Therapeutic innovation & regulatory science最新文献

Digital therapeutics (DTx) are emerging as a transformative approach in healthcare, offering software-driven, evidence-based interventions for the prevention, management, and treatment of medical conditions such as chronic diseases, mental health disorders, and substance use disorders. Unlike general wellness applications or traditional digital health tools, DTx products are subject to rigorous clinical validation and regulatory scrutiny, ensuring their safety, efficacy, and integration into clinical practice. This manuscript explores the defining characteristics of digital therapeutics, differentiating them from other digital health technologies, and examines their role in patient-centric care. It further investigates global regulatory frameworks, including those in the United States, Europe, and Korea, highlighting the need for harmonized guidelines and structured approval pathways. The paper also discusses the importance of robust clinical trial design, validation methods, and post-market surveillance to support the adoption and reimbursement of DTx. Real-world examples such as EndeavorRx^®, reSET, DaylightRx and Somryst illustrate the growing potential of DTx to reshape medical treatment. As digital therapeutics continue to evolve, this review emphasizes the critical need for regulatory agility, evidence-based implementation, and collaborative efforts to fully realize their benefits within modern healthcare systems.

Artificial intelligence (AI) and big data are increasingly applied in drug regulation and have demonstrated significant potential worldwide. The U.S. Food and Drug Administration (FDA) has developed a relatively comprehensive approach through strategic frameworks, regulatory guidelines, and pilot programs. The European Medicines Agency (EMA) has promoted AI adoption via the Big Data Task Force, DARWIN EU^®, and a multi-annual work plan, while Japan, Canada, and other countries have also advanced relevant initiatives and strengthened international cooperation. In China, smart regulation has been incorporated into the "14th Five-Year Plan" and subsequent strategies, with progress in establishing national regulatory data platforms, pharmaceutical traceability systems, and pilot AI applications. Nevertheless, AI in drug regulation remains at an exploratory stage, facing challenges such as limited model reliability and interpretability, insufficient data standards and interoperability, regulatory gaps, and ethical as well as public trust concerns. Future progress will depend on strengthening regulatory standards, enhancing data governance, improving regulatory capacity, and deepening international collaboration to achieve more scientific, intelligent, and efficient drug regulation.

Background: Researchers of rare diseases affecting neurodevelopment struggle with concept and outcome assessment identification issues that are uniquely associated with developmental concepts but common across conditions. However, the potential to capitalize on the collective commonness of rare disease in order to achieve the large samples often required to create and validate clinical outcome assessments is insufficiently tapped. Identifying synergies in concepts of interest across conditions affecting neurodevelopment may accelerate clinical outcome assessment development for prioritized concepts. We conducted the first systematic review of patient focused drug development (PFDD) meeting reports, to identify concepts prioritized by patients and caregivers across conditions.

Methods: Sixteen reports on rare conditions affecting neurodevelopment were identified. The responses to two survey items, "top three most troublesome symptoms" and "top three ideal treatment targets," were coded into general concepts and the endorsement rates were aggregated across the conditions.

Results: Full consensus about any individual troublesome symptom or treatment target was rare for any condition. Three conditions had no concept that exceeded 30% endorsement. However, for 11 of the 16 conditions, at least 30% of the respondents endorsed the developmental concepts of Communication or Cognitive/Developmental as a most troublesome symptom and as an ideal treatment target.

Conclusions: This empirical support for the shared prioritization of developmental concepts across heterogeneous conditions is an important first step in unifying clinical outcome assessment development efforts to promote clinical trial readiness in rare disease.

