New Chemical Entities Research Articles

US FDA's Dose Optimization Postmarketing Requirements and Commitments of Oncology Approvals and the Impact on Product Labels from 2010 to 2022: An Emerging Landscape from Traditional to Novel Therapies.

Dose optimization is a focal point of many US Food and Drug Administration (FDA) drug approvals. We sought to understand the impact of the FDA's Postmarketing Commitments/Postmarketing Requirements (PMCs/PMRs) on dose optimization and prescriber labeling for oncology drugs. Publicly available information was aggregated for all FDA oncology drug approvals between January 1, 2010, and December 31, 2022. Study completion dates were compared to product labeling before and after PMC/PMR fulfillment dates to evaluate labeling changes associated with dose-related PMCs/PMRs. Data were analyzed individually (2010-2015 and 2016-2022) due to differences in available information. From 2010 to 2015, 14 of 42 (33.3%) new molecular entities (NMEs) had dose-related PMCs/PMRs, with 6 of 14 (42.9%) resulting in a relevant label change. From 2016 to 2022, of the 314 new or supplemental applications approved, 21 had dose-related PMCs/PMRs (6.7%), which trended upward over time; 71.4% of dose-related PMCs/PMRs were NMEs. Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were the most affected drug classes. Ten of the 21 approvals with dose-related PMCs/PMRs fulfilled their dosing PMCs/PMRs, and 3 of the 10 (30%) had relevant label changes. Most dose-related PMRs/PMCs were issued for NMEs. Of these, KIs and ADCs/PDCs were highly represented, reflecting their novelty and greater uncertainty around their safety profile. PMC/PMR issuance broadly increased over time. With the implementation of the FDA's Project Optimus in 2021, it remains to be seen whether fewer dose-related PMCs/PMRs emerge in future due to enhanced dose optimization in the premarketing setting.

Semisynthetic phytochemicals in cancer treatment: a medicinal chemistry perspective.

Cancer is the uncontrolled proliferation of abnormal cells that invade other areas, spread to other organs, and cause metastases, which is the most common cause of death. A review of all FDA-approved new molecular entities (NMEs) shows that natural products and derivatives account for over one-third of all NMEs. Before 1940, unmodified products and derivatives accounted for 43% and 14% of NME registrations, respectively. Since then, the share of unmodified products has decreased to 9.5% of all approved NMEs, while the share of derivatives has increased to 28%. Since the 1940s, semi-synthetic and synthetic derivatives of natural substances have gained importance, and this trend continues to date. In this study, we have discussed in detail isolated phytoconstituents with chemical modifications that are either FDA-approved or under clinical trials, such as podophyllotoxin, Taxol (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastine), camptothecin, genistein, cephalotaxine, rohitukine, and many more, which may act as essential leads to the development of novel anticancer agents. Furthermore, we have also discussed recent developments in the most potent semisynthetic phytoconstituents, their unique properties, and their importance in cancer treatment.

Characteristics and outcomes of new molecular oncology drug approvals, in combination or monotherapy

ImportanceUnderstanding the factors that are associated with new molecular entity (NME) cancer drug approvals as a single agent and in combination, and European Society for Medical Oncology (ESMO) scores, can aid in identifying suitable factors to consider in trial designs for future drugs. In addition, the association between the various outcomes can aid in determining benefit when surrogate outcomes are used in approval consideration. ObjectiveThis study aims to (1) use the measures used in evaluating clinical trials by ESMO scores to determine the differences in the characteristics of 2013–2022 Food and Drug Administration (FDA) oncology NME drug approvals for those approved for use in combination or as a monotherapy, and (2) analyze the association between survival outcomes and the response rate for monotherapy NME drugs and/or drugs approved in combination. DesignCross-sectional analysis. SettingUS FDA Oncology Drug Approvals (2013–2022) ParticipantsUS FDA Oncology Drug Approvals (2013–2022) ExposuresTrial-level characteristics (tumor types, basis of approval, randomized or not, phase) and associations between overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) and whether NME drugs were approved as monotherapy or in combination . ResultsDrugs approved for use as a monotherapy are less likely to be approved using a randomized study (p < 0.001) and more likely to be approved via the accelerated pathway (p = 0.012) and be open-label (p < 0.001). Drugs approved for use as a combination or monotherapy significantly differed on their approval basis (p = 0.002), phase of trial at the time of approval (p = 0.02), and ESMO scores (p = 0.02). There was low correlation between response rate and either PFS or OS metrics. However, nearly all of the drugs with large improvements in OS (> 5months) were drugs with robust ORR. Conclusions and relevanceDrugs approved as monotherapy with a low response rate are likely to have marginal benefit in OS and PFS.

