BACKGROUND: Adult patients and clinicians are faced with several pharmacological options to manage attention-deficit/hyperactivity disorder (ADHD). If types or rates of adverse experiences vary among these options, these differences could inform the shared decision-making process.
METHODS: To discern differentiating evidence-based patterns of risk, we analyzed data from FDA package labels for drugs approved to treat adult ADHD and reports from the registration trials used to create these labels. Three analyses of adverse effects were conducted: placebo-corrected occurrence at rates of 1 in 5, 10, and 20 participants, association with discontinuation, and uniqueness of occurrence within the treatment options.
RESULTS: Among the 7 agents approved to treat adult ADHD, the number of types of side effects experienced during a mix of fixed and flexible-dose studies was greatest among the nonstimulant medications, but the stimulant medications had higher rates of occurrence of side effects. The minimum frequency at which all medications had adverse events was 1 in 10 participants. Overall discontinuation rates did not differ among the stimulant medications nor between stimulants and nonstimulants.
CONCLUSIONS: To our knowledge, this is the first study to compile and compare data from all FDA registration trials for medications approved to treat adult ADHD. This article describes a process by which readily available adverse event reporting data can be used as a tool to inform shared clinical decision-making. While differences in the methodology and outcome reporting of the trials included may limit generalizability, the number of individual patients included and the completeness of the discontinuation data can be used to inform discussions with patients about the relative likelihood of adverse experiences and other patient concerns.

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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: None.

暂无摘要。

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.

Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides (ASOs), 6 small interfering ribonucleic acids (siRNAs), and 1 mixture of single-stranded and double-stranded polydeoxyribonucleotides have been identified. A typical oligonucleotide formulation is composed of an oligonucleotide with buffering agent(s), pH adjusting agents, and a tonicity adjusting agent. All the products are presented as 2.1 - 200 mg/mL solutions at pH between 6 and 8.7. Majority of the products are approved for intravenous (IV) and subcutaneous (SC) routes, with two for intravitreal (IVT), two for intrathecal (IT), and one for intramuscular (IM) routes. The primary packaging includes vials and prefilled syringes (PFS). Products approved for IV and IT administration routes and requiring >1.5 mL dose volumes are supplied in vials, while those approved for SC, IM, and IVT and requiring ≤1.5 mL dose volume are supplied in PFS. Based on the compiled dataset, we propose a generalized starting point for an oligonucleotide formulation during early phase development for IV, SC, and IT administration routes. Overall, we believe this harmonized evaluation and understanding of various oligonucleotide drug product attributes will help derive platform generalizations and allows for accelerated early phase development for first-in-human studies.

暂无摘要。

An analysis of all new entities approved by both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) identified the approval of 69 new entities in the year 2023, 50 % more than in the previous year. Oncology drugs tied with congenital and infectious diseases drugs for the most approvals. Although orphan and priority approvals continued at a high pace, the rate of fast-track approvals continued to decline. The rate of industry consolidation also picked up again after decreasing slightly in 2022.

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as \"first-in-class\" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first-ever approval of a CRISPR-Cas9-based gene-editing cell therapy.

BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency\'s feedback on its strengths and key challenges.
RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients\' baseline characteristics, missing information, and potential bias and measurement errors.
CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.

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.