Sustaining competition for biosimilars on the pharmacy benefit: Use it or lose it.

Congress passed the Biologic Price Competition and Innovation Act of 2009, specifically to offer market competition as a counterweight to the rising costs of biologic medicines. As of April 15, 2024, 49 biosimilars have been approved by the US Food and Drug Administration in 15 biologic categories. Biosimilar competition has been undeniably successful: Through 2022, biosimilars have saved the US health system $23.6 billion, without significant care disruption or reduced quality. Through 2023, adalimumab biosimilar competition has added an additional $6.5 billion to this total, primarily through greater rebates from the reference manufacturer. Despite launching at discounts as great as 85%, adalimumab biosimilars have not been given preferred formulary positioning in the vast majority of cases and have thus gained only 3% of market share through 2023, largely because of payers' and pharmacy benefit managers' preference for rebates over discounts. This situation may negatively influence future biosimilar development, posing a threat to a biosimilar pipeline that represents hundreds of billions in savings over the next 10 years.

Application of the ESMO Magnitude of Clinical Benefit Scale to assess the clinical benefit of antibody drug conjugates in solid cancer: a systematic descriptive analysis of phase III and pivotal phase II trials.

OBJECTIVE: The aim of this study was to assess the clinical benefit value of approved antibody drug conjugates (ADCs) for solid tumours using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) V.1.1. DESIGN: Systematic descriptive analysis. DATA SOURCES: PubMed was searched for publications from 1 January 2000 to 18 October 2023. ELIGIBILITY CRITERIA: We included the phase III randomised controlled trials or phase II pivotal trials leading to approval of ADCs in solid tumours. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and discrepancies were resolved by consensus in the presence of a third investigator. RESULTS: ESMO-MCBS Scores were calculated for 16 positive clinical trials of eight ADCs, which were first approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China National Medical Products Administration and the Japanese Pharmaceuticals and Medical Devices Agency for solid cancers. Among 16 trials, 4 (25%) met the ESMO-MCBS benefit threshold grade, while 12 (75%) of the regimens did not meet the ESMO-MCBS benefit threshold grade. 5 (31%) of the 16 trials had no published scorecard on the ESMO website due to the approval by other jurisdictions but not by the FDA or EMA. Discrepancies between our results and the ESMO scorecard were observed in 4 (36%) of 11 trials, mostly owing to integration of more recent data. CONCLUSIONS: ESMO-MCBS is an important tool for assessing the clinical benefit of cancer drugs, but not all drugs met the meaningful benefit threshold.

Beyond the Label: Real-World Side Effects Experienced With FDA-Approved Drugs for Non-Melanoma Skin Cancers.

With immunotherapy historically focused on cutaneous melanoma, there has been a new wave of systemic medications available for treating non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). The immune checkpoint inhibitors approved by the FDA target programmed cell death protein 1 (PD-1) and the Hedgehog (Hh) signaling pathway. These medications have expanded treatment options; however, side effects are an important consideration. We used the FDA Adverse Events Reporting System (FAERS) to characterize the most prevalent, real-world side effects experienced by patients on these agents. Muscle spasms (23.45%), alopecia (16.06%), ageusia (12.02%), taste disorder (11.91%), and fatigue (11.67%) were the five most common side effects reported with medications used for BCC treatment. Logistic regression analysis showed males on vismodegib for BCC having greater odds of experiencing muscle spasms (aOR 1.33, P<0.001) and ageusia (aOR 1.34,  P<0.001) versus females, who were more likely to exhibit alopecia (aOR 1.82, P<0.001) and nausea (aOR 1.96, P<0.001). With SCC treatment, the 5 most reported adverse events were fatigue (5.58%), rash (3.59%), asthenia (3.59%), pruritus (3.19%), and pyrexia (2.79%). Patients taking cemiplimab-rwlc for BCC compared to SCC were more likely to experience disease progression (aOR 10.98, P=0.02). With medication labels providing an excessively daunting list of side effects, we characterize practical side effects seen in patients receiving systemic treatments for non-melanoma skin cancers.  J Drugs Dermatol. 2024;23(5):301-305. doi:10.36849/JDD.7968.

In silico Screening of Food and Drug Administration-approved Compounds against Trehalose 2-sulfotransferase (Rv0295c) in Mycobacterium tuberculosis: Insights from Molecular Docking and Dynamics Simulations.

