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Policy Points Current medical device regulatory frameworks date back half a century and are ill suited for the next generation of medical devices that involve a significant software component. Existing Food and Drug Administration efforts are insufficient because of a lack of statutory authority, whereas international examples offer lessons for improving and harmonizing domestic medical device regulatory policy. A voluntary alternative pathway built upon two-stage review with individual component review followed by holistic review for integrated devices would provide regulators with new tools to address a changing medical device marketplace.

Vaccines are one component to the public health strategies to alleviate the COVID-19 pandemic. Hesitancy regarding COVID-19 vaccines in the United States has been problematic, which is not surprising given increasing overall vaccine hesitancy in recent decades. Most vaccines are administered during childhood years. Consequently, understanding hesitancy toward administration of vaccines in this age group may provide insight into possible interventions to reduce vaccine hesitancy. The present study analyzed a subset of over 130,000 public comments posted in response to a notice of meeting of the vaccine advisory group to the Food and Drug Administration. The meeting addressed whether to recommend Emergency Use Authorization (EUA) of the COVID-19 vaccine for children ages 5-11. The results of the study demonstrate that most comments opposed EUA and these comments were associated with statements that indicated misperceptions of risk. Findings provide interesting insights regarding the role of public comments generally but also suggest that the public participation process in notice and comment can be modified to serve as an intervention to align individual perceptions of risk more closely with evidence-based assessment of risk. In addition, the findings provide opportunities to consider strategies for public health messaging.

Mohs micrographic surgery (MMS) is the gold standard for removing basal cell carcinomas (BCCs) due to its ability to guarantee 100% margin evaluation through frozen section histopathology, offering the highest cure rate among current treatments. However, noninvasive imaging technologies have emerged as promising alternatives to clinical assessment for defining presurgical margins. This systematic scoping review examines the efficacy of these imaging modalities, focusing on those approved for clinical use by the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A systematic search of EMBASE, Scopus, PubMed, and the Cochrane Public Library databases identified 11 relevant studies out of 2123 records, encompassing 644 lesions across five imaging techniques. The findings suggest that dermoscopy, high‐frequency ultrasound (HFUS), optical coherence tomography (OCT), line‐field optical coherence tomography (LC‐OCT), and reflectance confocal microscopy (RCM) show potential in detecting BCC margins, which could enhance MMS by providing better preoperative planning, informing patients of expected defect size, aiding in reconstruction decisions, and reducing overall procedure costs. This review discusses the benefits and limitations of each technique, offering insights into how these innovations could influence the future of BCC management. Emerging imaging techniques could enhance MMS by improving BCC margin assessment and reducing costs. Their adoption will depend on price and ease of use. [ABSTRACT FROM AUTHOR]

Purpose: Oncology products often leverage accelerated approval program to seek earlier launches in the United States. Little is known about how the Food and Drug Administration (FDA) has been balancing evidence and access, and the factors that may characterize post-accelerated approval requirements. The present study aimed to obtain insights on how accelerated approval is determined by investigating the balance between pre-accelerated approval and supplemental clinical evidence required for future regular approval. Methods: The product properties, pre-accelerated approval evidence, rationale, post-accelerated approval requirements, and prior regulatory designations for oncology accelerated approvals were summarized based on public databases. Regression analyses were performed to investigate factors that may have been associated with the post-accelerated approval requirements. Results: Hundred fifty-seven accelerated approvals were granted between 1992 and 2021. An increase in the number of pre-accelerated approval trials by one trial resulted in a 20% decrease in supplemental trials. The endpoint for the post-accelerated approval trial tended to be more robust when products were indicated for common cancers, while less robust when products had been used to treat fewer subjects, when products were indicated for respiratory and skin cancers, or when less malignant cancers were targeted. Conclusions: Accelerated approvals for oncology products were often based on the response rate of a noncomparative trial. However, considerable variation was observed in the post-accelerated approval requirements. Factors such as the quality and quantity of pre-accelerated approval evidence, regulatory designations, and operational feasibility may have been considered when determining the accelerated approvals and post-accelerated approval requirements. [ABSTRACT FROM AUTHOR]

Purpose: Research and regulatory approval for pediatric uses of prescription drugs often lag years after adult approvals, during which time substantial off‐label use of medications in children can occur. We evaluated whether US Food and Drug Administration (FDA) regulatory actions affected the pediatric use of omalizumab, a biologic drug used to treat asthma. Methods: In this serial cross‐sectional study, we identified quarterly cohorts of children (0–18 years) with moderate‐to‐severe asthma within two large national claims databases of those with commercial insurance and Medicaid from 2003 to 2019. Using an interrupted time‐series analysis, we fit segmented linear regression models to identify changes in the incidence of omalizumab use in 6–11‐year‐old children compared with 12–18‐year‐olds after two time points: (1) 2009Q3 when an FDA advisory committee voted against use for 6–11‐year‐old children and (2) 2016Q2 when FDA expanded omalizumab's labeling to include 6–11‐year‐old children. Results: We identified 9298 new pediatric omalizumab users (84% Medicaid). Among 6–11‐year‐old children, the incidence of omalizumab use did not change following the FDA's initial review of evidence in 2009 and increased after 2016 Q2 FDA approval for this age group in both Medicaid (58 per 100 000 children with asthma, 95% confidence interval [CI] 27–89, p < 0.001) and commercial insurance (57 per 100 000, 95% CI 21–94, p = 0.003) compared with 12–18‐year‐old children. Conclusions: The use of omalizumab among asthmatic children aged 6–11 years remained steady after FDA advisory committee concerns in 2009 and increased after FDA expanded the indication to include this population in 2016. Additional market incentives may help to ensure the timely generation of evidence and regulatory approval of medications for children. [ABSTRACT FROM AUTHOR]