In-silico Design of Potent Anti-tubercular Agents containing Isatinylthiosemicarbazone Pharmacophore

A recent study reveals that Isatinylthiosemicarbazone analogues inhibit mycobacterial growth by inhibiting the isocitrate lyase (ICL). Hence two-dimensional (2D), three-dimensional (3D), and group QSAR (GQSAR) studies were performed to reduce the amount of pharmacophore needed to make effective ICL inhibitors. New chemical entities (NCEs) were created based on the findings of all QSAR studies. It was discovered that QSAR models produced noticeably positive statistical findings. i.e. (r2 &gt; 0.7), cross-validation (q2 &gt; 0.6), and external validation (pred_r2 &gt; 0.6), indicating high predictability of all models. Utilizing molecular docking studies, the binding affinities of designed NCEs were investigated for the ICL enzyme (PDB code: 1F8M). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of designed NCEs were expected to have a pharmacokinetic profile similar to their drug. Overall, it is important to state that the methodology used for pharmacophore optimization using 2D, 3D, G-QSAR, and molecular docking ADMET research works was discovered to be extremely accurate.

Approval Delay in Drugs from Non-Global Company in Europe and Japan: Analysis of Novel Drugs for Hematologic Malignancies

Background: Since most therapeutic agents for hematologic malignancies are developed and first approved in the US, it is important for each country to review and approve these agents without delay. Recently, the number of drugs developed by non-global companies including biotech start-ups has increased. Most of these non-global companies are located in the US, and typically do not have offices outside of the US. Thus, it is possible that drugs developed by non-global companies are likely to be approved later in countries other than the US, including the EU. However, their characteristics have not been fully evaluated. Study Design and Methods: Using the public database of the Food and Drug Administration (FDA) from January 2011 to December 2020, new molecular entity (NME) drugs for hematological malignancies that were approved in the US during the relevant period were identified. Cellular products, including chimeric antigen receptor (CAR)-T cells, were excluded from this analysis. NMEs for hematological malignancies were divided into two categories according to the applicant company: NMEs from non-global companies (non-Global group) and NMEs from global companies (Global group). Global companies were defined as those with branches or headquarters in all following regions: the US, the EU, and Japan. The others were classified as non-global companies. Based on the public databases of Japanese regulatory agency (PMDA) and European regulatory agency (EMA), we estimated the rate at which these drugs remained unapproved (unapproved rate) using the Kaplan-Meier method. The unapproved rate of NMEs was compared between the non-Global and Global groups. Results: A total of 39 NMEs for hematologic malignancies approved in the US during the study period were identified. Of these, 13 (33%) NMEs were from non-global companies (non-Global group) and 26 (67%) NMEs were from global companies (Global group). The proportion of orphan drug (13/13 vs. 26/26, p=1.000) and priority review designation (12/13 [92%] vs. 22/26 [85%], p=0.648) were not significantly different between the non-Global and Global groups. In the non-Global group, 12 (92%) NMEs were from the companies headquartered in the US, while 10 (39%) NMEs were from the US companies in the Global group. The proportion of pivotal phase Ⅰ/Ⅱ trial used for marketing authorization in the US was significantly higher in the non-Global group (11/13 [85%] vs. 13/26 [50%], p=0.045). The proportion of pivotal trials enrolling Japanese participants was lower in the non-Global group (0/13) than in the Global group (6/26 [23%]), while the proportion was similar in the EU (9/13 [69%] in the non-Global group and 16/26 [62%] in the Global group). In the EU, the unapproved rate 2 years after the US approval was higher in the non-Global group (54% vs. 22%), but the 5-year unapproved rate was rather lower than that in the Global group (15% vs. 22%) (Figure 1a). Similarly, in Japan, the unapproved rate of NMEs in the non-Global group was higher at 2 years (92% vs. 65%), but rather slightly lower than that in the Global group at 5 years (20% vs. 35%) (Figure 1b). After the US approval, 9 (69%) of the 13 NMEs filed by non-global companies had subsequently partnered with or been acquired by the global companies. Discussion and Conclusion: In both the EU and Japan, drugs in the non-Global group had a higher unapproved rate at 2 years. Notably, 54% of the drugs in the non-Global group were not approved in the EU, even though the participation rate in the pivotal trial used for US approval was similar between the non-Global and Global groups in the EU. However, at 5 years, the unapproved rate had decreased to approximately 20% in both the EU and Japan, presumably due to the fact that lots of the non-global companies were subsequently partnered with or acquired by the global companies.