BACKGROUND: Tuberculosis (TB) remains a prominent global health challenge, distinguished by substantial occurrences of infection and death. The upsurge of drug-resistant TB strains underscores the urgency to identify novel therapeutic targets and repurpose existing compounds. Rv0295c is a potentially druggable enzyme involved in cell wall biosynthesis and virulence. We evaluated the inhibitory activity of Food and Drug Administration (FDA)-approved compounds against Rv0295c of Mycobacterium tuberculosis, employing molecular docking, ADME evaluation, and dynamics simulations. METHODS: The study screened 1800 FDA-approved compounds and selected the top five compounds with the highest docking scores. Following this, we subjected the initially screened ligands to ADME analysis based on their dock scores. In addition, the compound exhibited the highest binding affinity chosen for molecular dynamics (MD) simulation to investigate the dynamic behavior of the ligand-receptor complex. RESULTS: Dihydroergotamine (CHEMBL1732) exhibited the highest binding affinity (-12.8 kcal/mol) for Rv0295c within this set of compounds. We evaluated the stability and binding modes of the complex over extended simulation trajectories. CONCLUSION: Our in silico analysis demonstrates that FDA-approved drugs can serve as potential Rv0295c inhibitors through repurposing. The combination of molecular docking and MD simulation offers a comprehensive understanding of the interactions between ligands and the protein target, providing valuable guidance for further experimental validation. Identifying Rv0295c inhibitors may contribute to new anti-TB drugs.

Gene therapy in pediatrics - Clinical studies and approved drugs (as of 2023).

Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating a range of genetic disorders that manifest in childhood. Gene therapy involves the modification or correction of a mutated gene or the introduction of a functional gene into a patient's cells. In general, it is implemented through two main modalities namely ex vivo gene therapy and in vivo gene therapy. Currently, a noteworthy array of gene therapy products has received valid market authorization, with several others in various stages of the approval process. Additionally, a multitude of clinical trials are actively underway, underscoring the dynamic progress within this field. Pediatric genetic disorders in the fields of hematology, oncology, vision and hearing loss, immunodeficiencies, neurological, and metabolic disorders are areas for gene therapy interventions. This review provides a comprehensive overview of the evolution and current progress of gene therapy-based treatments in the clinic for pediatric patients. It navigates the historical milestones of gene therapies, currently approved gene therapy products by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for children, and the promising future for genetic disorders. By providing a thorough compilation of approved gene therapy drugs and published results of completed or ongoing clinical trials, this review serves as a guide for pediatric clinicians to get a quick overview of the situation of clinical studies and approved gene therapy products as of 2023.

Pathway to Approval of Innovative Radiopharmaceuticals in China.

Since the late 1950s, radiopharmaceuticals have been used for diagnosis and treatment in clinical nuclear medicine in China. Over the decades, China has successfully established a relatively sophisticated system for radiopharmaceutical production and management, supported by state-of-the-art facilities. With the rapid growth of the national economy, the radiopharmaceutical market in China is expanding at a remarkable pace. This burgeoning market has led to an escalating demand for clinical-stage radiopharmaceuticals, either produced domestically or imported. Despite this positive trajectory, the development and application of radiopharmaceuticals in China have been hindered by several challenges that persist, such as inadequate research, insufficient investment, limited availability of radionuclides, shortage of trained personnel in related fields, and imperfections in policies and regulations. In an exciting development, the regulation reforms implemented since 2015 have positively affected China's drug regulatory system. The introduction of the "Mid- and Long-Term Development Plan (2021-2035) for Medical Isotopes" created concurrently an opportune environment for the advancement of innovative radiopharmaceuticals. In this review, we aim to provide an overview of the approval process for novel radiopharmaceuticals by the National Medical Products Administration and the status of radiopharmaceuticals in research and development in China. Preclinical development and clinical translation of radiopharmaceuticals are undergoing rapid evolution in China. As practitioners in the field in China, we provide several practical suggestions to stimulate open discussions and thoughtful consideration.

Health care decision-maker perceptions and trends in the utilization of preapproval information for formulary decision-making.

