New Chemical Entities Research Articles

Conditional early approval for new drug applications in Japan: Current and emerging issues.

Conditional early approval for new drug applications in Japan: Current and emerging issues.

The Irwin Test and Functional Observational Battery (FOB) for Assessing the Effects of Compounds on Behavior, Physiology, and Safety Pharmacology in Rodents.

The modified Irwin procedure or functional observational battery (FOB) can be used to achieve several goals. New chemical entities (NCEs) can be behaviorally screened for nervous system effects at a variety of doses to identify potential therapeutic uses and in the selection of appropriate doses for subsequent assays. NCEs can also be evaluated in the behavioral battery and compared with reference standards to assess liabilities in a new compound class, with an estimated therapeutic index being suggested by the doses used in comparison to therapeutic doses. For the assessment of neurotoxicology, the FOB is often used. The differences between the two assays are subtle. The procedures used are essentially the same, but when considering neurotoxicology, the FOB is often conducted using GLP guidelines, with more animals being used per group, and doses that are low enough to determine a no effect level and high enough to induce marked nervous system behaviors. © 2023 Wiley Periodicals LLC. Basic Protocol: The Irwin test and FOB for assessing the effects of compounds on behavior, physiology, and safety pharmacology in rodents.

Development of solid dispersions based on 3- (2,6-difluorobenzyl) -5- (5-bromo-1H-indol-3-ylmethylene) thiazolidine-2,4-dione for schistosomicidal treatment

Schistosomiasis is an endemic disease in Brazil. It is important to broaden the treatment options to control and containment of the disease. Thiazolidine derivatives appear as important alternatives to treatment. In vitro studies have demonstrated excellent schistosomiasis activity for LPSF/GQ-238. The molecule, however, has poorly water-soluble. This study focused on increasing the aqueous solubility of LPSF/GQ-238 by obtaining solid dispersions. Were prepared by the solvent techniques, using Soluplus®, Polyethylene glycol (PEG), and Polyvinylpyrrolidone (PVP-K30) as carriers. Solubility tests, Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), Exploratory Differential Calorimetry (DSC), and Raman Spectroscopy characterized these new intermediate products. The solubility tests showed that the higher the proportion of polymer used in the preparation of the dispersion, the greater the solubility presented. The observation of the morphology by SEM analysis, elucidated, that the new chemical entity (NCE) has a characteristic crystalline structure. The folding of this structure by the polymer was observed in all analyzed dispersions, thus demonstrating the amorphous state of the product. The scales observed in the structures of the dispersions demonstrate the successive wrinkles that occurred. The greater the proportion of the polymer, the greater the number of folds that occurred, which may explain the greater solubility observed in these preparations. The X-ray diffraction profile of the NCE reveals the presence of intense peaks, presenting a crystalline pattern. The polymer, on the other hand, shows amorphous nature, evidenced by the absence of peaks. All the analyzed dispersions did not present the characteristic peaks of the NCE, evidencing the amorphous behavior of the products. The thermal degradation profile of the NCE presents a characteristic crystalline structure endothermic peak. This peak was not observed in any of the obtained dispersions, evidencing the obtaining of a new solid state. Raman spectroscopy showed that peaks in the range 200–400 (cm-1) by NCE were lost when compared to all analyzed dispersions, showing a slight change in the structure of the molecule when dispersed, probably due tothe formation of hydrogen bonds with the polymer. The in vitro study showed a significant improvement in the activity of the NCE against the adult worm and to the schistosomulae. It was possible to observe that the obtained solid dispersions were physicochemically and biologically viable for schistosomicidal treatment due to the increase of solubility of the molecule.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

Abstract 3448: Discovery of HYP-2A,a 2nd- generation KRASG12C inhibitor exhibits potent in vivo efficacy in drug resistant tumor models