Background: Overall inferior vena cava filter (IVCF) utilization has decreased in the United States since the 2010 US Food and Drug Administration (FDA) safety communication. The FDA renewed this safety warning in 2014 with additional mandates on reporting IVCF-related adverse events. We evaluated the impact of the FDA recommendations on IVCF placements for different indications from 2010 to 2019 and further assessed utilization trends by region and hospital teaching status. Methods: Inferior vena cava filter placements between 2010 and 2019 were identified in the Nationwide Inpatient Sample database using the associated International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision codes. Inferior vena cava filter placements were categorized by indication for venous thromboembolism (VTE) "treatment" in patients with VTE diagnosis and contraindication to anticoagulation and "prophylaxis" in patients without VTE. Generalized linear regression was used to analyze utilization trends. Results: A total of 823 717 IVCFs were placed over the study period, of which 644 663 (78.3%) were for VTE treatment and 179 054 (21.7%) were for prophylaxis indications. The median age for both categories of patients was 68 years. The total number of IVCFs placed for all indications decreased from 129 616 in 2010 to 58 465 in 2019, with an aggregate decline rate of −8.4%. The decline rate was higher between 2014 and 2019 than between 2010 and 2014 (−11.6% vs −7.2%). From 2010 to 2019, IVCF placement for VTE treatment and prophylaxis trended downward at rates of −7.9% and −10.2%, respectively. Urban nonteaching hospitals saw the highest decline for both VTE treatment (−17.2%) and prophylactic indications (−18.0%). Hospitals located in the Northeast region had the highest decline rates for VTE treatment (−10.3%) and prophylactic indications (−12.5%). Conclusion: The higher decline rate in IVCF placements between 2014 and 2019 compared with 2010 and 2014 suggests an additional impact of the renewed 2014 FDA safety indications on national IVCF utilization. Variations in IVCF use for VTE treatment and prophylactic indications existed across hospital teaching types, locations, and regions. Clinical Impact: Inferior vena cava filters (IVCF) are associated with medical complications. The 2010 and 2014 FDA safety warnings appeared to have synergistically contributed to a significant decline in IVCF utilization rates from 2010 – 2019 in the US. IVC filter placements in patients without venous thromboembolism (VTE) declined at a higher rate than VTE. However, IVCF utilization varied across hospitals and geographical locations, likely due to the absence of universally accepted clinical guidelines on IVCF indications and use. Harmonization of IVCF placement guidelines is needed to standardize clinical practice, thereby reducing the observed regional and hospital variations and potential IVC filter overutilization. [ABSTRACT FROM AUTHOR]

Policy PointsWith increasing public attention to cases of inaccurate and misleading laboratory‐developed tests, there have been calls for regulatory reform.To protect patients from faulty laboratory tests, we need a framework that balances comprehensive test review with laboratory flexibility.The Verifying Accurate Leading‐edge IVCT [In Vitro Clinical Test] Development (VALID) Act would have helped ensure laboratory test safety and validity through a much‐needed expansion of Food and Drug Administration (FDA) oversight. However, Congress did not pass the VALID Act in 2022, forcing the FDA to start the regulatory reform process on its own. [ABSTRACT FROM AUTHOR]

An increase in total drug (small molecules and biologics) approvals by the Food and Drug Administration (FDA) was seen in 2023 compared with the previous year. Cancer remained the disease most targeted by monoclonal antibodies (mAbs), followed by autoimmune conditions. Our data reveal the prevalence of approvals for biologics even during years when the total number of authorizations was low, such as in 2022. Over half the drugs that received the green light in 2023 benefited from expedited programs, as the incidence of many diseases increased. In addition, over half of the biologics approved received Orphan Drug Designation from the FDA. This narrative review delves into details of the most significant approvals in 2023, including mAbs, enzymes, and proteins, explaining their mechanisms of action, differences from previous drugs, placebo, and standards of care, and outcomes in clinical trials. Given the varying number of drugs authorized annually by the U.S. health authority, this review also examines the limits of external influences over the FDA′s decisions and independence regarding drug approvals and withdrawals. [ABSTRACT FROM AUTHOR]

Introduction: A sizeable minority of commercially available blood glucose monitoring (BGM) systems fail to satisfy regulatory accuracy requirements, such as ISO 15197:2013, after approval. This study assessed whether the BGMs tested could consistently meet these ISO requirements by investigating their accuracy in a non-standardized setting. Methods: In this 18-month post-market performance study, using the ISO criteria, healthcare professionals tested the accuracy of four CE-marked BGM systems (Roche Diabetes Care, Mannheim, Germany) on European adults with diabetes mellitus. ISO criteria included 95% of blood glucose (BG) values being within ± 15 mg/dl of a reference measurement for BG < 100 mg/dl or ± 15% for BG ≥ 100 mg/dl and, in the Parkes Consensus Error grid for type 1 diabetes comparing capillary BGM measurements versus reference method, 99% of BG values falling within zone A (no effect on clinical action or outcome) and zone B (altered clinical action with little or no effect on clinical outcome). Results: BGM readings were obtained from 1650 participants, and the number of readings per BGM system was between 1712 and 2376. The percentage of BGM readings that fell within ISO 15197:2013 limits ranged from 99.4 to 99.9%. For all meter types, 100% of data points fell within zone A or zone B, and most data points for each meter (≥ 99.9%) were in zone A. Conclusion: All four CE-marked BGM models showed results within the accuracy limits defined by ISO 15197 in a non-standardized setting and thus consistently met regulatory accuracy requirements. [ABSTRACT FROM AUTHOR]