Solubility Enhancement of Poorly Water-Soluble Drugs by Solid Dispersion Techniques

The fact that newly discovered API’s (about 90%) or new molecular entity (NME) have little or poor aqueous solubility, causes a significant challenges to the initialization of development and commercialization of dosage form at the manufacturing facility. Poor aqueous solubility of API’s has critical role in drug dissolution or availability of drug at the site of actionor bioavailability, when a dosage form is administered orally. Various techniques are available for the enhancement of solubility but all individual techniques have its own limitations for commercialization. The known Solubility enhancement techniques like Solid dispersions involved the dispersion of poorly soluble drug in a suitable inert carrier at a molecular level and form amorphous and highly soluble compounds. The conversion of compound in to amorphous form or reduction of particle size to its molecular level caused enhanced solubility of poorly soluble by the application of solid dispersion techniques.

Evaluation of the impact of reliance on the regulatory performance in the South African Health Products Regulatory Authority: implications for African regulatory authorities.

The World Health Organization (WHO) advocates the use of reliance practices to enable national regulatory authorities (NRAs) to improve patients' access to medicines. This study considered whether reliance review translates into swifter medicine authorization. Abridged review outcomes were examined for New Chemical Entity (NCE) and generic applications to the South African Health Products Regulatory Authority (SAHPRA) in Chemistry, Manufacturing and Controls (CMC) and clinical/bioequivalence (BE), as well as overall NCE authorization times. SAHPRA NCE CMC review time was 91 days (abridged) vs. 179 days (full), applicant response time was 34 vs. 105 days, respectively, and there was a >2-fold time reduction for abridged vs. full CMC review (125 vs. 284 days). There was a 99-day decrease in clinical approval time through an abridged review (230 vs. 329 days) and a decrease in marketing authorization time for NCE abridged assessment (446 vs. 619 days). SAHPRA review time for generic applications was 97 days (abridged) vs. 191 days (full); applicant response time was 26 days (abridged) vs. 81 days (full) and there was a >2-fold time reduction for CMC and BE abridged vs. full review (122 vs. 272 days). These results clearly support World Health Organization recommendations for the use of reliance-based regulatory review to expedite the worldwide availability of safe, effective and needed medications.