Periodontal disease is a chronic inflammatory disorder that gradually destroys tooth-supporting tissues including the alveolar bone, periodontal ligament, and cementum. In recent years, interest has grown in repurposing metformin, a well-known oral antidiabetic drug, as an adjunct to periodontal therapy. Experimental studies have indicated that metformin can aid periodontal healing by promoting stem cell-driven regeneration, enhancing osteoblast activity, and reducing osteoclast-mediated resorption. Clinical trials have further reported that both systemic and local applications of metformin, when used alongside conventional non-surgical treatment, can improve probing depth, clinical attachment, and radiographic markers of bone recovery. However, the results remain inconsistent across study designs, dosage strategies, and delivery methods, and concerns about safety and long-term outcomes persist. This review examines the potential role of metformin in periodontal therapy, with a focus on its mechanisms of action, clinical and experimental evidence, and the current challenges of its use in periodontology. Overall, metformin shows promise as a host-modulatory and regenerative adjunct in periodontal therapy, warranting further large-scale clinical trials.

Background: Physician awareness of evidence about off-label uses of prescription drugs can affect prescribing decisions. We tested approaches to disclosing unsupportive data about off-label uses and assessed disclosure impact on perceptions and intentions.

Design: Primary care providers (PCPs) and oncologists viewed a brief report describing an off-label use of trazodone for insomnia (PCPs) or imiquimod for lentigo maligna (oncologists) and provided their perceptions of its Usefulness and Importance for prescribing decisions, and Intentions to search for additional information about the off-label use. We tested four variations (plus control) of a disclosure about the existence of unsupportive data for the off-label use: complete brief report (specific information about the off-label use), summary plus citation (specific information about the off-label use), citation (general information about the off-label use), and statement that other data may exist (general information about the off-label use).

Results: Physicians who read any disclosure about the existence of unsupportive data for the off-label use rated the information as more Important for prescribing decisions than those receiving only information about the off-label use (control) (p = 0.01). PCPs reported specific data disclosures were more Useful for prescribing decisions (p < 0.001) than less specific disclosures. Oncologists found all disclosures about unsupportive data Useful but those who read disclosures stating unsupportive data may exist reported greater Intention to search for additional information about the off-label use of the drug (p = 0.03). Frequent off-label prescribing was associated with lower ratings for information Importance for prescribing decisions for both groups (p < 0.05). Prescribing the drug previously was associated with lower ratings of information Importance and Usefulness for prescribing decisions among PCPs (p < 0.001) and greater Intention to search for additional information about the drug (p < 0.001) among oncologists.

Conclusions: Disclosures about unsupportive data for off-label uses are important and useful for prescribing decisions. Physicians who prescribe drugs for off-label uses more frequently or have prescribed the drug previously may discount the importance of the information. Tailoring the specificity of the disclosure to the needs of the audience may increase its effectiveness.

Background: In 2019, the US Food and Drug Administration (FDA) finalized guidance for designating interchangeable biosimilars requiring pre-approval phase III clinical trials to evaluate safety when reference and biosimilar formulations are interchanged. In June 2024, Draft FDA Guidance on interchangeability relaxes FDA approval criteria focusing on analytic rather than clinical findings. This study examines US trends in interchangeable biosimilar approvals between 2019 and 2025, manufacturer strategies, and regulatory timelines.

Methods: We used the FDA Purple Book archive (September 2025) to identify interchangeable biosimilars, associated Biologic License Application (BLA) numbers, manufacturers, reference products, and FDA approval dates. FDA submission dates were obtained from FDA approval letters. We analyzed trends by year, manufacturer, product, and product class to assess patterns in approval timing and strategy.

Results: Since 2020, the FDA has approved 26 interchangeable biosimilars, with 19 approved between January 2024 and September 2025. Six are adalimumab biosimilars. Manufacturers employed two strategies: concurrent submission for interchangeability (17 cases) or delayed pursuit (9 cases). Average approval timelines decreased from 798 days for applications dated in 2020 to 364 days for applications dated in 2024. All interchangeable biosimilars completed pre-approval switching studies.

Conclusions: Concurrent interchangeable designation is now the predominant regulatory pathway. The FDA June 2024 Draft Guidance, removing switching studies requirement for interchangeability might cut biosimilar development costs and development timelines. These changes, alongside provider and patient education, could enhance biosimilar uptake and reduce biologic drug costs.

