Time Of Approval Research Articles

Evaluation of the Generic Drug User Fee Act (GDUFA) Program for Fiscal Years 2013-2022.

The effectiveness of the regulatory initiatives, strategies, and incentives put forth in the first two authorizations of the Generic Drug User Fees Act (GDUFA) were evaluated using factors including the number of Abbreviated New Drug Application (ANDA) withdrawals and first-cycle approvals. GDUFA was originally authorized in 2012 for FY 2013-2017 (GDUFA I) and reauthorized for FY 2018-2022 (GDUFA II). ANDA approvals were analyzed from the Drugs @ FDA database covering 2013-2022. From the applications, the approval time, dosage form and route of administration (ROA), product indication, market status of the product, first generic status, company and company size filing the ANDA were noted. Despite the COVID pandemic, there was more than a 40% increase in ANDA approvals during GDUFA II relative to GDUFA I. Oral and parenteral drugs were the two leading categories of approved generics during both iterations of GDUFA. There was more than a 120% increase in withdrawn applications during GDUFA II, which reflects the partial refund that is now offered to incentivize companies to withdraw inadequate applications prior to review. This also appears to have contributed to an increase in the number of first-cycle approvals, which increased by 100% between GDUFA I and II. Due to the COVID-19 public health emergency, there was a decrease in activity within the generic drug program and market. Therefore, it is important to consider this impact when observing actual trends from this study.

CavitOmiX Drug Discovery: Engineering Antivirals with Enhanced Spectrum and Reduced Side Effects for Arboviral Diseases.

Advancing climate change increases the risk of future infectious disease outbreaks, particularly of zoonotic diseases, by affecting the abundance and spread of viral vectors. Concerningly, there are currently no approved drugs for some relevant diseases, such as the arboviral diseases chikungunya, dengue or zika. The development of novel inhibitors takes 10-15 years to reach the market and faces critical challenges in preclinical and clinical trials, with approximately 30% of trials failing due to side effects. As an early response to emerging infectious diseases, CavitOmiX allows for a rapid computational screening of databases containing 3D point-clouds representing binding sites of approved drugs to identify candidates for off-label use. This process, known as drug repurposing, reduces the time and cost of regulatory approval. Here, we present potential approved drug candidates for off-label use, targeting the ADP-ribose binding site of Alphavirus chikungunya non-structural protein 3. Additionally, we demonstrate a novel in silico drug design approach, considering potential side effects at the earliest stages of drug development. We use a genetic algorithm to iteratively refine potential inhibitors for (i) reduced off-target activity and (ii) improved binding to different viral variants or across related viral species, to provide broad-spectrum and safe antivirals for the future.

Characteristics of Clinical Trials for the US Food and Drug Administration Accelerated Approval and Subsequent Confirmatory Trials: Implications for Drug Approval in Japan.

The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established to facilitate and expedite access to new drugs for serious or life-threatening conditions. Although many drugs have granted AAs in the US, the number of approvals under the conditional approval system in Japan remains limited. This study aimed to examine whether confirmatory trials after the US AA are conducted in accordance with the design of postmarketing requirements and assess the timing of regular approval (RA) in Japan for drugs that have been granted US AA. Utilizing FDA databases and Japanese regulatory data from 1992 to 2023, we analyzed indications, postmarketing requirements, and clinical trial designs. Our findings indicate that the AA program in the US is well-managed as most AAs were converted to RAs based on confirmatory study data that met the designations. From the Japanese perspective, our findings show that the over half of Japanese RAs can be obtained without waiting for confirmatory trial results. By granting RA, instead of conditional approval, based on exploratory trial data in the US AA, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Therefore, further improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.

Health-related quality of life outcomes reporting associated with FDA approvals in haematology and oncology

ObjectiveHealth-related quality of life (HRQoL) outcomes are important in making clinical and policy decisions. This study aimed to examine the HRQoL reporting in cancer drug trials leading to Food and...