Drug Solubility: Importance and Enhancement Techniques

One of the key factors in achieving the optimum drug concentration in the systemic circulation for the desired (expected) pharmacological response is solubility, the phenomenon of solute dissolving in solvent to produce a homogeneous system. The main issue in developing formulations for new chemical entities as well as for generic development is low water solubility. Over 40% of NCES (new chemical entities) created in the pharmaceutical business are essentially water Insoluble. A significant difficulty for formulation scientists is solubility. Any medicine that is to be absorbed must be present in solution at the absorption site. Poorly soluble medications can be made more soluble using a variety of strategies, including physical and chemical drug changes and other approaches like Changed Words – Structural Changes Longest Unchanged Words particle reduction, crystal engineering, salt creation, solid dispersion, surfactant use, complexation, and other processes. The choice of a solubility-improving technique depends on the drug’s properties, the site of absorption, and the requirements for the dosage form.

Acoustic droplet ejection facilitates cell-based high-throughput screenings using natural products

Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field. Industrial-scale HTS of NP libraries can be limited due to the difficulties entailed in working with tiny extract volumes and the variability in viscosity of NP extracts. For these reasons, the implementation of new technologies to miniaturize different reagent volumes grows to be fundamental. Since Acoustic Droplet Ejection (ADE) emerged as a helpful tool in HTS campaigns for the transference of compound libraries. The aim of this work was to test the effectiveness of ADE for the dispensation of NP extract libraries in cell-based HTS assays.

CSL-Tox: an open-source analytical framework for the comparison of short-term and long-term toxicity end points and assessing the need of chronic studies in drug development

In-vivo toxicity assessment is an important step prior to clinical development and is still the main source of data for overall risk assessment of a new molecular entity (NCE). All in-vivo studies are performed according to regulatory requirements and many efforts have been exerted to minimize these studies in accordance with the (Replacement, Reduction and Refinement) 3Rs principle. Many aspects of in-vivo toxicology packages can be optimized to reduce animal use, including the number of studies performed as well as study durations, which is the main focus of this analysis. We performed a statistical comparison of adverse findings observed in 116 short-term versus 78 long-term in-house or in-house sponsored Contract Research Organizations (CRO) studies, in order to explore the possibility of using only short-term studies as a prediction tool for the longer-term effects. All the data analyzed in this study was manually extracted from the toxicology reports (in PDF formats) to construct the dataset. Annotation of treatment related findings was one of the challenges faced during this work. A specific focus was therefore put on the summary and conclusion sections of the reports since they contain expert assessments on whether the findings were considered adverse or were attributed to other reasons. Our analysis showed a general good concordance between short-term and long-term toxicity findings for large molecules and the majority of small molecules. Less concordance was seen for certain body organs, which can be named as “target organ systems’ findings”. While this work supports the minimization of long-term studies, a larger-scale effort would be needed to provide more evidence. We therefore present the steps performed in this study as an open-source R workflow for the Comparison of Short-term and Long-term Toxicity studies (CSL-Tox). The dataset used in the work is provided to allow researchers to reproduce such analysis, re-evaluate the statistical tools used and promote large-scale application of this study. Important aspects of animal research reproducibility are highlighted in this work, specifically, the necessity of a reproducible adverse effects reporting system and utilization of the controlled terminologies in-vivo toxicology reports and finally the importance of open-source analytical workflows that can be assessed by other scientists in the field of preclinical toxicology.

DESIGN OF POTENT ANTICANCER MOLECULES COMPRISING PYRAZOLYL-THIAZOLINONE ANALOGS USING MOLECULAR MODELLING STUDIES FOR PHARMACOPHORE OPTIMIZATION