Background: Leiomyosarcoma (LMS) is an uncommon type of tumour found in the uterus, comprising about one percent of cancers in women and playing a substantial role in uterine cancer fatalities. The resemblance to benign leiomyomas complicates pre-surgery detection, possibly leading to improper use of myomectomy and morcellation, causing concerns. Managing Uterine Leiomyosarcoma (ULMS) is particularly challenging due to its aggressive nature and resistance to standard therapies. Predictive algorithms provide accurate forecasts, although the time of diagnosis is critical for survival. Aim of the study: This study evaluates the effectiveness of existing surgical and medicinal treatments for ULMS, concentrating on targeted therapy and examining the influence of uterine morcellation on gynaecologic surgical practices. The main goal is to improve knowledge of ULMS, investigate early detection techniques, and assess new treatments. Materials and Methods: Study employs a comprehensive analysis of existing literature, emphasizing surgical techniques, medicinal approaches, and the effects of certain medicines including olaratumab, trabectedin, and pazopanib. The current examination focuses on aromatase inhibitors and immunotherapies. Results: However, treating ULMS is challenging, Food and Drug Administration (FDA)-approved targeted therapies have shown efficacy against uterine and other LMSs. The present research concentrates on creating methods for detecting diseases at an early stage and exploring new treatments, such as aromatase inhibitors and immunotherapies. Conclusion: Study emphasizes the necessity for enhanced detection methods for ULMS due to its deceptive resemblance to benign tumours. Investigation of new treatments and the effects of uterine morcellation on surgical techniques is crucial for improving the management of ULMS, even with the effectiveness of FDA-approved therapies. [ABSTRACT FROM AUTHOR]

Background: 3D printing, also known as additive manufacturing, is a rapidly advancing technology in the life sciences sector. Several countries, including the USA, Canada and Singapore, have established regulations for 3D printing of pharmaceutical products. The growing demand for personalized medical devices presents a significant challenge to traditional manufacturing methods. Materials and Methods: This study aims to provide a concise overview of the introduction, history and evolution of 3D printers, their development process and their role and guidelines and focus is on exploring regulatory parameters related to 3D printing in the United States, Canada and Singapore. The Food and Drug Administration (FDA) has issued guidance outlining its initial considerations for technical aspects specific to devices using additive manufacturing. The regulatory landscape of 3D-printed medical devices and biologics in the United States is discussed, emphasizing key challenges and considerations. Results and Discussion: A comparative analysis in Selected counties was conducted across various aspects, including user needs, design input, performance requirements, design processes, functional requirements, design output, verification and validation, bio-printing regulatory perspectives, standardization and certification. Conclusion: As additive manufacturing technology advances, 3D bio-printing has emerged as an efficient tool for regenerative medicine and tissue engineering, integrating computer-aided manufacturing into healthcare delivery. The applications of 3D printing in the healthcare field extend to creating and implementing patient-specific solutions. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify discrepancies between Jordan Food and Drug Administration (JFDA) vaccine licensure indications and directorate of communicable diseases (DCD) on immunization practices recommendations and assess the knowledge, practices, and attitudes of healthcare providers regarding these discrepancies. Study Design: A cross-sectional study. Methods: Data was extracted from Jordan National Drug Formulary documents, and corresponding information was collected from the DCD at the ministry of health and the National Immunization Technical Advisory Group. Self-administered Survey was used to assess knowledge and practices of paediatricians and gynaecologists related to vaccine licensure indications and recommendations differences. Descriptive statistics were used for data analysis. Results: Twelve cases of discrepancies were identified and, mainly were related to age indications, administration schedules, and management differences. The survey included 116 gynaecologists and 100 paediatricians with an overall response rate of approximately 46% and 50%, respectively. A total of fifty-nine gynaecologists (50.9%) correctly responded that only the JFDA licensure indications in the package inserts were required before vaccines may be marketed and only 44 paediatricians (n=44, 44%) correctly responded that only the DCD at the ministry of health is the lead organization that makes recommendations for vaccine use in Jordan. Analysis shows that only 64.7% (n=75) of gynaecologists and one-third (n=27, 27%) of paediatricians were aware of the differences between JFDA licensure and the DCD at the ministry of health recommendations for any specific vaccine. Most gynaecologists (n=81, 69.8%) and almost half of the paediatricians (n=46, 46%) stated that they follow publications from specific guidelines as the primary source of information on immunization schedules and vaccine recommendations. Conclusions: The findings suggest a need for better communication and coordination between regulatory bodies and healthcare providers to ensure consistent and evidence-based immunization practices.. [ABSTRACT FROM AUTHOR]

The article offers information on a unique fellowship opportunity between the Children's National Hospital (CNH) Pediatric Infectious Diseases division and the US Food and Drug Administration (FDA). Topics include the regulatory experiences of CNH fellows in the FDA's Center for Drug Evaluation and Research (CDER), the enrichment of fellows' training and career prospects through these experiences, and the structure of the pediatric infectious diseases fellowship at CNH.