Abstract Although activating mutations in KRAS are well recognized as a hallmark of cancer, KRAS was considered an undruggable target for over 30 years after its discovery, due to the intrinsic characteristics of KRAS proteins. The pocket of KRAS is small and has a considerably smooth and shallow surface, resulting in difficulty for small molecule to bind to the protein. Recent accelerated approval of Sotorasib (AMG 510) by FDA marked the first marketed KRASG12C inhibitor for the treatment of 2nd line KRASG12C mutation-positive NSCLC patients. Although great clinical benefits were delivered by this breakthrough medicine, intrinsic or acquired drug resistances were developed in a large portion of patients treated. HYP-2A is a new chemical entity (NCE) being developed by Sichuan Huiyu Pharmaceuticals for the treatment of KRASG12C inhibitor resistant tumors. It is an orally bioavailable, potent KRASG12C inhibitor that shows very high anti-proliferation activities in NCI-H358 cell line and various Sotorasib and Adagrasib (MRTX 849) resistant tumor cell lines in vitro and demonstrates strong in vivo efficacy in the corresponding xenograft mouse models. It inhibits NCI-H358, H358 AMGR, Mia PaCa-2, PaCa-2 AMGR, KYSE-410, and SW1573 cell lines with IC50 values range from low double-digit to single-digit nanomolar. When dosing at 10 mpk via PO, HYP-2A demonstrates significant efficacy (TGI > 75%) in SW1573 Xenograph mouse model, whereas neither Sotorasib nor Adagrasib shows any obvious efficacy at 30 mpk with TGIs less than 20% in the same experiment. Similarly, when dosing at 10 mpk via PO, HYP-2A exhibits strong efficacy (TGI > 90%) in KYSE-410 Xenograph mouse model, while neither Sotorasib nor Adagrasib shows any significant efficacy (TGI < 50%) at 30 mpk via PO dosing in the same experiment. In an acute toxicity study in rats, the maximum tolerated dose (MTD) of HYP-2A is found higher than 30 mpk. In a two-week toxicity studies in rodents, rats are found well tolerated when treated with HYP-2A via PO at 3-10mpk (QD) for 14 consecutive days. The MTD of HYP-2A is determined higher than 10 mpk. In this presentation, we will highlight the research program that leads to the discovery of HYP-2A, which is currently under IND-enabling studies. Citation Format: Shoujun Chen, Xiaoming Qiang, Haibo Wang, Yong Xiong, Ke Liu, Dengming Liao, Nan Zhong, Mingdeng Liu, Xuemei Mu, Rudan Huang, Min Li, Dengwei Gui, Meilin Huang, Yuting Chen, Yuanfu Pan, Wengang Yao, Yingte Song, Zhongbo Wang, Wenbin Wang, Jun Liu, Xingchi Yu, Zhen Liang, Yike Yuan, Zhao Ding. Discovery of HYP-2A,a 2nd- generation KRASG12C inhibitor exhibits potent in vivo efficacy in drug resistant tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3448.

Evaluation of clinical trial designs for novel anticancer drugs in China: A cohort study of drugs approved between 2015 and 2021

China has greatly facilitated the approval of many novel anticancer drugs since the drug regulatory reform in 2015. Here, we review the clinical trial designs used in pivotal clinical trials for approved anticancer agents in China from 2015 to 2021. Overall, 79 new molecular entities (NMEs) with 140 anticancer indications were identified. Of these, adaptive randomized controlled trial (RCT) designs were used most frequently in pivotal clinical trials (n=83, 49%), followed by single-arm design trials (n=52, 30%) and traditional RCT design trials (n=36, 21%). The single-arm trials and adaptive RCTs can significantly shorten clinical trial duration compared with traditional RCT designs. Our findings showed that novel clinical trial designs were widely used in China to accelerate the launch of anticancer drugs.

Does Therapeutic Repurposing in Cancer Meet the Expectations of Having Drugs at a Lower Price?

Therapeutic repurposing emerged as an alternative to the traditional drug discovery and development model (DDD) of new molecular entities (NMEs). It was anticipated that by being faster, safer, and cheaper, the development would result in lower-cost drugs. As defined in this work, a repurposed cancer drug is one approved by a health regulatory authority against a non-cancer indication that then gains new approval for cancer. With this definition, only three drugs are repurposed for cancer: Bacillus Calmette-Guerin (BCG) vaccine (superficial bladder cancer, thalidomide [multiple myeloma], and propranolol [infantile hemangioma]). Each of these has a different history regarding price and affordability, and it is not yet possible to generalize the impact of drug repurposing on the final price to the patient. However, the development, including the price, does not differ significantly from an NME. For the end consumer, the product's price is unrelated to whether it followed the classical development or repurposing. Economic constraints for clinical development, and drug prescription biases for repurposing drugs, are barriers yet to be overcome. The affordability of cancer drugs is a complex issue that varies from country to country. Many alternatives for having affordable drugs have been put forward, however these measures have thus far failed and are, at best, palliative. There are no immediate solutions to the problem of access to cancer drugs. It is necessary to critically analyze the impact of the current drug development model and be creative in implementing new models that genuinely benefit society.