Informing the United States Medicare Drug Price Negotiation for Apixaban and Rivaroxaban: Methodological Considerations for Value Assessments Many Years After Launch

ObjectivesTo demonstrate how health technology assessment methods can be used to support Medicare’s price negotiations for apixaban and rivaroxaban. MethodsFollowing the statutory outline of evidence that will be considered by Medicare, we conducted a systematic literature review, network meta-analyses, and decision analyses to evaluate the health outcomes and costs associated with apixaban and rivaroxaban compared with warfarin and dabigatran for patients with nonvalvular atrial fibrillation. Our methods inform discussions about the therapeutic impact of apixaban and rivaroxaban and suggest price premiums above their therapeutic alternatives over a range of cost-effectiveness thresholds. ResultsNetwork meta-analyses found apixaban resulted in a lower risk of major bleeding compared with warfarin and dabigatran and a lower risk of stroke/systemic embolism compared with warfarin but not compared with dabigatran. Rivaroxaban resulted in a lower risk of stroke/systemic embolism versus warfarin but not dabigatran, and there was no difference in major bleeding. Decision-analytic modeling of apixaban suggested annual price premiums up to $4350 above the price of warfarin and up to $530 above the price for dabigatran at cost-effectiveness thresholds up to $200 000 per equal value of life-years gained. Analyses of rivaroxaban showed an annual price premium of up to $3920 above warfarin and no premium above that paid for dabigatran. ConclusionsAlthough health technology assessment is typically performed near the time of regulatory approval, with modifications, we produced comparative clinical and relative cost-effectiveness findings to help guide negotiations on a “fair” price for drugs on the market for over a decade.

Assessment of the Incidence of Müllerian Anomalies in Central Illinois

Introduction: Müllerian anomalies include a spectrum of malformations resulting from the underdevelopment of the Müllerian duct during embryological development. This results in a malformed vagina, uterus or both. Complete agenesis of one or both of these structures in a subset of these cases is known as Mayer‐Rokitansky‐Küster‐Hauser (MRKH) syndrome. There are two types of Müllerian agenesis: Type I MRKH only affects the upper vagina, cervix and uterus, whereas Type II MRKH has associated malformations affecting the renal, auditory and skeletal systems. The reported prevalence is approximately 1 in 5,000 for MRKH syndrome and ~5.5 in 100 for all Müllerian anomalies; however, there is a broad range in the described incidence rates. Purpose: We hypothesized the patient population served by the Department of Ob/Gyn, Division of Reproduction, Endocrinology and Infertility (REI) at Southern Illinois University (SIU) School of Medicine has a higher incidence of Müllerian anomalies and MRKH. Our objective was to assess the incidence of these Müllerian anomalies and describe the types of anomalies that affect women in Central Illinois. Methods: All patients receiving care at SIU Ob/Gyn, Division of REI from 01/1/2010-07/31/2021 were queried using specific ICD-9 and 10 codes and further screened to verify eligibility. A retrospective review (IRB# 21-893) was then conducted on all eligible subjects and relevant health information was extracted from the electronic health record. Continuous variables were measured by central tendency (mean or median) and dispersion (standard deviation or range). Categorical variables were described using frequencies and percentages. Results: The initial query identified 282 individuals of which 81 were deemed eligible (i.e., confirmed Müllerian anomaly). The total number of unique patients who underwent an ultrasound at REI during that time of study approval was 697. Based on these data, the calculated incidence of Müllerian anomalies in the REI patient population is ~11.6% and the incidence of MRKH is 57 in 5000. Demographics included: 74 subjects were White (91.4%), two Black or African American (2.5%), one Asian (1.2%) and 4 declined to report their race or identified as more than one race (4.9%); two subjects were of Hispanic ethnicity (2.5%). Mean ages at menarche and diagnosis were 12.7 ± 1.7 and 27.8 ± 6.4 years, respectively. Eight subjects diagnosed with MRKH had Type I MRKH. The specific type of anomalies identified included: uterine septum (29.1%), arcuate uterus (25.3%), unicornuate uterus (19.0%), agenesis (10.1%), bicornuate uterus (6.3%), uterus didelphys (6.3%) and 3.8% had another type of anomaly. The majority of patients underwent surgery within approximately one year of diagnosis (74%). Postoperative complications were rare (~7%) and included mild constipation, urinary retention and bleeding from the incision site. Pregnancy outcomes were as follows: prior to diagnosis, 3 (30%) infants were preterm vs. 7 (70%) term and those were spontaneous conceptions; after diagnosis 4 (30%) infants were preterm vs 9 (70%) term deliveries and the most common methods of conception were spontaneous and ovulation induction; post-surgery 11 (31%) infants were born preterm vs 24 (69%) term deliveries, and the most common methods of conception were ovulation induction and in-vitro fertilization. Conclusions: From this initial investigation, we found the incidence of Müllerian anomalies in the SIU Ob/Gyn, REI population is higher than the wide range of reported values. As expected, the vast majority of these patients underwent surgical management with little or no complications. We aim to further study what factors/exposures may be impacting the development of female fetuses resulting in Müllerian anomalies.