Introduction: Recent Food and Drug Administration (FDA) draft guidelines are intended to improve representation and formalize the assessment of race and ethnicity in drug development, but how regulators and industry stakeholders plan to implement and enforce new requirements is still being determined. Materials and methods: Here, a 10-question survey was developed to assess the experiences of industry stakeholders in developing diversity plans. These survey results informed an analysis of postmarketing studies to understand how diversity requirements have been enforced to date. Results and Discussion: Among 13 survey responders, experience submitting and receiving feedback on diversity plans was limited. A variety of challenges have been associated with developing these plans, including questions regarding regulatory guidance. Sponsors have utilized several data sources, including real-world datasets, to define enrollment goals. Diversity-related postmarketing studies most commonly related to oncologic diseases, and endpoints frequently related to efficacy. Most marketing applications associated with diversity-related postmarketing studies received Orphan drug designation (ODD) and Accelerated Approval. Conclusions: These results show that industry experience with diversity plans remains limited in the absence of finalized regulatory guidance. Sponsors are beginning to develop strategies for submitting diversity plans, which include identifying key functions and data sources to support enrollment goals, although definitive conclusions were difficult to draw from the small responder pool. In the postmarketing setting, studies are already underway to improve the understanding of racial and ethnic differences in responses to approved drugs. Development programs relating to oncology, which has historically suffered from a lack of diverse representation, have been a primary focus of such studies thus far. [ABSTRACT FROM AUTHOR]

Objectives Surface the urgent dilemma that healthcare delivery organizations (HDOs) face navigating the US Food and Drug Administration (FDA) final guidance on the use of clinical decision support (CDS) software. Materials and Methods We use sepsis as a case study to highlight the patient safety and regulatory compliance tradeoffs that 6129 hospitals in the United States must navigate. Results Sepsis CDS remains in broad, routine use. There is no commercially available sepsis CDS system that is FDA cleared as a medical device. There is no public disclosure of an HDO turning off sepsis CDS due to regulatory compliance concerns. And there is no public disclosure of FDA enforcement action against an HDO for using sepsis CDS that is not cleared as a medical device. Discussion and Conclusion We present multiple policy interventions that would relieve the current tension to enable HDOs to utilize artificial intelligence to improve patient care while also addressing FDA concerns about product safety, efficacy, and equity. [ABSTRACT FROM AUTHOR]

This article examined the inclusion of patient-reported outcome (PRO) data in new drug applications (NDAs) submitted to the Food and Drug Administration (FDA) and approved from 2018 to 2021. The importance of assessing PROs, which capture patients' perspectives on the disease and treatment experience, has been underscored by many stakeholders, including regulatory authorities. Despite the increasing inclusion of PRO assessments in registration trials, inclusion of language related to PRO results in approved product labeling varies widely. This study examined FDA submission packages for NDAs approved by the FDA from 2018 to 2021 to identify critical reviewer comments related to PROs. Comments were identified and categorized by the type of criticism. Reviewers considered both oncology and nononcology indications. Assessment of PROs was included in 66.2% of the 210 submissions reviewed. Critical comments were identified in 45.3% of these applications; comments most commonly related to statistical analysis considerations, fit for purpose, and study design. Other categories of critical comment included data quality, lack of treatment benefit, administrative considerations, and miscellaneous issues. Differences were observed between oncology and nononcology NDAs with regard to the number and type of comments included in each of these categories. The findings highlight the importance of planning statistical analyses, establishing content validity, carefully considering study design, maximizing data quality, and demonstrating treatment benefit, among other issues. Overall, this study offers insight into the landscape of PRO data included in recently approved NDAs, along with recommendations for improving the quality and reporting of PROs in clinical trials. • This article examined patient-reported outcome (PRO)-related reviewer comments included in approved new drug applications (2018-2021). The insights from this review shed light on the quality of contemporary PRO strategy and implementation and on regulatory consideration for these data. • This study identifies comments on the differences in the quality of PRO data, including administration, analysis, and interpretation. Differences were particularly notable between oncology and nononcology submissions. • These findings help advance our understanding of the value of PRO data to support regulatory decision making, offering valuable guidance on improving the incorporation of the patient experience into clinical trials through the assessment of PROs. [ABSTRACT FROM AUTHOR]

Capsaicin is the primary alkaloid from capsicum plant (red chili pepper) and is approved by the Food and Drug Administration (FDA) for treating multiple ailments. It activates the transient receptor potential vanilloid 1 (TRPV1) gene, leading to sodium and calcium influx into cells. This triggers the depolarization of nociceptive neurons, causing spiciness perception. Recent studies underscore the health benefits of red chili pepper extract. This investigation aims to understand capsaicin's potential in treating and preventing kidney stones. The potential link between capsaicin and decreased kidney stone risk was also determined. Recently published articles on capsaicin's medical properties and the underlying potential mechanisms were searched out. Relevant references were obtained by searching PubMed electronic databases from April 2020 to September 2020. The impact of parameters such as calcium and oxalate levels were evaluated as common components of kidney stones. Capsaicin may have an impact on body weight, which may have an indirect effect on the risk of kidney stones. Several theories centered around the regular consumption of capsaicin, including the role of TRPV1 gene stimulation have been presented in this study. Stimulation of the TRPV1 gene by capsaicin may protect against kidney stone development. Individuals with a history of kidney stones who incorporate capsaicin into their diet may experience a significantly reduced risk of recurring kidney stone disease. This review elucidates theories supporting this protective effect. The consistent daily intake of red chili pepper (capsaicin) has been associated with a diminished incidence of stone formation. Further research is essential to establish the efficacy and safety of capsaicin. [ABSTRACT FROM AUTHOR]