Objectives: Numerous tiny receptor tyrosine kinase inhibitors have been reported as anticancer medications over the past 10 years. However, a lot of them lack effectiveness in vivo, selectivity, or do not last long before developing resistance. Methods: We used molecular modeling research to improve the pharmacophore to get beyond these limitations. For the purpose of linking the chemical makeup of pyrazolyl thiazolinone analogs with their anticancer activity, quantitative structure activity relationship (QSAR) investigations in two dimensions (2D) and three dimensions (3D) were carried out. Pyrazolyl thiazolinone pharmacophore’s stearic, electronic, and hydrophobic requirements were calculated using 3D QSAR. Results: By leveraging the findings of QSAR investigations, the pharmacophore was refined and new chemical entities (NCEs) were generated. The r2 and q2 values obtained for the best model No. 4 of 2D QSAR were 0.9244 and 0.8701, respectively. A drug-like pharmacokinetic profile was ensured by studying the binding affinities of proposed NCEs on epidermal growth factor receptor-TK using docking studies and estimating their absorption, distribution, metabolism, and excretion features. Conclusion: When statistical significance is closely examined, predictability of the model and its residuals (actual activity minus predicted activity) is found to be close to zero, leading us to draw the conclusion that the logic behind the design of NCEs was determined to be sound.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Design, Synthesis, Molecular Docking, ADMET, and Biological Studies of Some Novel 1,2,3-Triazole Linked Tetrazoles as Anticancer Agents.

1,2,3-Triazole-tetrazoles have received substantial attention because of their unique bioisosteric properties and an extraordinarily broad spectrum of biological activity, making them interesting for the drug design, and synthesis of a delightful class of widely investigated heterocyclic compounds. To address major health concerns, it is consequently important to devote ongoing effort to the identification and development of New Chemical Entities (NCEs) as possible anticancer medicines. We began our initial investigation of the reaction between 5-(azidomethyl)-1H-pyrrolo[ 2,3-b]pyridine and 1-phenyl substituted-5-(prop-2-yn-1-ylthio)-1 H-tetrazole under click chemistry to give the corresponding triazole precursors and screened for their cytotoxicity reported by variations in therapeutic actions of the parent molecule. All of the prepared scaffolds were characterized by proton, carbon resonance spectroscopy, IR, and mass spectral techniques. When tested for in vitro antitumor activity the prepared compounds 7e, 7h had a significant anticancer activity against human adenocarcinoma Hs766T cell line with IC50 = 5.33, 4.92 μg/mL and Hs460 cell line with IC50 = 4.82, 6.15 μg/mL respectively. Final scaffolds 7f, 7h, and 7j acquire the highest potential drug binding scores ΔG = -10.42, -8.80, -9.37 Kcal/, with amino acids residues Ala A:11 (2.195 A˚), Asp A:119 (1.991 A˚), Thr A:58 (1.890 A˚), Lys A:16 (1.253 A˚), Asp A:38 (2.013 A˚), Lys A:117 (2.046 A˚) respectively and process Lipinski's rule of five as good agents for oral bioavailability. The molecular framework for the synthesis of novel Aza indole 1,2,3-triazole scaffolds coupled to tetrazole core was discovered in our study and evaluated for their anticancer activity.

Drug repurposing: A futuristic approach in drug discovery

Drug repurposing (DR), also known as drug repositioning, is a strategy aimed at identifying new therapeutic uses for existing drugs. It offers an effective approach to discovering or developing drug molecules with novel pharmacological or therapeutic indications. In recent years, pharmaceutical companies have increasingly embraced the drug repurposing strategy in their drug discovery and development programs, leading to the identification of new biological targets. This strategy is highly efficient, time-saving, cost-effective, and carries a lower risk of failure compared to traditional drug discovery methods. By maximizing the therapeutic value of existing drugs, drug repurposing increases the likelihood of success. It serves as a valuable alternative to the lengthy, expensive, and resource-intensive process of finding new molecular entities (NMEs) through traditional or de novo drug discovery approaches. Drug repurposing combines activity-based or experimental methods with in silico-based or computational approaches to rationally develop or identify new uses for drug molecules. It leverages the existing safety data of drugs tested in humans and redirects their application based on valid target molecules. This approach holds great promise, particularly in addressing rare, difficult-to-treat diseases, and neglected diseases. By utilizing the wealth of knowledge and resources available, drug repurposing presents an emerging strategy for optimizing the therapeutic potential of existing medicines. It offers a pathway to rapidly identify effective treatments and repurpose approved drugs for new indications, benefiting patients and healthcare systems alike.