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

Sarcoma drug approvals in Latin America compared to the FDA and EMA: An analysis by the LACOG Sarcoma Group.

e13731 Background: Drug approval processes by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) often shape regulatory decisions globally. This study describes the particularities of drug approval of systemic therapies for sarcomas by the FDA and EMA and compares them with those of three Latin American regulatory authorities: Brazil's ANVISA, Argentina's ANMAT, and Mexico's COFEPRIS. The aim is to elucidate the similarities and differences in approval practices, which may inform future regulatory strategies in these regions. Methods: We conducted a comprehensive review of all cancer drugs approved by the FDA and EMA for the treatment of sarcoma over the past 15 years and matched to approvals in Brazil, Argentina, and Mexico. These countries were chosen due to their population size and the accessibility of their health agencies’ databases. The regulatory agencies’ websites were consulted for the registration of drugs approved between January 1st, 2009, and January 1st, 2024. We analyzed the characteristics of studies, availability of approvals based on randomized controlled trials (RCTs), overall survival (OS), and the interval between FDA and EMA approvals compared to each of the three assessed Latin American regulatory agencies. Additionally, we included drugs granted tissue-agnostic approval, recognizing the potential necessity for sarcoma treatments to be guided by biomarker-driven decisions. Results: Over the past 15 years, 19 drugs have been approved for by the FDA to treat sarcomas, and 13 by the EMA. The FDA led the approvals, granting authorization to 18 of these treatments first, with Trabectedin being the sole exception, approved earlier by the EMA and COFEPRIS. Mifamurtide is the only new drug against sarcoma licensed by the EMA but not by the FDA. During this period Argentina approved 8 of these drugs, Mexico 7, and Brazil 6. When comparing the median approval times, there was a 3.03-year interval from the FDA to the Latin American agencies (range: -6 to 5.7 years) and a 3.22-year interval from the EMA (range: -0.2 to 11.8 years). Phase 3 trial-based approvals constituted 83.3% for COFEPRIS, 75% for ANMAT, 66.7% for ANVISA, 61.5% for EMA, and 36.8% for FDA. Regarding approvals contingent on OS data, ANMAT had 37.5%, ANVISA: 33.3%, COFEPRIS 28.5%, compared to EMA 23%, and FDA 10.5%. Additionally, within this timeframe, 52.3% of FDA approvals were contingent on biomarkers, compared to 50% for EMA, 10.5% for ANVISA, and 5.2% for both ANMAT and COFEPRIS. Conclusions: The observed discrepancies in drug approval timelines and the lower number of drug approvals in Latin American countries, as compared to those by the FDA and EMA, may exacerbate disparities in treatment accessibility for sarcoma patients in these regions. Approvals of sarcoma drugs by regulatory agencies of Latin American countries were more frequently conditioned to phase 3 trials and overall survival benefit.

Acceptance of offshore wind farm in Southwest Sardinia in Italy. Do regional energy policies matter?

