QT Myopia and Cardiac Safety: Expanding the Aperture of Arrhythmia Assessment in Early Phase Drug Development.

Toxicity of agents used for opioid withdrawal: a case-based approach.

To assess the effect of elotuzumab on corrected QT (QTc) intervals and cardiac safety. Patients with high-risk smoldering multiple myeloma who had been treated with elotuzumab monotherapy (10 or 20mg/kg) in Study CA204011 (NCT01441973) underwent electrocardiogram (ECG) examination over 8-10weeks (treatment cycles 1-3). ECG intervals and changes relative to baseline were assessed. The key ECG endpoint was change from baseline in QT interval corrected with Fridericia's method (ΔQTcF). The relationship between elotuzumab concentration and ΔQTcF was assessed using time-matched ΔQTcF data and linear regression. Adverse events (AEs) potentially related to abnormal ECG findings were summarized. There was no trend of change from baseline in QTcF, PR and QRS intervals among all 31 evaluable patients from Study CA204011, and no patient assessed had a QTcF interval >480ms or a ΔQTcF >60ms. Concentration-response modeling indicated that there was no significant relationship between ΔQTcF and elotuzumab serum concentration: Upper limits of 90% confidence intervals for mean change in QTcF were <10ms over the range of observed elotuzumab concentrations. No ECG-assessed patient had an AE associated with abnormal ECG findings potentially related to proarrhythmia. Study CA204011 ECG data indicate that elotuzumab treatment was not associated with QT/QTc prolongation. Concentration-response modeling demonstrated that baseline-adjusted QTcF changes did not cross thresholds for clinical or regulatory concern.

ObjectivesTo understand the regulatory landscape in the UK and globally before the introduction of the Medicines and Healthcare Products Regulatory Agency’s (MHRA) International Recognition Procedure (IRP). This paper aims to inform on the IRP’s potential impact on access to innovative medicines, by comparing medicines approval in the UK with other international regulatory agencies.MethodsA retrospective analysis of 154 technologies (medicine(s) + studied indication(s)) was conducted based on the National Institute for Health and Care Research Innovation Observatory technology briefings submitted to the National Institute for Health and Care Excellence (NICE) in 2020. These briefings serve as the trigger for the NICE Technology Assessment process. Data on the medicines’ submission and approval dates were extracted across five IRP reference regulators, which are the regulators from the US (Food and Drug Administration (FDA)), European Union (EU) (European Medicines Agency (EMA)), Japan (Pharmaceuticals and Medical Devices Agency (PMDA)), Australia (Therapeutic Goods Administration (TGA)) and Singapore (Health Science Authority (HSA)). The dates were compared with data from the UK (MHRA).Results95 (62%) medicines were approved by at least one regulatory agency, while 59 (38%) medicines were not approved by any regulatory agency. The number of medicines approved by the following regulatory agencies is FDA (n=84, 55%), EMA (n=80, 52%), MHRA (n=71, 46%), TGA (n=51, 33%), HSA (n=41, 27%) and PMDA (n=38, 25%). The first submissions were primarily to the FDA (n=64) or the EMA (n=24). The FDA had the highest number of first approvals (n=70), followed by the EMA (n=17), PMDA (n=5) and the MHRA (n=1). The FDA used more expedited pathways than other regulators (n=61). Compared with the MHRA, FDA approvals were on average 360 days faster and EMA approvals 86 days faster.ConclusionThere were significant differences in market access timelines across the five reference regulators, with the FDA and EMA having the highest number of approved medicines, first submissions and first approvals. IRP applications with the FDA or EMA as reference regulators may expedite access to innovative medicines in the UK by reducing the approval dates gap between the FDA/EMA and the MHRA. This understanding of the regulatory landscape will help inform future planning to accommodate the disruption that the IRP may cause.

Ivabradine toxicity: A case report and review

More transparency for clinical trial data: The decision by the European Medicines Agency to make clinical trial reports publicly available could provide a boon for biomedical research.

Endpoints of Clinical Trials for Marketing Authorization of Drugs for Hematologic Malignancy in Japan, the US and the EU

Electrocardiographic intervals in nonagenarians: What are the “normals”?

