Clinical development and marketing application review times for novel orphan-designated drugs.

Development of an orphan-designated drug has been more challenging and financially less attractive than that of other drugs due to low prevalence of the condition, poorly defined biomarkers and lack of experience of healthcare providers in diagnosing and treating the condition. Guidance and incentives in some countries support the sponsors in developing orphan-designated drugs despite the challenges. Expedited regulatory programs as offered by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) support the development of drugs, provide shorter marketing application review times or provide preliminary approval. In this study, we analyze marketing application review times in the US and in the European Union (EU) and clinical development times for novel, i.e., containing new molecular entity, orphan-designated drugs that were approved in the US between 1 June 2020 and 31 May 2023, and their correlation with expedited regulatory programs. Seventy-three marketing applications for novel orphan-designated drugs were approved by the FDA, and 39 also received a positive opinion from the EMA. The marketing application review time by the FDA for the 73 novel orphan-designated drugs approved in the US was 244 days (n = 73, median), and the marketing application review time by the EMA for the 39 drugs that were also approved in the EU was 353 days (n = 39, median). The typical clinical development time for a novel orphan-designated drug was 7.2 years (n = 72).

Clinical development time is shorter for new anticancer drugs approved via accelerated approval in the US or via conditional approval in the EU.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) offer expedited regulatory approval programs for drugs with high potential patient value applicable at different stages leading to marketing authorization: (i) drug development (fast track designation (FTD), breakthrough therapy designation (BTD), regenerative medicine advanced therapy designation in the United States, and priority medicines scheme in the European Union), (ii) review of marketing authorization application (priority review in the United States and accelerated assessment in the European Union), (iii) approval of drug (accelerated approval in the United States and conditional approval in the European Union). Typical clinical development time of 76 new anticancer drugs, for which the EMA gave a positive opinion between January 2010 and December 2019, was 6.7 years: 5.8 years for small molecules and 7.7 years for biotechnology-derived products. Drugs following only BTD (5.6 years) typically had a shorter clinical development time than drugs following only FTD (6.4 years) or both FTD and BTD (6.4 years), compared to drugs not following any expedited regulatory approval program at the drug development stage (7.7 years). Drugs following an expedited regulatory approval program at the stage of drug development and accelerated approval in the United States (FDA1 [4.5 years] and FDA3 [5.6 years]), and drugs following the standard procedure at the stage of drug development and conditional approval in the European Union (EMA5 [5.5 years] and EMA7 [4.5 years]) typically had a reduced clinical development time. These findings provide insight for the industry into combinations of expedited regulatory approval programs correlated with shorter clinical development time of new anticancer drugs.

A detailed analysis of expedited regulatory review time of marketing authorization applications for new anticancer drugs in the US and EU.

The aim of this study was to assess the effect of expedited regulatory approval programs used by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), type of product (small molecule or biotechnology-derived product) and consulting scientific advisory committees on the regulatory review time of the marketing authorization applications (MAAs) for new anticancer drugs. A dataset composed of 76 new anticancer drugs was constructed. The date of submission of the MAAs in the United States and the European Union were comparable. The typical review time of MAAs was 136 days shorter in the United States (201 days [median]) than in the European Union (337 days [median]). The type of product did not have a high impact on the review time. The review time of the MAAs for drugs undergoing priority review in the United States or accelerated assessment in the European Union at the stage of review of MAA was generally shorter than that for drugs following the standard regulatory pathway. The regulatory pathway using at least one expedited regulatory program at the stages of drug development, review of MAA, and approval of drug in the United States (172 days [median]), and that at the stages of review of MAA and approval of drug in the European Union (183 days [median]) enabled the shortest review time of MAAs. Referral to advisory committee meeting increased the review time of MAAs for drugs undergoing one or more expedited regulatory approval programs in the United States and the European Union close to that for drugs undergoing the standard regulatory approval pathway.

Genetic Characterization of Mutations Related to Conidiophore Stalk Length Development in Aspergillus niger Laboratory Strain N402.

Aspergillus niger is an important filamentous fungus in industrial biotechnology for the production of citric acid and enzymes. In the late 1980s, the A. niger N400/NRRL3 strain was selected for both fundamental and applied studies in relation to several processes including gluconic acid and protein production. To facilitate handling of A. niger, the N400 wild-type strain was UV mutagenized in two consecutive rounds to generate N401 and N402. N402 was used as a reference laboratory strain and exhibits the phenotypes with reduced conidiophore stalk length and reduced radial growth. The conidiophore stalk length and radial growth of A. niger strain N400 were determined and compared to N401 and N402. The length of N400 conidiophore stalks (2.52 ± 0.40 mm) was reduced in N401 and N402 to 0.66 ± 0.14 mm and 0.34 ± 0.06 mm, respectively. Whereas N400 reached a colony diameter of 6.7 ± 0.2 cm after 7 days, N401 and N402 displayed reduced radial growth phenotype (4.3 ± 0.1 and 4.1 ± 0.1, respectively). To identify the mutations (dubbed cspA and cspB) responsible for the phenotypes of N401 and N402, the genomes were sequenced and compared to the N400 genome sequence. A parasexual cross was performed between N400 and N402 derivatives to isolate segregants which allowed cosegregation analysis of single nucleotide polymorphisms and insertions and deletions among the segregants. The shorter conidiophore stalk and reduced radial growth in N401 (cspA) was found to be caused by a 9-kb deletion on chromosome III and was further narrowed down to a truncation of NRRL3_03857 which encodes a kinesin-like protein homologous to the A. nidulans UncA protein. The mutation responsible for the further shortening of conidiophore stalks in N402 (cspB) was found to be caused by a missense mutation on chromosome V in a hitherto unstudied C2H2 transcription factor encoded by the gene NRRL3_06646. The importance of these two genes in relation to conidiophore stalk length and radial growth was confirmed by single and double gene deletion studies. The mutations in the laboratory strain N402 should be taken into consideration when studying phenotypes in the N402 background.