US FDA Postmarketing Requirements and Commitments: A Systematic Assessment of Clinical Pharmacology Studies and Their Impact on US FDA Prescribing Information.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

Contemporary Review on Solubility Enhancement Techniques

The limited water solubility of pharmacoactive molecules hinders their ability to be used as pharmacological agents, yet the indispensability of a certain solubility parameter precludes any compromises. To overcome this challenge, various methods are employed in order to increase their bioavailability. Pharmaceutical molecules with lower solubility present an elevated risk of failure for drug development and innovation. Their solubility affects important processes such as pharmacokinetics, pharmacodynamics, distribution, protein binding, and absorption. As a result these parameters are greatly impacted by the dissolution rate of a particular molecule. Out of all pharmaceutical dosage forms, more than half are oral. For the drug molecule to reach its target site and be effective therapeutically, solubility and bioavailability must be taken into consideration. Unfortunately, during screening programs conducted by the pharmaceutical industry it became evident that nearly 40% of new chemical entities (NCEs) face various roadblocks when transitioning from formulation to development due to their poor solubility and bioavailability. The pharmaceutical industry is constantly confronted with the difficulty of improving drug bioavailability and solubility in formulations. This article covers a range of technological advancements to boost the solubility of insoluble drugs, such as complexation, emulsions and micelles production, microemulsion generation with cosolvents, polymeric micelle preparation methods, particle size decrease techniques, pharmaceutical salts application, prodrugs usage, solid-state alteration practices, soft gel technology implementation crystal engineering approaches and nanomorphology. Through this review, we will discuss a variety of more complex methods for improving solubility and bioavailability such as crystal engineering, micronization, solid dispersions, nano sizing, and use of cyclodextrins, solid lipid nanoparticles (SLNPs), colloidal drug delivery systems and drug conjugates. We'll also provide references to studies that have been conducted in connection with these topics.
 Keywords: Solubility, permeability, bioavailability, nano particles drug delivery systems, microemulsions, low water solubility

Clinical Evaluation Based on a New Approach to Improve the Accuracy of 4β-Hydroxycholesterol Measurement as a Biomarker of CYP3A4 Activity

This study examines 4β-Hydroxycholesterol (4β-HC), which is considered to be a potential marker for the CYP3A4 induction of new chemical entities (NCEs) in drug development. To ensure the use of 4β-HC as a practical biomarker, it is necessary to accurately measure 4β-HC and demonstrate that CYP3A4 induction can be appropriately assessed, even for weak inducers. In clinical trials of NCEs, plasma is often collected with various anticoagulants, in some cases, the plasma is acidified, then stored for an extended period. In this study, we examined the effects of these manipulations on the measurement of 4β-HC, and based on the results, we optimized the plasma collection and storage protocols. We also found that a cholesterol oxidation product is formed when plasma is stored, and by monitoring the compound, we were able to identify when plasma was stored inappropriately. After evaluating the above, clinical drug-drug interaction (DDI) studies were conducted using two NCEs (novel retinoid-related orphan receptor γ antagonists). The weak CYP3A4 induction by the NCEs (which were determined based on a slight decline in the systemic exposure of a probe substrate (midazolam)), was detected by the significant increase in 4β-HC levels (more specifically, 4β-HC/total cholesterol ratios). Our new approach, based on monitoring a cholesterol oxidation product to identify plasma that is stored inappropriately, allowed for the accurate measurement of 4β-HC, and thus, it enabled the evaluation of weak CYP3A4 inducers in clinical studies without using a probe substrate.