PurposeThe social acceptance of wind energy is increasingly conditioning the Italian Government and regions to authorize the construction of these plants. The proposal of offshore wind farm in the south-west of Sardinia has raised many perplexities both from the marine environmental point of view and from concern about increasing the electricity production in a region that already exports electricity to the peninsula. The purpose of this study is to evaluate what are the factors that most affect the coastal residents’ acceptability of an offshore wind farm.Design/methodology/approachThe data is based on a Sardinia-wide in-person survey with about 512 participants in the period between May and June 2023. Respondents were selected randomly from five different locations in Carloforte region. Multiple regression analysis investigates the factors that influenced acceptability to construction and development of offshore wind power plant. Four independent variables were selected in the regression models such as (i) interest towards wind energy, (ii) attitude towards renewable energy production, (iii) perceived regional energy policy and (iv) attitude towards offshore wind farm. The dependent variables are the rates of coastal local residents’ acceptance of offshore wind farm for respondents in five coastal towns.FindingsFishermen and summer tourism operators’ respondents expressed significant reluctance to accept the new project because they perceive a strong risk of environmental impact on both tuna fishing and marine recreational activities in the vicinity. The distance between the turbines at sea and local residents along the coast and surrounding small islands does not have an influence to accept wind energy. The energy policy of the Region of Sardinia, which is perceived by respondents as an expansive energy policy in the production of electricity that exceeds their needs, not being accompanied by a scenario of reducing that from fossil fuels, is the variable that led about 70% of respondents to express a negative opinion towards this project.Research limitations/implicationsA potential problem associated with the survey is that local response produced sample selection bias. The proportion of respondents with secondary education and no school certificate is quite high. It is possible that respondents who provided valid questionnaires were more low-educated and therefore, the sample may be biased towards lower-educated people. While this does not invalidate the results of this study, it is important to note that the sample was on average less educated than the overall population in Italy. In addition, people with lower incomes were more likely to complete the questionnaires; the results are more representative of a portion of the population with incomes below the national average.Practical implicationsResults showed how coastal communities are in favour of wind energy within their island, but not within a marine protected area that is considered unique for its beauty and marine ecosystem. Wind energy developers should, before submitting a proposal for an offshore wind farm project, consider among other things the long approval time and understand the activities carried out by local communities and their attachment to those places. Politicians and developers should develop a coherent energy transition policy based on a long-term vision of zero emissions, because according to the findings of this study, it was the regional energy policy that is the most controversial reason for residents to reject the project.Originality/valueThe contribution of this study is to fill a part of the research gap linking to ongoing energy transitions. In particular, this study analysed for the first time in Italy the acceptability level of an offshore renewable energy project considering the environmental implications and risks in the fragile marine ecosystem of Carloforte waters. This study also made it possible to analyse the impact of the regional energy policy on the acceptability of residents towards the development of offshore wind farms, which is scarcely discussed in the literature.

Abstract PO1-17-04: Influence of regulatory agency approval of trastuzumab-deruxtecan on the diagnosis of HER2-low status at a reference cancer center in Brazil