Identification of a Conserved Transcriptional Activator-Repressor Module Controlling the Expression of Genes Involved in Tannic Acid Degradation and Gallic Acid Utilization in Aspergillus niger.

Tannic acid, a hydrolysable gallotannin present in plant tissues, consists of a central glucose molecule esterified with gallic acid molecules. Some microorganisms, including several Aspergillus species, can metabolize tannic acid by releasing gallic acid residues from tannic acid by secreting tannic acid specific esterases into the medium. The expression of these so-called tannases is induced by tannic acid or gallic acid. In this study, we identified a conserved transcriptional activator-repressor module involved in the regulation of predicted tannases and other genes involved in gallic acid metabolism. The transcriptional activator-repressor module regulating tannic acid utilization resembles the transcriptional activator-repressor modules regulating galacturonic acid and quinic acid utilization. Like these modules, the Zn(II)2Cys6 transcriptional activator (TanR) and the putative repressor (TanX) are located adjacent to each other. Deletion of the transcriptional activator (ΔtanR) results in inability to grow on gallic acid and severely reduces growth on tannic acid. Deletion of the putative repressor gene (ΔtanX) results in the constitutive expression of tannases as well as other genes with mostly unknown function. Known microbial catabolic pathways for gallic acid utilization involve so-called ring cleavage enzymes, and two of these ring cleavage enzymes show increased expression in the ΔtanX mutant. However, deletion of these two genes, and even deletion of all 17 genes encoding potential ring cleavage enzymes, did not result in a gallic acid non-utilizing phenotype. Therefore, in A. niger gallic acid utilization involves a hitherto unknown pathway. Transcriptome analysis of the ΔtanX mutant identified several genes and gene clusters that were significantly induced compared to the parental strain. The involvement of a selection of these genes and gene clusters in gallic acid utilization was examined by constructing gene deletion mutants and testing their ability to grow on gallic acid. Only the deletion of a gene encoding an FAD-dependent monooxygenase (NRRL3_04659) resulted in a strain that was unable to grow on gallic acid. Metabolomic studies showed accumulation of gallic acid in the ΔNRRL3_04659 mutant suggesting that this predicted monooxygenase is involved in the first step of gallic acid metabolism and is likely responsible for oxidation of the aromatic ring.

Neuromuscular electrical stimulation as an adjunct to endurance and resistance training during pulmonary rehabilitation in stable chronic obstructive pulmonary disease.

AIM: The purpose of this study was to investigate whether adding neuromuscular electrical stimulation (NMES) to a comprehensive pulmonary rehabilitation (cPR) program would have additive effects on clinical-functional outcomes. METHODS: Twenty-seven chronic obstructive pulmonary disease patients participating in a 10-week cPR program were randomly allocated to NMES + cPR (n = 13) or Sham + cPR (n = 14) groups. Quadriceps strength, exercise capacity, symptoms, mood, activities of daily living and quality of life were evaluated pre- and post-interventions. RESULTS: There were no significant differences in any of the physiological and subjective improvements induced by NMES + cPR versus Sham + cPR (p > 0.05). In fact, the NMES + cPR group showed lower increases in incremental shuttle walk test (ISWT) distance (38.4 vs 69.2 m, respectively) and %ISWT distance (5.1 vs 9%, respectively) compared with the Sham + cPR group (p < 0.05). CONCLUSION: The increase in exercise capacity is less important when NMES is used as an adjunct to the cPR.

Comparison of the effects of neuromuscular electrical stimulation and endurance training in patients with severe chronic obstructive pulmonary disease.

INTRODUCTION: In severely disabled patients who are not capable of following formal pulmonary rehabilitation (PR) and/or tolerating higher training intensities, neuromuscular electrical stimulation (NMES) has been successfully utilized as a localized training method. MATERIALS AND METHODS: In this non-randomized controlled observational study 50 patients with severe chronic obstructive pulmonary disease (COPD), who were allocated into two groups. Endurance training group (ET) (n= 27) and NMES group (n= 23). To compare the effects of NMES and ET on health-related quality of life (HRQOL), exercise capacity, muscle strength, dyspnea, psychological status, and body composition in patients with severe COPD. Before and after PR program, the study parameters were assessed using the Medical Research Council (MRC) scale, incremental and endurance shuttle walking tests (ISWT, ESWT), manual muscle testing (MMT), the St. George's Respiratory Questionnaire (SGRQ), bioelectrical impedance analysis, and the Hospital Anxiety and Depression Scale (HADS). RESULTS: After the PR program, walking distance and endurance time significantly increased in both groups (p< 0.001 for each), whereas the MRC scores of both groups significantly decreased (p< 0.001 for each). In the ET group, significant decreases were noted in all domains of SGRQ and HADS. In the NMES group, significant improvements were observed in the HADS scores and in all SGRQ domain except symptom domain. No significant differences were observed between the NMES and ET groups regarding the changes from baseline to after PR program in walking distance (p= 0.140), endurance time (p= 0.376), the MRC (p= 0.540), HRQOL (p> 0.05) and HADS (p> 0.05) scores, body-mass index (BMI) (p= 0.49), fat-free mass (FFM) (p= 0.50) and fat-free mass index (FFMI) (p= 0.94). CONCLUSION: NMES can be used as an effective treatment strategy in PR programs for peripheral muscle training in patients with severe COPD.