Background: Options for patients to receive unauthorised medicines through compassionate use (CU) in Europe vary greatly. There are two CU pathways: cohort programmes, regulated uniformly by the Regulation across EU member states, and individual patient requests (IPRs) governed by the Directive. The latter allows member states to determine their own laws, resulting in heterogeneous regulatory requirements and challenges in operationalization. Consequently, patients may experience delays in accessing CU medicines depending on their country of residence. To compare CU availability across European countries and formulate recommendations for improvement, we analyzed 8,934 patient requests from 30 European countries.

Methods: An exploratory post-hoc analysis was conducted using pooled collaborative data from 8,934 patient requests provided by Merck KGaA, Novartis, Roche, and Sanofi, tracked from January 1, 2020 to April 30, 2023 across 30 countries. All requests with complete dates for submission, company approval, relevant Ethics Committees or Health Authorities, and shipment dates were included.

Results: While internal company CU approval steps were found to be similar with a median approval time of 5 days (median interquartile range (IQR) of 1 (0-6) for cohorts; median IQR 4 (1-8) for IPRs), the time from company approval until shipment varied between cohort requests (median IQR 5 (1-16) days) and IPRs (median IQR 8 (1-22) days). Challenges experienced included differences in the use of CU terminologies, scope, settings, regulatory, and operational requirements.

Conclusion: Our findings indicate that differing national requirements across Europe lead to operational challenges and inter-country variability in CU implementation posing operational challenges for stakeholders, highlighting the need for improved harmonization.

In generic drug development, achieving bioequivalence followed by biowaivers for additional strengths are crucial for timely market entry. As per regulatory guidance, bioequivalence must be demonstrated for at least one strength-typically the highest, though sometimes a lower strength is chosen due to safety or tolerability concerns. Biowaivers for other strengths can be granted if specific criteria are met, that includes linear pharmacokinetics, same manufacturing process, proportional formulation composition, and similar dissolution profiles under defined conditions. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has introduced harmonized guidance, ICH M13B on biowaiver requirements for additional strengths. This guidance is currently under draft stage and shall be finalized soon. In this context, the present review article outlines the biowaiver criteria mentioned in the ICH M13B guidance and compares with that of requirements in European Medicines Agency (EMA) and the United States Food and Drug Administration (USFDA). This review highlights the advantages and challenges of ICH M13B at each stage: pharmacokinetic linearity, formulation proportionality, and dissolution similarity in comparison with existing requirements. Based on the assessment performed in the manuscript, there are challenges and advantages for additional strength biowaivers for USFDA and EMA. Because of the significant changes in dissolution similarity assessments, this review highlights the rationale, risk and benefit in comparison with previous criterion. Overall, this review article summarizes the current understanding and interpretation of ICH M13B against existing biowaiver criteria and provides a way forward for successful regulatory submissions for additional strength biowaivers.

Background: Post-marketing risk minimization measures for medicines, e.g. package leaflets and patient cards, aim to ensure that patients and health care professionals receive timely and relevant medicines safety information. The use of digital technologies for risk minimization is emerging but still limited, despite being central in patients' and healthcare professionals' information access. There is currently limited high-level, strategic discussion about the digitalization of additional risk minimization measures.

Objective: To elicit key expert stakeholders' future visions of digital risk minimization measures in the European Union and to explore possible policy and healthcare implications of future digital risk minimization technologies.

Methods: Co-design workshops were conducted in three EU member states with clinicians, industry representatives, regulators, health information technology developers, and legal experts. Workshop transcripts and visual products were analyzed thematically in two coding cycles.

Results: Digitalizing risk minimization measures will transform roles, responsibilities, and collaborations, as stakeholders revise their remits with digital strategies and forge new collaborations to ensure the effectiveness and sustainability of new digital solutions. Success depends on revised implementation pathways that reflect patients' and healthcare professionals' digital access to medicines information and the diverse information ecosystems across the EU. Patients may gain new roles as active data subjects through remote monitoring, raising new ethical and legal considerations.

Conclusion: Digital risk minimization in the EU offers opportunities for timely, personalized interventions but presents challenges in implementation complexity, healthcare professionals' workload, and patient ethics, warranting more focused policy deliberation and research on digital health.