Since its commencement as part of the Food and Drug Administration’s (FDA) Prescription Drug User Fee Act (PDUFA) V in 2012, patient-focused drug development (PFDD) has become an integral part of the drug development paradigm. FDA encourages the development and use of Patient-Experience Data (PED) as it provides important information on the patients’ needs and perspectives and inform regulatory decision-making. While the FDA is required to fill out a table which includes a list of various types of Patient Experience Data (PED) and if such data was reviewed by FDA as part of a drug application, there is still a need to understand how FDA uses PED in its regulatory decision-making. This article examines whether new policies are needed to ensure the full potential of PFDD.

ABSTRACTThe ‘Antibodies to Watch’ article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody–drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14–32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) induced cytokine storm is the major cause of COVID-19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear Factor‑Kappa B (NF‑κB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARS‑CoV‑2 induced cytokine storm pathway. We developed machine-learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID‑19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein-ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.

Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.

BackgroundIn trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States.MethodsThis prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections.FindingsThe study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim.InterpretationThis phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.Fundingwas provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

Blood glucose monitoring constitutes a pivotal element in the clinical management of Type 1 diabetes (T1D), a globally escalating metabolic disorder. Continuous glucose monitoring (CGM) devices have demonstrated efficacy in optimizing glycemic control, mitigating adverse health outcomes, and augmenting the overall quality of life for individuals afflicted with T1D. Recent progress in the field encompasses the refinement of electrochemical sensors, which enhances the effectiveness of blood glucose monitoring. This progress empowers patients to assume greater control over their health, alleviating the burdens associated with their condition, and contributing to the overall alleviation of the healthcare system. The introduction of novel medical devices, whether derived from existing prototypes or originating as innovative creations, necessitates adherence to a rigorous approval process regulated by the Food and Drug Administration (FDA). Diverse device classifications, stratified by their associated risks, dictate distinct approval pathways, each characterized by varying timelines. This review underscores recent advancements in blood glucose monitoring devices primarily based on electrochemical sensors and elucidates their regulatory journey towards FDA approval. The advent of innovative, non-invasive blood glucose monitoring devices holds promise for maintaining stringent glycemic control, thereby preventing T1D-associated comorbidities, and extending the life expectancy of affected individuals. [ABSTRACT FROM AUTHOR]

Background: The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program. Results: We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data. Conclusions: The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development—from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs. [ABSTRACT FROM AUTHOR]

By definition, biosimilar medicinal products are biological medicinal products that are similar to other biological medicinal products that are already on the market—the reference medicinal products. Access to biosimilar medicines is a current reality. However, to achieve this goal, it is extremely important to consistently and scientifically substantiate the regulatory requirements necessary for biosimilar medicines when accessing the market. Based on an analysis of the raw materials and the type of methods used in the manufacturing processes of biological medicines, it is known that this tends to be more complex for the quality of the finished product than the manufacture of molecules obtained through a chemical process. It is then relevant to highlight the main differences between both products: biological medicines manufactured using biotechnology and the current generics containing active pharmaceutical ingredients (APIs) obtained from synthetic processes. Once arriving at the approval process of these medicinal products, it is imperative to analyse the guidance documents and the regulatory framework that create the rules that allow these biosimilar medicinal products to come to the market. The present review aimed at documenting comparatively the specific provisions of European legislation, through the European Medicines Agency (EMA), as well as the legislation of the United States of America, through the Food and Drug Administration (FDA). This was then translated into a critical appraisal of what concerns the specific criteria that determine the favourable evaluation of a biosimilar when an application for marketing authorisation is submitted to different regulatory agencies. The gathered evidence suggests that the key to the success of biosimilar medicines lies in a more rigorous and universal regulation as well as a greater knowledge, acceptance, and awareness of health professionals to enable more patients to be treated with biological strategies at an earlier stage of the disease and with more affordable medicines, ensuring always the safety and efficacy of those medicines. [ABSTRACT FROM AUTHOR]

Helicobacter pylori is a class I carcinogen that infects more than 100 million individuals in the United States. Antimicrobial therapy for H. pylori has typically been prescribed empirically rather than based on susceptibility testing. Until recently, therapeutic recommendations have generally ignored the principles of antibiotic stewardship. A combination of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin (triple therapy) remains popular despite increasing clarithromycin resistance and poor cure rates. Concomitant therapy (a PPI, amoxicillin, clarithromycin, and metronidazole) is recommended and widely used despite all patients receiving at least one unneeded antibiotic. In 2020, the Food and Drug Administration approved vonoprazan, amoxicillin, and clarithromycin triple therapy, which administers unneeded clarithromycin to >90% of patients (i.e., ~6 tons of unneeded clarithromycin/million treatments). In the late 1980s, the infectious disease community functionally transferred responsibility for the management of H. pylori to gastroenterology, which has managed the infection as another common gastrointestinal disease such as constipation. In 2022, both traditional and noninvasive molecular-based susceptibility testing for H. pylori became available in the United States. In order to reduce and prevent antibiotic misuse, the infectious disease community should reclaim responsibility for the management of this important infectious disease. [ABSTRACT FROM AUTHOR]

