinical trials and observational studies, with over 93,000 individual anonymized patient‐level records, with global access to many datasets through the C‐Path Online Data Repository (CODR). The unparalleled breadth, depth and wealth of data will enable us to discover yet‐to‐be identified unmet needs and unanswered questions. Further, CODR is interoperable with the Global Alzheimer’s Association Interactive Network (GAAIN), Vivli and other data platforms. The secure and neutral data sharing framework of CPAD has resulted in the development of several regulatory‐grade tools that help optimize drug development and accelerate bringing new therapies to patients in need. Sufficient case examples of successful data sharing are now available and should inform and encourage future data sharing initiatives.

Determining Commonalities in the Experiences of Patients with Rare Diseases: A Qualitative Analysis of US Food and Drug Administration Patient Engagement Sessions.

Rare diseases are estimated to affect more than one in ten Americans. However, most patients with a rare disease face significant emotional, physical, and social challenges. To better understand the burden of disease and unmet needs, the US Food and Drug Administration (FDA) conducts and supports multiple patient engagement platforms. We analyzed summaries from these discussions to identify commonalities among patients with disparate rare diseases, the results of which could inform priorities for cross-disease policies and medical product development. We conducted a qualitative analysis of patient engagement session summaries to investigate shared experiences across rare diseases. Cross-disease similarities were identified within four dimensions: product development/regulatory, clinical/physical, social/psychological, and economic/financial. Summaries from 29 rare diseases were included in our analyses. Within the product development/regulatory dimension, we observed that patients and caregivers across rare diseases shared the desire for development of medical products that cured their disease or improved their overall quality of life. In the clinical/physical dimension, we found that patients had numerous common symptoms, including pain and fatigue. In the social/psychological dimension, we observed significant negative impact on mental health. Within the economic/financial dimension, patients and caregivers shared that disease burden caused significant financial hardships. We found remarkable similarities among patients with rare diseases across all four dimensions. Our results indicate that, even among rare diseases with diverse etiologies, patients share numerous commonalties due to their diseases: a lack of effective treatment options, certain physical symptoms, mental health challenges, and financial concerns.

Co-creation of the Global Patient Experience Data Navigator: a multi-stakeholder initiative to ensure the patient voice is represented in health decision-making

BackgroundPutting patients’ needs and priorities at the forefront of healthcare initiatives and medical product development is critical to achieve outcomes that matter most to patients. This relies on the integration of early, meaningful patient engagement (PE) to learn what is important to patients, and collection of representative patient experience data (PXD). The increased number of PE/PXD efforts across global regulatory, health technology assessment, and healthcare systems is an important step forward to deliver improved health outcomes for patients. However, these initiatives are fragmented and lack integration, which is necessary to maximize efforts and reduce burden on patients. To overcome these challenges, the Global Patient Experience Data Navigator has been co-created by Patient Focused Medicines Development to provide practical resources that can facilitate and optimize PXD generation, collection, analysis, and dissemination for patient benefit and aims to be applicable across all therapeutic areas for all stakeholders.MethodsCo-creation of the Navigator took place through an iterative process of validation and formalization driven by a diverse, multi-stakeholder working group with individuals who have varying knowledge/experience in PE/PXD.ResultsA series of workshops took place to conduct a gap analysis, develop a taxonomy model, and integrate existing frameworks. The collective insights led to the development of the Navigator consisting of four specific tools in the form of downloadable templates, which can be used to: (1) prioritize outcomes that matter most to patients and their caregivers; (2) select appropriate measurement methods for these outcomes; (3) identify when and why PXD is used throughout the product development cycle for each stakeholder; (4) identify when and why PXD is used throughout the healthcare process for each stakeholder. A public consultation was carried out to collect user feedback before the Navigator was made publicly available in December 2022.ConclusionTo our knowledge, the Global Patient Experience Data Navigator is the only publicly available toolkit developed with a multi-stakeholder and disease-agnostic approach providing taxonomically grouped resources to optimize the collection and collation of PXD for patient benefit. Future work will aim to further engage patients by adding a PE dimension to the Navigator.

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.

End Point Considerations for Clinical Trials in Enteric Hyperoxaluria.

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration-approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include ( 1 ) an irreversible loss of kidney function as a surrogate for progression to kidney failure, ( 2 ) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, ( 3 ) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and ( 4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration.

Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.

The United States Food and Drug Administration (FDA) regulatory response to combat neglected tropical diseases (NTDs): A review.

The availability and accessibility of safe and effective drugs, vaccines, and diagnostics are essential to reducing the immense global burden of neglected tropical diseases (NTDs). National regulatory authorities, such as the United States Food and Drug Administration (FDA), play an essential role in this effort to ensure access to safe and effective medical products by working within a set of legal frameworks and regulatory functions. However, medical product development for NTDs remains neglected, as combating NTDs is not a viable commercial market for pharmaceutical companies. To spur research and development (R&D) of NTD products, the US government has authorized various programs and policies to engage pharmaceutical companies, many of which provide FDA with the legal authority to implement NTD programs and pathways. Thus, this review provides a clear overview of the various regulatory pathways and programs employed by the FDA to increase the availability of NTD drugs, vaccines, and diagnostics. The review assesses the available information on various regulatory considerations and their impact on NTD product development as a first step in estimating the importance of such programs. Next, findings related to currently approved NTD products through these programs are discussed. Lastly, gaps in NTD R&D are identified and suggestions on how to address these are presented. The available data shows that while such incentive programs are factored into companies' decisions to pursue NTD R&D, approved products for NTDs remains vastly insufficient. Most approved products that utilize these NTD regulatory pathways and programs are overwhelmingly for tuberculosis and malaria-both of which are not considered NTDs by the World Health Organization (WHO). Dedicated efforts are needed to facilitate and accelerate NTD product including employing multiple incentive programs, regular assessment of such programs, and leveraging on public-private partnerships.

Establishment of multicenter COVID-19 therapeutics preclinical test system in Republic of Korea

Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.

Editor’s Note: Special Section on a Collection of Articles on Opportunities and Challenges in Utilizing Real-World Data for Clinical Trials and Medical Product Development

Editor’s Note: Special Section on a Collection of Articles on Opportunities and Challenges in Utilizing Real-World Data for Clinical Trials and Medical Product Development

Embedded Sensor Systems in Medical Devices: Requisites and Challenges Ahead.

The evolution of technology enables the design of smarter medical devices. Embedded Sensor Systems play an important role, both in monitoring and diagnostic devices for healthcare. The design and development of Embedded Sensor Systems for medical devices are subjected to standards and regulations that will depend on the intended use of the device as well as the used technology. This article summarizes the challenges to be faced when designing Embedded Sensor Systems for the medical sector. With this aim, it presents the innovation context of the sector, the stages of new medical device development, the technological components that make up an Embedded Sensor System and the regulatory framework that applies to it. Finally, this article highlights the need to define new medical product design and development methodologies that help companies to successfully introduce new technologies in medical devices.