Development and application of an enantioselective liquid chromatography – tandem mass spectrometry method for the quantification of enantiomers to evaluate in vivo chiral inversion in beagle dog

To assess whether a suspected metabolic chiral inversion of a new chemical entity (NCE) with a single chiral centre occurred in an in vivo pharmacokinetic (PK) study of UCB-1, a quantitative enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. Chromatographic screening of authentic standards of the two enantiomers was carried out using a range of Phenomenex Lux chiral columns under various isocratic conditions to achieve optimum chromatographic resolution. Protein precipitation was used for analyte extraction from 40 µL of dog plasma. The subjects were given a po dose of either 1, 3 or 10 mg/kg followed by blood sample collection at timepoints over a 72-hour period. For the analysis, a Shimadzu liquid chromatography system was coupled to a Sciex QTRAP 5500 mass spectrometer operated using multiple reaction monitoring (MRM) in positive ion mode. The regression for the two enantiomers was (R2 ≥ 0.999) over the range of 10 – 20,000 ng/mL while employing a quadratic fit, with a lower limit of quantification (LLOQ) of 10 ng/ml. The method was validated for intra- and inter-day precision and accuracy, which were within +/- 20%. The enantiomers were stable in dog plasma at room temperature for 4 h and after three freeze-thaw cycles. The method was successfully applied to a pharmacokinetic study in dog, after po administration of UCB-1 where a significant level of chiral inversion was observed in plasma.

Evaluation of Free Online ADMET Tools for Academic or Small Biotech Environments.

For a new molecular entity (NME) to become a drug, it is not only essential to have the right biological activity also be safe and efficient, but it is also required to have a favorable pharmacokinetic profile including toxicity (ADMET). Consequently, there is a need to predict, during the early stages of development, the ADMET properties to increase the success rate of compounds reaching the lead optimization process. Since Lipinski's rule of five, the prediction of pharmacokinetic parameters has evolved towards the current in silico tools based on empirical approaches or molecular modeling. The commercial specialized software for performing such predictions, which is usually costly, is, in many cases, not among the possibilities for research laboratories in academia or at small biotech companies. Nevertheless, in recent years, many free online tools have become available, allowing, more or less accurately, for the prediction of the most relevant pharmacokinetic parameters. This paper studies 18 free web servers capable of predicting ADMET properties and analyzed their advantages and disadvantages, their model-based calculations, and their degree of accuracy by considering the experimental data reported for a set of 24 FDA-approved tyrosine kinase inhibitors (TKIs) as a model of a research project.

Preclinical Drug Development Process: Formulation and Development Aspects

Drug discovery and development process aims to make available new pharmacological entities to prevent, treat, mitigate or cure disease in a safe and effective manner. It involves rigorous testing and optimization of selected compounds to identify the drug that is most effective. Drug development starts with a target identification and validation, followed by drug candidate (hits) discovery, and lead drug (compound with favourable pharmaceutical, safety, efficacy and pharmacokinetic profile) selection and optimization then preclinical research, clinical research, FDA drug review, FDA post-market drug safety monitoring. In the stage of preclinical study, pharmaceutical preformulation and development and toxicity studies are the major concerns. The chapter focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. During preformulation studies the parameters evaluated are: solubility in different media and solvents, dissolution of the active pharmaceutical ingredient (API), accelerated stability studies under various conditions, solid state properties (polymorphs, particle size, particle shape, etc.), formulation development of new chemical entity (NCE),optimization of existing formulations, process development for selected dosage form, novel formulations for improved delivery of existing dosage forms, controlled release and sustained release formulations, micro and nano formulations, partition coefficient, pKa determination. It also emphasizes on Pharmacokinetic studies. The chapter also provides detailed information related to a vast pool of excipients available which is of immense help in designing preclinical formulations. A light is thrown on key aspects of preclinical formulation development by cited examples.

Advanced Processes for Clinical Pharmacology Evaluation in Board Exams

As a medical educator for over 30 years, and a member of the National Board of Osteopathic Medical Examiners (NBOME) for 20 of this time, I am concerned about the burden placed on those taking boards. In the USA, an increase in Biologic License Applications (BLAs) plus New Molecular Entities (NMEs) over these past two decades is extensive. Considering that there was not an equivalent number of agents withdrawn from the market leaves a large net amount of new medicines to be learned in additional to what we are already teaching. In my opinion, this is an overload and one of the causes contributing to increased burnout among young physicians-to-be. As recently concluded, “Advances in medicine and technology mean that medical students are expected to learn significantly more information than their predecessors in the same amount of time1.” Other contributory factors cited in this article include participation in extracurricular, research and leadership activities, all designed to improve chances for admission into targeted residencies.