149 Background: New anticancer therapies have led to substantial improvements in prognosis across many cancers. Commercial access to a drug is not possible until the drug has received regional regulatory authority market authorization. In prior work (1), we found that European Medicines Agency (EMA) drug approvals frequently lagged US Food and Drug Administration (FDA) approvals from 2010-2019. Here, we expand the analytic time period to 2004-2023 and include two additional regulatory agencies – Health Canada (HC) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). Methods: Drugs with an anticancer indication and first global approval from 2004-2023 were preliminarily identified. Only drugs with an approval by all 4 regulators were included. For each drug, the first and last regulator’s initial approval dates were determined, and the interval between first and last approval was calculated. For drugs approved by all 4 regulators within 1 year (y), it was further determined whether they were considered first-in-class. Results: 209 drugs met the preliminary criteria, and 98 (47%) had approvals by all 4 regulators. The FDA was most commonly the first to approve (84 drugs), followed by PMDA (9 drugs), then EMA (5 drugs); HC was never first to approve. 43 of the FDA-first approvals (51%) were by the accelerated approval (AA) pathway; none of the EMA-first approvals were on the conditional marketing pathway. PMDA was most commonly the last to approve (62 drugs), followed by HC (21 drugs), the EMA (14 drugs), then the FDA (1 drug). The median (IQR) time between first and last regulator’s first approval was 2.4 y (1.3-3.5 y). Some drugs had &gt;5 y between first and last regulator’s approval (Table 1). Conversely, only 16 drugs were approved by all regulators within 1 y, and only 1 drug (isatuximab) was approved by all within 6 months. Of the 16 drugs approved within 1 y by all regulators, 6 (37.5%) were first-in-class: asciminib, elotuzumab, idecabtagene vicleucel, inotuzumab ozogamicin, sotorasib, and trastuzumab emtansine. Conclusions: This study shows that patients with cancer in the US usually have access to new cancer drugs earlier than those in Europe, Japan, and Canada, at least in part due to AA pathways. Less than 8% of newly approved cancer therapies are approved by all 4 regulatory agencies within 1 y of first approval, with a lengthy median first-to-last delay that could exceed the life expectancy of many patients with advanced cancer. Greater global regulatory collaboration in the approval of new anticancer drugs is essential to ensure patients have aligned and coordinated access. (1) Lythgoe et al. JAMA Network Open 2022.[Table: see text]

Introduction: Ondansetron is a 5-HT3 receptor antagonist commonly used as an antiemetic to prevent nausea and vomiting associated with anti-cancer drugs, cancer radiotherapy or postoperatively. Recently, the US Food and Drug Administration (FDA) issued a warning for ondansetron due to a potential for prolongation of the QT interval of the electrocardiogram (ECG), a phenomenon that is associated with an increased risk of the potentially fatal arrhythmia torsade de pointes.Areas covered: The authors undertook a review of the cardiac safety of ondansetron. Their primary sources of information were PubMed (with downloading of full articles) and the Internet.Expert opinion: The dose of ondansetron that the FDA has concerns about is 32 mg i.v. (or several doses that are equivalent to this), which is only used in preventing nausea and vomiting associated with cancer chemotherapy. This suggests that ondansetron may be safe in lower doses used to prevent nausea and vomiting in radiation treatment or postoperatively. However, as there is a report that a lower dose of ondansetron prolonged the QT interval in healthy volunteers, this needs to be clarified by the FDA. More research needs to be undertaken on the relationship between QT prolongation and torsades in order that the FDA can produce clear-cut evidence of proarrhythmic risk when introducing warnings for this.

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

Prolongation of the QTc interval has been associated with proarrhythmia resulting from a potentially fatal form of polymorphic ventricular tachycardia called torsades de pointes (TdP). Genetic forms of the long-QT syndrome (LQTS) associated with high arrhythmic risk have been causally related to mutations in ion channels responsible for the cardiac action potential; genetic factors associated with milder degrees of QTc prolongation and arrhythmic risk have also been described. Acquired forms of QTc prolongation and proarrhythmia, particularly related to drug therapy, are frequently related to drug effects on the same ion channels involved in genetic forms of LQTS. As is true for genetic forms of LQTS, there is a wide spectrum of potential drug effects on the QTc interval ranging from trivial to potentially lethal. Drug-induced QTc prolongation is a complicated phenomenon related not just to the properties or dose of a particular drug but also to drug-drug interactions and a variety of patient factors, including age, gender, the presence and severity of underlying heart disease, and genetic predisposition. Additionally, drug effects on other ion channels, including blockade of sodium channels (causing prolongation of the QRS interval rather than the QTc interval), are an important cause of drug-induced proarrhythmia. The purpose of this review is to summarize the available data related to acquired forms of LQTS, with particular focus on drug-related LQTS and proarrhythmia. A brief summary is presented here of genetic LQTS because the relevant genes and proteins form the basis for an understanding of the causes of acquired LQTS, and in any given patient, the QTc is determined by genetic, substrate, and environmental factors. Emphasis is placed on practical strategies for clinicians, with the goal of minimizing the risk of dangerous proarrhythmia related to the use of both cardiac and noncardiac drugs with the potential for QTc prolongation. Genetic …