Abstract BACKGROUND HER-2 low status is defined by immunohistochemistry (IHC) expression for human epidermal growth factor receptor 2 (HER-2) 1+ or IHC 2+ without gene ERBB2 amplification. HER2-low breast cancers (BC) accounted for approximately 55% of all cases, and among hormone receptor positive (HR+) tumors it represents up to 60% of patients (pts), while 10-20% in triple negative tumors (TNBC). Trastuzumab-deruxtecan (T-dxd) has been FDA approved for HER-2 low breast cancer after Destiny-Breast 04 trial (DB04) demonstrated a robust overall survival benefit either in HR+ or TNBC heavily pre-treated pts. The Brazilian Health Regulatory Agency (ANVISA) has later approved T-dxd for HER-2 low BC. However, due to its dynamic nature and subjectivity, the definition of HER-2 low status still lacks better criteria. This study aims to evaluate whether HER-2 low status diagnosis was impacted according to the time of the diagnosis - before DB04 publication and after ANVISA drug approval - in a reference cancer center in Brazil. METHODS This retrospective study was conducted in a single institution in Sao Paulo, Brazil. Pts diagnosed with BC between October 1st 2021 to June 1st 2023 were classified in 2 groups according to the time of diagnosis. Group 1 (g.01) included those who were diagnosed between October 1st 2021 until DB04 publication in July 7th 2022; and Group 2 (g.02) included pts diagnosed after ANVISA T-dxd approval on October 31st, 2022 until June 1st 2023. All pathological analysis of the primary breast tumor was performed by 2 experienced breast pathologists. HER-2 IHQ Score was defined according to ASCO/CAP guideline 2018. The primary endpoint was to evaluate the proportion of patients who were defined as HER-2 low according to the time of diagnosis. Secondary endpoint consists in evaluate change in pathologists practice to distinguish IHC 1+ results from 0 after the definition of HER-2 low. To compare the categorical variables between the groups, the Chi-square test was used. P values below 0.05 were considered statistically significant. Statistical analyses were carried out with the R program (R Foundation, Vienna, Austria). RESULTS A total of 713 pts with diagnosis BC were included in the study, 401 (56%) in g.01 and 312 (44%) in g.02. Overall, before DB04 publication, the diagnosis HER “Negative-NOS” without subdivision in score 0 or 1 was found in 127 (31.7%), but only in 27 (8.7%) reports in g.02 (p=0.007-13). HER-2 low status was observed in 12.2% in g01 and in 33.3% of the pts in g.02 (p < 0.00001). Specifically, negative score 0 was found in 45.6% of pts in g.01 and 44.6% in g.02 (p= 0.014). A significant difference was also observed among pts with negative Score 1+ between groups (6.0% vs 21.2%, p=0.009-3), as shown in Table 1. No significant difference was seen in the frequency of HER2 score 2+ and score 3+ between g.01 and g.02. CONCLUSION The recent impact of a highly effective treatment derived from definition of HER-2 low BC led to a greater relevance in differentiating IHC 1+ from IHC 0, both considered HER negative by ASCO/CAP protocols. Distinguishing between HER2 0 and 1+ is subject to considerable interobserver variability , and the time of regulatory approval demonstrated a direct influence on the HER-low diagnosis. Table 1 Distribution of HER2 IHQ results in Group 1 and Group 2 Citation Format: Paula Martinez Vianna, Venancio Avancini Ferreira Alves, Pedro Exman. Influence of regulatory agency approval of trastuzumab-deruxtecan on the diagnosis of HER2-low status at a reference cancer center in Brazil [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-04.

Abstract PO1-11-02: Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review

Abstract BACKGROUND As the treatment for metastatic breast cancer (MBC) often includes sequential lines of therapy, data on post-protocol treatment in clinical trials are valuable in the assessment of long-term outcome. The objective of this study was to assess the reported data on post-protocol therapy in clinical trials supporting US Food and Drug Administration (FDA) approval of drugs for MBC. METHODS We identified all initial and subsequent published trials supporting FDA approved indications for MBC between 1/2000-2/2023. Collected data included study design, patient characteristics and whether reporting on post-protocol therapy was available. Differences in study design and population between studies with and without data on post-protocol therapy were evaluated. FINDINGS A total of 41 indications for MBC were identified. Supporting studies comprised 20,152 patients. Data were evaluated from 241 publications or abstracts. Reporting of post progression therapy was available for 21 (51%) indications. Of these, post-progression therapy data were often partial and the appropriateness of the therapy could not be evaluated. At the time of FDA approval, data on overall survival (OS) were reported only in 17 (41%) studies. Of these, in 8 studies OS was significantly improved, in 7 studies OS was not improved and 2 studies were single arm. Differences between studies with and without data on post progression therapy are presented in the Table. Studies with OS as their primary endpoints were associated with significantly higher reporting of post-protocol therapy, while studies with both OS and progression free survival (PFS) as their primary endpoint had low reporting rate. There were no other statistically significant differences. Reporting post-protocol therapy has not changed over time with reported data in 50% and 52% studies between 2000-2010 and 2011-2023, respectively. CONCLUSIONS Data on post progression therapy in trials supporting FDA approval of drugs for MBC are available in fewer than half of indications. Reported data are often partial and may not include sequential therapies consistent with standard of care. As subsequent lines of therapy may have a crucial role in patients' outcome, post protocol reporting should be included in the regulatory submission and be made available publicly. Differences between studies with and without data on post progression therapy Citation Format: Shlomit Shachar, Yasmin Korzets, Daniel Shepshelovich, Noa Zlotchover, Eitan Amir, Ariadna Tibau, Hadar Goldvaser. Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-02.