Introduction: MRI-guided focused ultrasound (FUS) is an incisionless thermo-ablative procedure that may be used to treat medication-refractory movement disorders, with a growing number of potential anatomic targets and clinical applications. As of this article's publication, the only US Food and Drug Administration (FDA)-approved uses of FUS for movement disorders are thalamotomy for essential tremor (ET) and tremor-dominant Parkinson's Disease (PD), and pallidotomy for other cardinal symptoms of PD. We present a state-of-the-art review on all non-FDA approved indications of FUS for movement disorders, beyond the most well-described indications of ET and PD. Our objective was to summarize the safety and efficacy of FUS in this setting and provide a roadmap for future directions of FUS for movement disorders. Methods: A state-of-the-art review was conducted on use of FUS for non-FDA approved movement disorders. All movement disorders excluding FDA-approved uses for ET and PD were included. Results: A total of 25 studies on 172 patients were included. In patients with tremor plus dystonia syndromes (n = 6), ventralis intermediate nucleus of the thalamus (VIM)-FUS gave >50% tremor reduction, with no improvement in dystonia and worsened dystonia in 2/6 patients. Ventral-oralis complex (VO)-FUS gave >50% improvement for focal hand dystonia (n = 6) and 100% return to musical performance in musician's dystonia (n = 6). In patients with multiple sclerosis (MS) and tremor (n = 3), improvement in tremor was seen in 2 patients with a favorable skull density ratio; no MS disease change was noted after VIM-FUS. In patients with tremor and comorbid ataxia syndromes (n = 3), none were found to have worsened ataxia after VIM-FUS; all had clinically significant tremor improvement. Subthalamic nucleus (STN)-FUS for PD (n = 49) gave approximately 50% improvement in PD motor symptoms, with dystonia and mild dyskinesias as possible adverse effects. Cerebellothalamic tract (CTT-FUS) for ET (n = 42) gave 55–90% tremor improvement, with gait dysfunction as a rare persistent adverse effect. Pallidothalamic tract (PTT-FUS) for PD (n = 50) gave approximately 50% improvement in motor symptoms, with mild speech dysfunction as a possible adverse effect. Conclusion: VIM-FUS appeared safe and effective for heterogenous tremor etiologies, and VO-FUS appeared most effective for isolated segmental dystonia. STN-FUS was effective for PD symptom reduction; postoperative dystonia and mild on-medication dyskinesias required medical management. Tractography-based targeting with CTT-FUS for ET and PTT-FUS for PD demonstrated promising early results. Larger prospective trials with long-term follow-up are needed to the evaluate the safety and efficacy non-FDA approved indications for FUS. [ABSTRACT FROM AUTHOR]

Background/objectiveExogenous Cushing syndrome is usually diagnosed in the setting of known glucocorticoid exposure; however, occult glucocorticoid use is possible. We present 2 cases of patients who developed Cushing syndrome while taking Artri King (AK), an over-the-counter "herbal" supplement for joint pains reported to contain glucocorticoids.Case reportPatient 1, a 49-year-old woman, reported rapid weight gain, large stretch marks, poor wound healing, and recent diagnoses of type 2 diabetes mellitus and hypertension over a course of 1 year. Her serum am cortisol level was

Abstract Background The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program. Results We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data. Conclusions The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development—from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

An increase in total drug (small molecules and biologics) approvals by the Food and Drug Administration (FDA) was seen in 2023 compared with the previous year. Cancer remained the disease most targeted by monoclonal antibodies (mAbs), followed by autoimmune conditions. Our data reveal the prevalence of approvals for biologics even during years when the total number of authorizations was low, such as in 2022. Over half the drugs that received the green light in 2023 benefited from expedited programs, as the incidence of many diseases increased. In addition, over half of the biologics approved received Orphan Drug Designation from the FDA. This narrative review delves into details of the most significant approvals in 2023, including mAbs, enzymes, and proteins, explaining their mechanisms of action, differences from previous drugs, placebo, and standards of care, and outcomes in clinical trials. Given the varying number of drugs authorized annually by the U.S. health authority, this review also examines the limits of external influences over the FDA′s decisions and independence regarding drug approvals and withdrawals.

This study aims to highlight the differences in adverse events (AEs) between cabozantinib (CAB) plus nivolumab (NIVO) versus ipilimumab (IPI) plus NIVO. We used the FAERS database. Drugs presented a disproportionate distribution of toxicities. Serious AEs were higher in patients receiving IPI + NIVO. These findings may help clinicians select therapy and improve the safety profile. Introduction: Recently, many agents and combinations for metastatic and advanced renal cell carcinoma have been approved. This study aims to highlight the comprehensive differences in adverse events (AEs) between cabozantinib (CAB) plus nivolumab (NIVO) and ipilimumab (IPI) plus NIVO based on a real-world big dataset. Material and Methods: We downloaded AE datasets of IPI + NIVO and CAB + NIVO from the Food and Drug Administration Adverse Event Reporting System database. We used the Medical Dictionary for Regulatory Activities to treat each AE as a preferred term and grouped it into the System Organ Class (SOC). We performed logistic regression analyses to compare IPI + NIVO and CAB + NIVO. Results: The incidence rates of 7 types of toxicities were higher for CAB + NIVO than for IPI + NIVO. On the other hand, the incidence rates of 3 types of toxicities were higher for IPI + NIVO than for CAB + NIVO. Serious AEs were higher in patients receiving IPI + NIVO. Conclusion: Our findings suggest that both combination therapies presented a disproportionate distribution of toxicities in several SOC. These findings may help clinicians select suitable therapy for the individual and improve the safety profile in patients with advanced renal cell carcinoma receiving NIVO + IPI and NIVO + CAB in a real-world setting. [ABSTRACT FROM AUTHOR]