Design of new chemical entities targeting both native and H275Y mutant influenza a virus by deep reinforcement learning

Influenza virus remains a major public health challenge due to its high morbidity and mortality and seasonal surge. Although antiviral drugs against the influenza virus are widely used as a first-line defense, the virus undergoes rapid genetic changes, resulting in the emergence of drug-resistant strains. Thus, new antiviral drugs that can outwit resistant strains are of significant importance. Herein, we used deep reinforcement learning (RL) algorithm to design new chemical entities (NCEs) that are able to bind to the native and H275Y mutant (oseltamivir-resistant) neuraminidases (NAs) of influenza A virus with better binding energy than oseltamivir. We generated more than 66211 NCEs, which were prioritized based on the filtering rules, structural alerts, and synthetic accessibility. Then, 18 NCEs with better MM/PBSA scores than oseltamivir were further analyzed in molecular dynamics (MD) simulations conducted for 100 ns. The MD experiments showed that 8 NCEs formed very stable complexes with the binding pocket of both native and H275Y mutant NAs of H1N1. Furthermore, most NCEs demonstrated much better binding affinity to group 2 (N2, N3, and N9) and influenza B virus NAs than oseltamivir. Although all 8 NCEs have non-sialic acid-like structures, they showed a similar binding mode as oseltamivir, indicating that it is possible to find new scaffolds with better binding and antiviral properties than sialic acid-like inhibitors. In conclusion, we have designed potential compounds as antiviral candidates for further synthesis and testing against wild and mutant influenza virus. Communicated by Ramaswamy H. Sarma

Pharmacobezoar Formation From HPMC-AS-Containing Spray-Dried Formulations in Nonclinical Safety Studies in Rats

Changing the physical state from crystalline to amorphous is an elegant method to increase the bioavailability of poorly soluble new chemical entity (NCE) drug candidates. Subsequently, we report findings from repeat-dose toxicity studies of an NCE formulated as a spray-dried amorphous solid dispersion (SD-ASD) based on hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in rats. At necropsy, agglomerates of SD-ASD were found in the stomach and small intestine, which in reference to literature were termed pharmacobezoars. We interpreted the pH-dependent insolubility of HPMC-AS in the acidic gastric environment to be a precondition for pharmacobezoar formation. Gastric pharmacobezoars were not associated with clinical signs or alterations of clinical pathology parameters. Pharmacobezoar-correlated histopathological findings were limited to the stomach and consisted of atrophy, erosion, ulcer, and inflammation, predominantly of the nonglandular mucosa. Pharmacobezoars in the small intestines induced obstructive ileus with overt clinical signs which required unscheduled euthanasia, prominent alterations of clinical pathology parameters indicative of hypotonic dehydration, degenerative and inflammatory processes in the gastrointestinal tract, and secondary renal findings. The incidence of pharmacobezoars increased with dose and duration of dosing. Besides the relevance of pharmacobezoars to animal welfare, they limit the non-observed adverse effect level in nonclinical testing programs and conclusively their informative value.

Phenotype-based screening rediscovered benzopyran-embedded microtubule inhibitors as anti-neuroinflammatory agents by modulating the tubulin–p65 interaction

Neuroinflammation is one of the critical processes implicated in central nervous system (CNS) diseases. Therefore, alleviating neuroinflammation has been highlighted as a therapeutic strategy for treating CNS disorders. However, the complexity of neuroinflammatory processes and poor drug transport to the brain are considerable hurdles to the efficient control of neuroinflammation using small-molecule therapeutics. Thus, there is a significant demand for new chemical entities (NCEs) targeting neuroinflammation. Herein, we rediscovered benzopyran-embedded tubulin inhibitor 1 as an anti-neuroinflammatory agent via phenotype-based screening. A competitive photoaffinity labeling study revealed that compound 1 binds to tubulin at the colchicine-binding site. Structure–activity relationship analysis of 1’s analogs identified SB26019 as a lead compound with enhanced anti-neuroinflammatory efficacy. Mechanistic studies revealed that upregulation of the tubulin monomer was critical for the anti-neuroinflammatory activity of SB26019. We serendipitously found that the tubulin monomer recruits p65, inhibiting its translocation from the cytosol to the nucleus and blocking NF-κB-mediated inflammatory pathways. Further in vivo validation using a neuroinflammation mouse model demonstrated that SB26019 suppressed microglial activation by downregulating lba-1 and proinflammatory cytokines. Intraperitoneal administration of SB26019 showed its therapeutic potential as an NCE for successful anti-neuroinflammatory regulation. Along with the recent growing demands on tubulin modulators for treating various inflammatory diseases, our results suggest that colchicine-binding site-specific modulation of tubulins can be a potential strategy for preventing neuroinflammation and treating CNS diseases.