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Cancer drug indication approvals in China and the United States: a comparison of approval times and clinical benefit, 2001–2020

Perceived delays in cancer drug approvals have been a major concern for policymakers in China. Policies have been implemented to accelerate the launch of new cancer drugs and indications. This study aimed to assess similarities and differences between China and the United States in the approvals, timing, and clinical benefit evidence of cancer drug indications between 2001 and2020. This study retrospectively identified all cancer drugs and indications approved in both China and the United States from January 1st, 2001 to December 31, 2020, and described differences in approval times as well as in submission and review times. Information on the availability of overall survival benefit evidence by December 31, 2020, was collected. Univariate and multiple logistic regression analyses were used to assess whether evidence of benefit and other factors affected the propensity and timing of approvals of cancer drug indications in China. Between 2001 and 2020, 229 indications corresponding to 145 cancer drugs approved in the United States were identified. Of those, 80 indications (34.9%) were also approved in China by the end of 2020. Cancer drug indications were approved in China at a median of 1273.5 days after approval in the United States. The median submission and review time differences for cancer drug indications in China were 1198.0 days and 180.0 days respectively. Submission time differences accounted for most of the approval time differences (p<0.001). Indications supported by overall survival benefit evidence had shorter median review time differences (145.0 days) than those without such evidence (235.0 days, p=0.008). Indications with overall survival benefit evidence were 3.94 times more likely to be approved in China compared to those without such evidence (p=0.001), controlling for approval year, cancer type, and the prevalence of cancer by site. FDA-approved cancer drug indications demonstrating a survival benefit were more likely to receive approvals in China with shorter regulatory review times compared to indications without such evidence. Given that manufacturer submission times were the main driver of cancer drug approval times in China, factors influencing submission timing should be explored. No funding.

China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)

Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKI) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Prior authorization for FDA-approved PARP inhibitors in ovarian cancer

ObjectivesPARP inhibitors (PARP-I) improve survival in ovarian cancer, especially in patients with germline or somatic BRCA mutations or other homologous recombination deficiency (HRD). With high efficacy and costs, insurers may enact barriers or facilitators to PARP-I. Our objective was to examine the prevalence of prior authorization for PARP-I in ovarian cancer. MethodsWe performed a retrospective cross-sectional study of patients with ovarian cancer prescribed a PARP-I within the University of Pennsylvania practices from December 2018 through May 2021. We assessed prevalence of prior authorization for PARP-I overall, by frontline or recurrent maintenance, and by genetic status. We then assessed approval and appeal rates and time to PARP-I start. ResultsOf 180 patients with a PARP-I prescription and information regarding prior authorization, 116 (64 %, 95 % CI 57–71) experienced prior authorization. Of patients in the frontline setting, 60 of 90 (67 %, 95 % CI 56–76) experienced prior authorization. Of patients prescribed PARP-I in recurrence, 55 of 85 (65 %, 95 % CI 54–74) experienced prior authorization. Having a germline or somatic genetic mutation was associated with higher risk of prior authorization (adjusted risk ratio 1.35, 95 %CI 1.09–1.67). 102 patients (89 %, 95 % CI 83–94) required one appeal, 8 required two appeals and 5 cases required 3 appeals. Five patients were denied. Mean time from PARP-I prescription to PARP-I start was 10 days longer for patients who experienced prior authorization. Conclusions64% of patients experienced prior authorization for PARP-I. Risk of prior authorization was increased for patients with BRCA, despite greater clinical benefit. Prior authorization contributes to delays in care, and reform is needed.