In vitro dissolution/permeation tools for amorphous solid dispersions bioavailability forecasting I: Experimental design for PermeaLoop™

Along with the increasing demand for candidate-enabling formulations comes the need for appropriate in vitro bioavailability forecasting. Dissolution/permeation (D/P) systems employing cell-free permeation barriers are increasingly gaining interest, due to their low cost and easy application as passive diffusion bio-predictive profiling in drug product development, as this accounts for nearly 75% of new chemical entities (NCEs) absorption mechanism.To this end, this study comprises theoretical considerations on the design and experimental work towards the establishment and optimization of a PermeaLoop™ based dissolution/permeation assay to simultaneously evaluate the drug release and permeation using Itraconazole (ITZ)-based amorphous solid dispersions (ASD) formulations, with different drug loads, based on a solvent-shift approach. Alternative method conditions were tested such as: donor medium, acceptor medium and permeation barrier were screened using both PermeaPad® and PermeaPlain® 96-well plates. A range of solubilizers, namely Sodium Dodecyl Sulfate, Vitamin E-TPGS and hydroxypropyl-β-cyclodextrin, were screened as possible solubilizing additives to the acceptor medium, while donor medium was varied between blank FaSSIF (phosphate buffer) and FaSSIF. The method optimization also included the ITZ dose selection, being the ITZ single dose (100 mg) considered the most adequate to be used in further experiments to allow the comparison with in vivo studies.In the end, a standardized approach that may be applied to predict the bioavailability of weakly basic poorly soluble drug-based formulations is described, contributing to strengthening the analytical portfolio of in vitro pre-clinical drug product development.

AUDIT OF USFDA APPROVALS FOR 2022 FROM THE PERSPECTIVE OF INNOVATION

Objectives: The United States of America (USA) is having a unique place in global innovation within the health-care sector due to the presence of a large number of research-oriented biopharmaceutical companies, contract research organizations, and government research agencies. The aim of this study was to analyze the U.S. Food and Drug Administration (USFDA) approvals for 2022 to increase the awareness among health-care professionals for better clinical decisions. Methods: This was an observational study conducted using online database of USFDA which is accessible freely by the public. The USFDA approvals for 2022 were assessed for new molecular entities (NMEs) including their source and therapeutic area, new indications (NIs) of previously approved drugs, new label extensions (NLEs) of previously approved drugs, new routes of administration (NRAs) of previously approved drugs, and new dosage forms (NDFs) of previously approved drugs. The data obtained were arranged in the tabular form using Microsoft Office Excel 2007. Descriptive statistics was used for analysis. Results: Out of 118 USFDA approvals considered for this study, 25.4% of them were given for NMEs, 27.9% approvals were given for NIs, 33.8% approvals were given for NLEs, 6.7% approvals were given for NRAs, and the remaining 5.9% approvals were given for NDFs. 14 out of 30 NMEs were biologicals and 43.3% of NMEs were indicated for different types of cancer. Conclusion: The USFDA continued to adopt several approaches such as Fast Track process, breakthrough therapy process, accelerated approval process, and priority review process to encourage the research-based biopharmaceutical companies involved in the development of therapeutic options for patients suffering from common as well as rare diseases. More emphasis was given to the approvals of anticancer drugs given the limited options available to treat the cancer in advanced or metastatic stages. However, a lack of discovery and development of antimicrobials with novel mechanism of actions to combat resistance is a cause of concern.

Anti-infectives Developed as Racemic Drugs in the 21st Century: Norm or Exception?

This viewpoint outlines the case for developing new chemical entities (NCEs) as racemates in infectious diseases and where both enantiomers and racemate retain similar on- and off-target activities as well as similar PK profiles. There are not major regulatory impediments for the development of a racemic drug, and minimizing the manufacturing costs becomes a particularly important objective when bringing an anti-infective therapeutic to the marketplace in the endemic settings of infectious diseases.