An In Vitro Model to Investigate the Potential of Solid Dispersions to Form Pharmacobezoars.

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of the carrier polymer to this process taking place in the acidic environment of the rodent stomach is conclusive, unawareness of the extent of in vivo pharmacobezoar formation is adverse. In order to evaluate the risk of pharmacobezoar formation before in vivo administration, we subsequently introduce an in vitro model to assess the agglomeration potential of solid dispersions. To verify that the pharmacobezoar formation potential can be assessed based on the observed agglomeration potential, we conducted a sequence of experiments with two HPMC-AS-based SD-ASD formulations. In vitro, we found their different in vivo pharmacobezoar formation potential reflected by a significantly increased agglomerated mass of formulation 1 per day compared to formulation 2. In order to find an approach to reduce the agglomeration potential of solid dispersion from suspensions, we further applied the model to investigate the impact of the viscosity of the vehicle used to prepare suspensions on agglomerate formation.

Assessment of the Delay in Novel Anticancer Drugs between China and the United States: A Comparative Study of Drugs Approved between 2010 and 2021.

Access to anticancer drugs has been a critical health issue in China for many years. We retrospectively analyzed the novel anticancer drugs approved in the United States (US) between 2010 and 2021 to assess the evolving landscape of the drug lags in China by taking Japan and the European Union (EU) as comparisons. The absolute and relative lags of drug initial approval (DIA) and indication approval were calculated between China (or Japan/European Union) and the US based on the US approval date of novel agents, the duration was divided into 2010-2015 and 2016-2021. Overall, 123 (244 indications) new molecular entities (NMEs) approved in the United States were included, of which 58 (94 indications), 72 (128 indications), and 99 (170 indications) NMEs were also approved in China, Japan, and the European Union, respectively. The absolute lags of DIA and indications for approval in China improved dramatically in 2016-2021 compared with 2010-2015. Similarly, the relative DIA and indication approval lags in China decreased significantly in 2016-2021. The median review lags for DIA of China in 2016-2021 were comparable to Japan but dramatically lower than that of the European Union. Nevertheless, China had significantly longer median submission lags for DIA (28 months) in 2016-2021 than that of Japan (6 months) and the European Union (1 month). Although the absolute and relative lags of anticancer drugs in China had been initially addressed, 53% of NMEs and 61% of indications were still not approved for cancers in China compared with the United States. Therefore, China should adopt steps to further reduce drug lags.

Innovation Options and Profitability of Pharmaceutical Brand Manufacturers

Much research exists covering clinical development success rates, development costs of new drugs, and market launch impact on stock market valuation of companies, but little systematic work has been done to establish the impact of research input on new product launches and, in turn, their impact on profitability of drug manufacturers. This article investigates these relations using data from the world’s largest pharmaceutical brand manufacturers and their product launches in the US over a period of more than 25 years. The objective is to determine the impact of innovation intensity on innovation output intensity and of innovation output intensity on profitability. It is shown that there is a complete lack of evidence that launches of New Molecular Entities (NMEs) necessarily lead to higher profitability, suggesting that many launches of NMEs are not particularly successful from an economic point of view. Furthermore, it was found that intangible knowledge assets acquired by company mergers and acquisitions do often not live up to their valuation. This leads to the conclusion that such intangible assets seem to be overpriced on average. The more and more frequently used strategy of launching new drugs without NMEs like combination drugs or extension of indications increased short-term profitability making this a valid approach to avoid setbacks when patent protection of blockbuster drugs expires.