Patient outcomes after therapy with 177Lu-PSMA-617 (LuPSMA) for metastatic castrate-resistant prostate cancer (mCRPC): A tertiary center experience.

87 Background: While LuPSMA has a proven overall survival (OS) benefit in patients (pts) with mCRPC who have received prior taxane chemotherapy and androgen receptor pathway inhibitors, there is limited data on outcomes and efficacy of subsequent therapy in pts who have received LuPSMA. This study aimed to assess the clinical and treatment courses of pts with mCRPC after LuPSMA. Methods: We queried an IRB-approved prospectively maintained registry to evaluate all pts with mCRPC who received standard-of-care LuPSMA at our institution between June 2022 and July 2023. Clinical data pertaining to LuPSMA therapy as well as subsequent treatments were extracted from the medical record, including type and number of subsequent systemic therapies, reason for treatment cessation, hematologic support, and PSA response to subsequent therapy. PSA-50 was defined as a ≥50% decrease in PSA on therapy. Hematologic adverse events to therapies after LuPSMA were recorded and graded per CTCAEv5.0. Results: A total of 96 patients were evaluated; median age was 72 years (range 52-87), and median follow-up was 10 months. 18 pts completed all 6 cycles, 35 discontinued prior to cycle 6 of LuPSMA due to progressive disease, 10 died mid-treatment, and 33 were midway through treatment; median number of cycles received for all pts was 4 (range 1-6). None of the 18 who completed all 6 cycles had yet transitioned to a next line therapy. Of the 35 who discontinued LuPSMA, 17 transitioned to hospice due to disease progression, 15 initiated a subsequent line of therapy, and 3 had a treatment break. Median overall survival was 13 months in the entire cohort. Of the 15 receiving another line of therapy, 11 received cabazitaxel ± carboplatin/cisplatin, 1 received carboplatin with cisplatin substituted during carboplatin shortage, and 4 received other non-chemotherapy regimens; a PSA-50 response to subsequent therapy was seen in 4 patients (27%), all of whom received cabazitaxel ± carboplatin/cisplatin. Of the 12 pts who received chemotherapy, the median number of cycles received was 3 (range 1-7); 4 pts (33%) had grade ≥3 anemia, 2 (17%) had grade ≥3 thrombocytopenia and 7 pts (47%) required platelet growth factor support or transfusion of blood products. Conclusions: 47% of pts discontinuing LuPSMA transitioned to hospice due to disease progression while 44% proceeded to a subsequent line of therapy, the majority of whom received cabazitaxel. Outcomes to subsequent therapy were generally poor, with a 27% PSA-50 response rate. This initial experience may be biased by number of patients with limited standard of care options at the time of FDA approval of LuPSMA and could improve with better patient selection. However, this also highlights the continued need to develop novel therapeutic strategies for CRPC pts post-LuPSMA.

Real-world reporting rates of administration-site reactions with on-demand treatment of hereditary angioedema attacks.

Background: Hereditary angioedema (HAE) is characterized by recurrent and unpredictable episodes of subcutaneous and/or submucosal swelling. Objective: To characterize the real-world treatment burden associated with existing on-demand therapies, we analyzed administration-site adverse drug reactions (ADR) associated with approved on-demand HAE therapies reported in the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). Methods: We searched the FAERS database from October 1, 2009, to March 31, 2022, for reports of all FDA-approved on-demand therapies for HAE: plasma-derived C1-inhibitor (pdC1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (rhC1-INH). ADRs in which the drug was listed as the "primary suspect" were recorded for each drug. ADR preferred terms were grouped into 18 ADR domains based on semantic and/or clinical similarity, and the number of reports for each drug was calculated per year from the time of approval through March 2022, and descriptive results were presented. Preferred terms associated with administration-site ADRs identified from clinical trials and denoted on approved HAE drug U.S. package inserts were examined in a complementary analysis. Results: The highest reported rates of administration-site ADRs per year were site pain (17.9 reports per year), site erythema (7.4 per year), and site swelling (6.7 per year). RhC1-INH was the only drug for which access-site complications and/or malfunctions were reported (9.5 per year). PdC1-INH had the highest rate of incorrect route of product administration (3.7 per year). PdC1-INH showed statistically significant elevated reporting rate of injection-site reactions (reporting odds ratio [ROR] 3.59 [2.36-5.46]; empirical Bayesian geometric mean [EBGM] 1.97 [1.39]). Icatibant and rhC1-INH showed a statistical trend toward an increased reporting rate of administration-site reactions. Conclusion: Real-world data from FAERS were generally consistent with adverse events reported in clinical trials and suggest that patients experience substantial treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks. It should be noted that ADR rates are not exposure adjusted and are based on spontaneous reporting.