AbstractConcepts and definitions of ‘healthy’ have been evolving within clinical treatment algorithms as well as reference standards such as Body Mass Index and Dietary Reference Intakes. Consumers’ perception of the word ‘healthy’ is also changing to reflect longer life span, need to stay active and in a good state of mental well-being while managing multiple diseases. Guidelines from the US Food and Drug Administration indicate that substantiating evidence for support of Structure/Function (S/F) claims for dietary supplements is best derived from clinical research conducted in a ‘healthy’ population. S/F claims cannot be represented to diagnose, treat, cure or prevent any disease. However, in this context, the term ‘healthy’ is non-descriptive and largely interpreted as an absence of disease. Guidelines for treatment of disease have been broadened to include biomarkers of disease risk such that the pool of ‘healthy’ volunteers eligible to be enrolled in clinical trials for S/F claim substantiation is greatly diminished. This perspective presents the challenges faced by the food and dietary supplement industry and by researcher efforts designed to substantiate S/F claims and suggest the phrase ‘physiologically stable’ or ‘apparently healthy’ as descriptions better suited to replace the term ‘healthy.’ [ABSTRACT FROM AUTHOR]

We sought to better understand the utility and role of animal models of infection for Food and Drug Administration (FDA)-approved antibiotics for the indications of community-, hospital-acquired-, and ventilator-associated bacterial pneumonia (CABP, HABP, VABP), complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), and acute bacterial skin and structural infections (ABSSSIs). We reviewed relevant documents from new drug applications (NDA) of FDA-approved antibiotics from 2014–2019 for the above indications. Murine neutropenic thigh infection models supported the choice of a pharmacokinetic-pharmacodynamic (PKPD) target in 11/12 NDAs reviewed. PKPD targets associated with at least a 1-log bacterial decrease were commonly considered ideal (10/12 NDAs) to support breakpoints. Plasma PK, as opposed to organ specific PK, was generally considered most reliable for PKPD correlation. Breakpoint determination was multi-disciplinary, accounting at minimum for epidemiologic cutoffs, non-clinical PKPD, clinical exposure-response and clinical efficacy. Non-clinical PKPD targets in combination with probability of target attainment (PTA) analyses generated breakpoints that were consistent with epidemiologic cutoffs and clinically derived breakpoints. In 6/12 NDAs, there was limited data to support clinically derived breakpoints, and hence the non-clinical PKPD targets in combination with PTA analyses played a heightened role in the final breakpoint determination. Sponsor and FDA breakpoint decisions were in general agreement. Disagreement may have arisen from differences in the definition of the optimal PKPD index or the ability to extrapolate protein binding from animals to humans. Overall, murine neutropenic thigh infection models supported the reviewed NDAs by providing evidence of pre-clinical efficacy and PKPD target determination, and played, in combination with PTA analysis, a significant role in breakpoint determination for labeling purposes. [ABSTRACT FROM AUTHOR]

The U.S. Food & Drug Administration (FDA) "For Consumers" web site is a section of the official FDA web site where general consumers can find trusted health and safety information. This section offers access to information about food and health products, minority health and health equity, and consumer updates. Some sections offer information geared toward a particular audience, like health care workers, industry experts, or educators. The main purpose for this web site is to provide science-based health information that is easily organized for consumers. [ABSTRACT FROM AUTHOR]

We aimed to ascertain the frequency and types of Food and Drug Administration (FDA)-identified clinical outcome assessment (COA) violations in US pharmaceutical promotional materials from 2013 to 2021 by updating the review by Symonds et al (covering the period 2006-2012 for patient-reported outcomes [PRO] measures), expanding to infringements across all types of COAs, and grouping by efficacy or overall patient experience. Warning letters (WLs) and untitled letters (ULs) issued by the FDA's Office of Prescription Drug Promotion were reviewed for COA violations and classified by their type: (1) COA measure not fit for purpose, (2) issue with study design or interpretation of results, and (3) inadequate statistical analysis. From 2013 to 2021, the FDA issued 22 WLs and 65 ULs. Year 2013 showed the highest number of letters issued (n = 24). Of the total 87 letters reviewed, 22 (25%) contained a COA violation, consisting of 6 WLs (27%) and 16 ULs (25%), including 20 (23%) with a PRO-related violation. The most common violations cited "study design or interpretation of results" (21 of 22 [95%]). Overall, the absolute number of WLs and ULs issued declined when comparing 2006 to 2012 with 2013 to 2021. Despite the overall reduction, this review still identified 25% of letters citing COA infringements (23% with PRO issues), which was similar to the prior review (19% PRO infringements). This may be due to increased FDA attention to patient-focused drug development. • Overall, the absolute number of warning letters and untitled letters issued declined when comparing 2006 to 2012 with 2013 to 2021. • Despite the overall reduction, this review still identified 25% of letters had clinical outcome assessments infringements (23% with patient-reported outcome issues), which is similar to a previous review (19% patient-reported outcome infringements). • This review identified a reduction in violations for specific subthemes, eg, "use of individual items from a multi-item measure or to support complex claims," which may be because of improvements in awareness about requirements by manufacturers and researchers following recent guidance about clinical outcome assessment measurement science. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration's controversial decision to grant accelerated approval to aducanumab (Aduhelm), a therapy for Alzheimer's disease, has motivated multiple policy reforms. Drawing a case series of other drugs granted accelerated approval and interviews of senior FDA officials, I argue that reform should be informed but not defined by aducanumab. Rather, structural reforms are needed to reshape FDA's core priorities and restore the regulatory system's commitment to scientific rigor. [ABSTRACT FROM AUTHOR]