BACKGROUND: Preapproval information exchange (PIE) has increased between biopharma companies and health care decision-makers (HCDMs) over the last several years. However, there still exists a gap in what HCDMs need and what biopharma companies are providing. OBJECTIVE: To assess trends in the utilization of preapproval information by HCDMs and identify resources that may best support organizations in evaluating product information for formulary coverage prior to US Food and Drug Administration approval. METHODS: A double-blinded, web-based survey was fielded to a research panel of HCDMs from FormularyDecisions from May 16, 2022, to May 23, 2022. RESULTS: A total of 30 advisors were invited to take the survey and 17 responded to the survey, with representation largely from health plans (41%), pharmacy benefit managers (24%), and integrated delivery networks (12%) across commercial, Medicare, and Medicaid lines of business. Of the respondents, 47% noted that the availability of preapproval information has shortened the time to make a formulary decision. Almost all respondents (90%) ranked the availability of clinical and economic information in a timely manner to evaluate budget impact as a top benefit for PIE. Respondents noted that Academy of Managed Care Pharmacy (AMCP) preapproval dossiers (88%), AMCP PIE webinars (76%), preapproval presentations/videos (65%), and posters and abstracts of clinical trials results (59%) were the main resources used to facilitate PIE. CONCLUSIONS: The availability of preapproval information for HCDMs (particularly content related to anticipated place in therapy and product pricing) has an impact on shortening formulary decision-making timelines.

Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

Drug development blossoms for rare, fatal bone disease.

Five drugs are now approved or in trials for genetic condition that triggers misplaced bone growth.

Effect of Project Orbis participation by the Swiss regulator on submission gaps, review times, and drug approval decisions between 2020 and 2022: a comparative analysis.

BACKGROUND: Expedited market access for novel and efficacious drugs is warranted for patients. Since 2020, Swissmedic (The Swiss Agency for Therapeutic Products) has been participating in Project Orbis, a collaborative parallel-review programme launched by the US Food and Drug Administration (FDA) in 2019 to expedite patient access to cancer drugs. This programme allows regulatory agencies to remain independent in their decisions. We aimed to evaluate the effect of the first 2 years of Project Orbis from the Swissmedic perspective. METHODS: In this comparative analysis, we compared submission gap (time between submission at the FDA and Swissmedic), review time, approval and consensus decision rate, and the approved indications between Swissmedic and the FDA for marketing authorisation applications (MAAs) in oncology submitted to Swissmedic through Project Orbis (Orbis MAAs) or outside of Project Orbis (non-Orbis MAAs) from Jan 1, 2020, to Dec 31, 2021. Swissmedic review time was evaluated with a decision until June 30, 2022. For the decision comparison analysis, non-Orbis oncology MAAs submitted and evaluated from Jan 1, 2009, to Dec 31, 2018 (referred to as the pre-Orbis era) were also considered. Inferential statistics were done using Wilcoxon rank-sum test and the 95% CI for the median was based on binomial distribution. For each hypothesis testing, the significance level was set to 5%. No correction for multiple testing was performed. FINDINGS: We analysed the submission gap, review time, and regulatory decision for 31 Orbis MAAs and 41 non-Orbis MAAs during the Orbis era. The median submission gap was 33·0 days (95% CI 19·0-57·0) for Orbis MAAs versus 168·0 days (56·0-351·0) for non-Orbis MAAs (p<0·0001). The median review time at Swissmedic was 235·5 days (198·0-264·0) for Orbis MAAs versus 314·0 days (279·0-354·0) for non-Orbis MAAs (p=0·0002). Approval rates at Swissmedic were consistent between Orbis MAAs (20 [77%] of 26) and non-Orbis MAAs (31 [76%] of 41). The rate of consensus decisions between Swissmedic and the FDA was 21 (81%) of 26 for Orbis MAAs and 31 (76%) of 41 for non-Orbis MAAs. Swissmedic approval rates were lower for indication extensions than for new active substances for Orbis MAAs (13 [72%] of 18 vs seven [88%] of eight) and non-Orbis MAAs (17 [71%] of 24 vs 14 [82%] of 17). Divergent decisions between agencies were predominantly observed for indication extensions (11 [73%] of 15 divergent decisions). During the pre-Orbis era, Swissmedic approved 61 (88%) of 69 MAAs for new active substances. INTERPRETATION: Submission gap and review time for oncology applications at Swissmedic were significantly reduced by participation in Project Orbis, and approval consensus decisions were increased between agencies. These findings suggests that participating in Project Orbis could lead to faster patient access to drugs. FUNDING: None.