Canadian status of "not acceptable" drugs as evaluated by Prescrire: A cohort study.

The independent French drug bulletin Prescrire International rates the therapeutic innovation of new drug-indications approved for marketing in France using an ordinal scale with the lowest rating being "not acceptable". This study investigates whether these drugs were approved by Health Canada. A list of "not acceptable" drug-indications was generated by handsearching all issues of Prescrire International between January 2013 and December 2022. The generic names, indications and reasons why Prescrire labeled them not acceptable were recorded. The approval date was determined by consulting the website of the European Medicines Agency (EMA). The status of these drug-indications in Canada was determined by searching multiple Health Canada websites. Therapeutic Evaluations for new drug-indications done by the Patented Medicine Prices Review Board (PMPRB) were recorded. Prescrire rated 57 new drug-indications and 42 new indications for existing drugs as not acceptable. Seventy of these drug-indications were available in Canada- 42 new drug-indications and 28 new indications for existing drugs. Twenty (90.9%) of the 22 new drugs evaluated by the PMPRB were rated as slight/no therapeutic improvement and 2 as moderate therapeutic improvement. The median difference, in days, between approval times by the EMA/ANSM and Health Canada was 129 (interquartile range -102, 341) in favour of the former. The majority of the not acceptable drug-indications were approved by Health Canada. The difference between when Prescrire and Health Canada examined the evidence for these drug-indications is unlikely to explain the difference in their evaluations. A change in regulatory standards at Health Canada may be one factor behind the presence of these drugs. To what degree those drugs led to more harms than benefits for patients who are taking them needs to be urgently investigated. Finally, the reasoning behind Health Canada's approval of these drugs should be interrogated.

Approval, Evidence, and "Off-Label" Device Utilization: The Patent Foramen Ovale Closure Story.

Following regulatory approval, medical devices may be used "off-label." Patent foramen ovale (PFO) closure is indicated to reduce recurrent stroke but has been proposed for other indications, including migraine, transient ischemic attack, and diving decompression illness. We sought to evaluate PFO closure rates and indications relative to the timing of regulatory approval and publication of key randomized trials. We performed a retrospective cohort study using the OptumLabs Data Warehouse of US commercial insurance enrollees from 2006 to 2019. We quantified PFO closure among individuals with ≥2 years of preprocedure coverage to establish indications, classified hierarchically as stroke/systemic embolism, migraine, transient ischemia attack, or other. We identified 5315 patients undergoing PFO closure (51.8% female, 29.2%≥60 years old), which increased from 4.75 per 100 000 person-years in 2006 to 6.60 per 100 000 person-years in 2019. Patients aged ≥60 years accounted for 29.2% of closures. Procedure volumes corresponded weakly with supportive clinical publications and device approval. Among patients with PFO closure, 58.6% underwent closure for stroke/systemic embolism, 10.2% for transient ischemia attack, 8.8% for migraine, and 22.4% for other indications; 17.6% of patients had atrial fibrillation at baseline; and 11.9% developed atrial fibrillation postprocedure. Those aged ≥60 years and male were less likely to undergo closure for migraine than stroke/systemic embolism. From 2006 to 2019, PFO closure use was consistently low and corresponded weakly with clinical trial publications and regulatory status. Nearly half of patients underwent PFO closure for indications unapproved by the Food and Drug Administration. Regulators and payers should coordinate mechanisms to promote utilization for approved indications to ensure patient safety and should facilitate clinical trials for other possible indications.