In "Missing the Forest for the Trees: Aduhelm, Accelerated Approvals & the Agency," Dr. Matthew Herder argues that agency capture and politicized discretion drive delays in confirmatory trials of accelerated approval drugs amongst other concerns at US Food and Drug Administration (FDA). In highlighting this important problem and offering nuanced insight into agency workings based in part on interviews with twenty-three unnamed FDA officials and a three-drug case study, Dr. Herder suggests two innovative solutions. However, amidst broader debates balancing agency expertise, data, and delegation, these proposed policy solutions would benefit from more corroborative evidence and consideration of institutional advantages within constitutional limits. [ABSTRACT FROM AUTHOR]

This article explores the legislation and guidelines surrounding the approval of biosimilars in the United States, with a focus on the role of the FDA in determining testing criteria. The author argues against the use of clinical efficacy testing in patients, citing its low sensitivity and the potential risk of approving products that may not meet analytical and clinical pharmacology assessments. Instead, the article suggests alternative methods such as PD biomarkers and computational modeling. The author concludes that clinical efficacy testing is less effective than analytical assessment and clinical pharmacology profiling in establishing biosimilarity, and that clinical trial data are not necessary to address uncertainties about biosimilar quality. The article also discusses the use of pharmacodynamic biomarkers and receptor binding assays as alternative evaluation methods, while raising ethical concerns about testing biosimilars in patients. [Extracted from the article]

Policy PointsThe increasing number of drugs granted accelerated approval by the Food and Drug Administration (FDA) has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries.We recommend several administrative and legislative approaches for improving FDA–Centers for Medicare and Medicaid Services (CMS) coordination around accelerated‐approval drugs, including promoting earlier discussions among the FDA, the CMS, and drug companies; strengthening Medicare's coverage with evidence development program; linking Medicare payment to evidence generation milestones; and ensuring that the CMS has adequate staffing and resources to evaluate new therapies.These activities can help improve the integrity; transparency; and efficiency of approval, coverage, and payment processes for drugs granted accelerated approval. Context: The Food and Drug Administration (FDA)'s accelerated‐approval pathway expedites patient access to promising treatments. However, increasing use of this pathway has challenged the Medicare program, which often pays for expensive therapies despite substantial uncertainty about benefits and risks to Medicare beneficiaries. We examined approaches to improve coordination between the FDA and Centers for Medicare and Medicaid Services (CMS) for drugs granted accelerated approval. Methods: We argue that policymakers have focused on expedited pathways at the FDA without sufficient attention to complementary policies at the CMS. Although differences between the FDA and CMS decisions are to be expected given the agencies' different missions and statutory obligations, procedural improvements can ensure that Medicare beneficiaries have timely access to novel therapies that are likely to improve health outcomes. To inform policy options and recommendations, we conducted semistructured interviews with stakeholders to capture diverse perspectives on the topic. Findings: We recommend ten areas for consideration: clarifying the FDA's evidentiary standards; strengthening FDA authorities; promoting earlier discussions among the FDA, the CMS, and drug companies; improving Medicare's coverage with evidence development program; tying Medicare payment for accelerated‐approval drugs to evidence generation milestones; issuing CMS guidance on real‐world evidence; clarifying Medicare's "reasonable and necessary" criteria; adopting lessons from international regulatory‐reimbursement harmonization efforts; ensuring that the CMS has adequate staffing and expertise; and emphasizing equity. Conclusions: Better coordination between the FDA and CMS could improve the transparency and predictability of drug approval and coverage around accelerated‐approval drugs, with important implications for patient outcomes, health spending, and evidence generation processes. Improved coordination will require reforms at both the FDA and CMS, with special attention to honoring the agencies' distinct authorities. It will require administrative and legislative actions, new resources, and strong leadership at both agencies. [ABSTRACT FROM AUTHOR]

Objectives: Since the initial release of biosimilars 18 years ago, regulations for their licensing have changed considerably; however, there is no global consensus on these regulations. Establishing harmonized regulatory guidelines for the approval of biosimilars with support from the ICH, an independent, non-profit association under Swiss law, will significantly enhance the affordability of biological drugs. Methods: Regulatory guidelines from the Food and Drug Administration (FDA), European Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA), and World Health Organization (WHO) were analyzed for historical changes and elements critical to the safety and efficacy of biosimilars. Results: Analysis of all EMA and FDA filings show that none of the animal testing and clinical efficacy testing failed because animals do not have the required receptors to initiate pharmacologic responses, and efficacy studies cannot be statistically powered to conclude any results. New analytical technologies will enable good biosimilarity determination, avoiding both tests. Conclusion: Scientifically based ICH guidelines that remove redundant studies will reduce development costs, improve safety, and allow global drug distribution based on single compliance. These guidelines are particularly necessary for emerging countries lacking the expertise and resources to evaluate biosimilar filings. [ABSTRACT FROM AUTHOR]