EE318 Trends in Prices of New Oral Drugs for Chronic Use Approved By the FDA (1980-2021)

To assess the trends and factors associated with the price at market entry of new molecular entities (NMEs) with oral formulations and chronic use approved by the FDA between 1980 and 2021.

Dosage optimization in drug development: An FDA Project Optimus analysis of postmarketing requirements issued to repair the cracks.

1598 Background: Dosage optimization (DO) is a critical aspect of oncology drug development. Because of this, the US FDA, through Project Optimus, has focused on reforming the DO and dosage selection paradigm for oncology products. When approving products, FDA may determine that although the recommended dosage possesses a favorable benefit:risk (BR) profile, there are significant safety concerns that require evaluation of alternative dosages to potentially improve the BR profile. Such postmarketing requirements (PMRs)—issued as a condition of approval—are examined here to better understand the characteristics and potential limitations of DO studies in the postmarketing setting. Methods: Between Jan. 1, 2010 to Dec. 31, 2022, oncology new molecular entities (NMEs) and original applications for biologics, hereafter referred to as new drugs, approved by CDER with at least one PMR issued for DO were identified in the FDA electronic records database. The designs and results of the associated trials or analyses for these PMRs, along with the status of the PMRs, were collected and evaluated. Results: There were 24 PMRs issued for 21 new drugs (15% of 138 total approved new drugs). The most common drug classes were: tyrosine kinase inhibitors (TKIs) (10), antibody drug conjugates (ADCs) (3), or GTPase Inhibitors (2). The following trials or analyses were planned to address these PMRs: randomized dose-comparison trials (18), non-randomized dose-finding trials (2), food effect trials (2), exposure-response analysis (1), and pending (1). The planned sample sizes for the 18 dose-comparison trials were 3 with &lt;100 patients, 4 with 100 to 199 patients, 7 with 200 to 500 patients, and 4 with &gt;500 patients. The dose-comparison trials used the following (co)primary endpoints: response rate (12), safety (7), OS (3), and PFS (2). Fourteen PMRs were either fulfilled (11) or released (3). Of the 11 fulfilled PMRs, 8 led to dosage changes for 5 new drugs (cabazitaxel, carfilzomib, ponatinib, ceritinib, and pexidartinib), and 3 did not lead to dosage changes. Ten PMRs are ongoing. The median time from issuance to fulfillment or release (not including ongoing PMRs) was 6 years (range: 0.7 to 8.3). Conclusions: A high proportion (15%) of new drugs required a PMR, which generally involved conducting a randomized trial with a substantial patient enrollment to evaluate an alternative dosage(s). This process was slow with a median of 6 years to fulfill a PMR. DO in the premarket setting has the potential to rapidly maximize BR, avoiding both patient exposure to unnecessary toxicity and large, resource-intensive, multi-year postmarketing trials. Project Optimus is working with stakeholders to advance a DO paradigm that occurs early and throughout premarket development to ensure an optimized recommended dosage at the time of approval.

Factors Affecting Success of New Drug Clinical Trials.

Clinical trials are an essential process in the development of new drugs. In spite of time-consuming processes and high costs, the overall success rate of clinical trials is only 7.9%, which is a high risk for biopharmaceutical companies. However, despite these huge risks, research on finding factors affecting clinical trials to overcome and manage to risks has been insufficient. Considering these characteristics of the pharmaceutical industry, this study investigated the factors affecting the success of sponsor-initiated clinical trials. The success factors investigated were categorized into four factors: quality of clinical trials, speed of clinical trials, relationship type, and communication. Logistic regression was performed to measure each factor by analyzing 24,295 cases of Phase 1 to 4 trials from ClinicalTrials.gov. Because of the analysis, the factors affecting the success of the clinical trials were varied according to each clinical phase and the drug types: New Molecular Entity (NME)/Biologics, and the success ratio in the quality variable affected the overall clinical trial phases. Additionally, the experience, speed, relationship type, and communication variables were also found to be statistically significant for the success of each phase and drug type.