No evidence of association between habitual physical activity and ECG traits: Insights from the electronic Framingham Heart Study

To clarify the rationales of delay or difference in the review of new drug applications among regulatory authorities for new drugs, those first approved in the world being in Japan. Among 80 new drugs first approved in Japan from 2008 to 2019, we identified those subsequently approved in the USA or Europe. Significant delays in approval time (boxplot outliers) and the rationales for the delays were assessed among the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Of the 80 Japan-first approvals, 25 and 24 were approved in the USA and Europe, respectively, and their median approval times in Japan, the USA and Europe were 285, 334 and 477 days, respectively. Significant delays were identified for pirfenidone (1806 days, FDA), alogliptin benzoate (1856 days, FDA), insulin degludec (1457 days, FDA) and romosozumab (750 days, PMDA; 994 days, FDA; 748 days, EMA). Due to concerns about cardiovascular risk, alogliptin benzoate and insulin degludec were requested for additional clinical trials by the FDA, and romosozumab required a much longer review period than the standard approval time in all three regions. Among the new drugs significantly delayed in approval time in Japan, the USA or Europe, there were some differences in the requirements, the participating regions and the assessment of clinical trials. The regulatory views on the cardiovascular risk also differed among the three regions. These divergences may be associated with the differences in approval histories.

1575 Background: Novel therapies are transforming cancer care. Regulatory review and approval are essential to deliver safe and efficacious innovations to patients. Studies prior to 2010 describe quicker approval decisions for new oncology drug registrations with the FDA compared to the EMA (median delay 238 days). Both regulatory agencies have subsequently improved procedures to expedite approval times. We compared regulatory market authorisation dates at the FDA and EMA for new oncology therapies from 2010-2020. Methods: New oncology therapeutic approvals between 2010-2020 were identified from the FDA and EMA regulatory databases. We analysed only initial approvals (not supplementary licenses) for active anti-cancer therapies (excluding biosimilars and supportive drugs). The delay in regulatory approval between the FDA and EMA was calculated in calendar days. We further analysed therapies by therapeutic class, evaluating for significant differences. Results: We identified 108 new therapy registrations during the study period. 104 (96.3%) therapies were approved by the FDA and 90 (83.3%) had EMA market authorisation. 4 (3.7%) drugs were not FDA registered, including 3 unsuccessful applications and 1 which sought licensing in a different indication. 18 (16.5%) drugs were not EMA registered, including 9 (8.8%) which did not pursue EMA licensing, 3 (2.9%) withdrawn licensing applications, 3 (2.9%) sought licensing in different tumour group/indication, 1 (0.9%) rejected application and 2 (1.9%) with applications under review at submission date. Of the 86 drugs approved by both agencies, 80 were approved first by the FDA and 6 by the EMA. The median delay in approval between the FDA and EMA was 227 days (IQR:124-354 days). Table shows approvals by therapeutic class. The shortest median time difference for approval was for monoclonal antibodies (171 days) with the longest for kinase inhibitors (281 days). Conclusions: This study shows more new oncology therapies are approved by the FDA than the EMA. Patients in the US typically have access to approved therapies earlier than in Europe. From 2010 to 2020 the median delay between FDA and EMA approval was 227 days, falling by 11 days compared to 2003-10, [non-statistically significant]. Such lengthy delays could exceed the life expectancy of many patients with advanced cancer. Innovations for accelerated approval at both the FDA (e.g. Project Orbis) and EMA (e.g., PRIME) have potential to lead to faster approval.[Table: see text]

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.