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Background: Over the years, Indian regulations have undergone numerous amendments, including stringent reporting deadlines, relatedness requirements, and compensation obligations for serious adverse event (SAE). A historic change, new drugs and trial rules-2019, was proposed on March 19, 2019. The purpose of the study was to ascertain whether various stakeholders were reporting in accordance with the evolving SAE criteria. Materials and Methods: Data were retrieved after the Ethics Committee's approval between August 2014 and December 2021. Data gathered before March 19, 2019, were categorized as "BEFORE" data, while the remaining data were categorized as "AFTER." Utilizing causality, on-site SAE reporting, and the ethics committee review procedure, we evaluated the compliance. The data were evaluated using descriptive statistics, and the Chi-square or Mann-Whitney tests were used to compare the "BEFORE" and "AFTER" groups. Results: A total of 77 SAEs were reported in 26 clinical trials, where most clinical trials were phase III. Endocrine projects made up 9/26 (34.61%). In the cardiology studies, the greatest SAE distribution was 21 SAEs/89 participants (23.59%) with approximately 48% of these being vascular. The "AFTER" group noticed a decrease in the total number and length of SAE subcommittee meetings. In the "AFTER" group, there was a significantly higher median number of agenda items/meetings (8 [4.5-10.75]) (P < 0.0001). The median interval between the onset of SAE and the first reporting date, however, was just 1 day (interquartile range: 1-5 days). In nondeath SAEs, there was no significant difference in the compensation paid. In the "AFTER" group, there were no discrepancies in reporting SAE. Conclusion: There is acceptable adherence to SAE reporting criteria.
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This article addresses the research and development (R&D) productivity challenge of the pharmaceutical industry, focusing on United States Food and Drug Administration (FDA)-related new drug approvals of the top 20 pharmaceutical companies (2014-2023). We evaluated the degree of innovation in new drugs to determine the innovativeness of these leading companies. A key finding of our analysis is the decline in the number of new drugs approved by the FDA for these leading companies over the investigated time period. This trend suggests that some of the leading companies are losing ground in R&D innovation, raising concerns about their ability to sustain competitive advantage, ensure long-term market success, and maintain viable business models.
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INTRODUCTION: Toxoplasmosis is a worldwide distributed zoonosis caused by Toxo-plasma gondii (T. gondii), an obligate intracellular protozoan. The infection in immunocompetent hosts usually progresses with mild or no symptoms. However, in immunocompromised individu-als, this disease can cause severe or fatal symptoms. METHOD: Sulfadiazine and pyrimethamine are two drugs used as standard therapies for human toxoplasmosis. Although they do not cause chronic infection, they may cause hematological tox-icity, hypersensitivity, intolerance, teratogenic effects, gastrointestinal disorders, and bone mar-row suppression. RESULT: The limited effect, significant toxicity, and emerging resistance to current drugs available to treat T. gondii infections require investigating other effective, nontoxic, and well-tolerated al-ternatives. Medicinal plants are, traditionally, the most promising sources used to treat infectious diseases. CONCLUSION: This review provides data on new therapeutic and prophylactic methods for T. gondii infection based on the use of extracts and/or compounds derived from natural products, which have been reported to be useful as alternative treatment options in the last 20 years.
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Purpose: An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them. Patients and Methods: We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional). Results: All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was "requests from physicians and medical institutions" (nine companies, 90.0%), and the most common reason for not implementing an EACT was "the applicability of the system" (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised. Conclusion: An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due.
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Skin cancer encompasses a range of cutaneous malignancies, with non-melanoma skin cancers (NMSCs) being the most common neoplasm worldwide. Skin exposure is the leading risk factor for initiating NMSC. Ultraviolet (UV) light induces various genomic aberrations in both tumor-promoting and tumor-suppressing genes in epidermal cells. In conjunction with interactions with a changed stromal microenvironment and local immune suppression, these aberrations contribute to the occurrence and expansion of cancerous lesions. Surgical excision is still the most common treatment for these lesions; however, locally advanced or metastatic disease significantly increases the chances of morbidity or death. In recent years, numerous pharmacological targets were found through extensive research on the pathogenic mechanisms of NMSCs, leading to the development of novel treatments including Hedgehog pathway inhibitors for advanced and metastatic basal cell carcinoma (BCC) and PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC). Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise with long-term treatment. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. This review summarizes the current and emerging therapies used to treat NMSC.
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Skin Neoplasms , Humans , Skin Neoplasms/therapy , Skin Neoplasms/pathology , Carcinoma, Basal Cell/therapy , Carcinoma, Basal Cell/pathology , Carcinoma, Basal Cell/drug therapy , Standard of Care , Carcinoma, Squamous Cell/therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/drug therapy , Tumor Microenvironment , Immune Checkpoint Inhibitors/therapeutic use , AnimalsABSTRACT
Aim: Studies show the presence of a mismatch between drug research and disease burden. A study conducted in the European Union found that new drug development was restricted to certain diseases. A study of biosimilar approvals in India found that 87% of drugs were for treating noncommunicable diseases. This study aimed to determine the new drugs approved in India from 2017 to 2021 and the top ten causes of morbidity and mortality and detect the presence of any discordance between these. Methods: A descriptive study was conducted using data on new drug approvals accessed from the Central Drugs Standard Control Organization website. The top ten causes of mortality and morbidity in India from 2015 to 2019 were identified from the Global Burden of Diseases database. Descriptive statistics were used to compare the drug approvals and the leading diseases. Results: One hundred twenty-six drugs were approved during the study period. Antineoplastic drugs constituted 19.84% of the approvals, antimicrobials 18.25%, and cardiovascular drugs 9.52%. Ischemic heart disease and chronic obstructive pulmonary disease were the two leading causes of morbidity and mortality. Diarrheal diseases, lower respiratory tract infection, and drug-susceptible tuberculosis were among the top ten causes. Ten antibacterials, including four antitubercular drugs, were approved during this period. Two drugs were approved for rare diseases. Conclusion: Our study showed that the drugs approved were largely in line with the prevalent disease burden, and there was no significant discordance observed. Some diseases, such as ischemic stroke/intracranial hemorrhage, require further efforts in bringing forth newer pharmacotherapy options.
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Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects.
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BACKGROUND: Integrated Stress Response Inhibitor (ISRIB) works by inhibiting the integrated stress response, a cellular pathway involved in the regulation of protein synthesis during stress conditions. Conditions that have been studied or suggested as potential candidates for treatment with ISRIB include neurological and metabolic disorders, cognitive impairment, viral infections, and cancer. OBJECTIVE: The study aimed to discuss the challenges related to specificity, long-term safety, and disease-specific considerations crucial for realizing the full potential of ISRIB. METHOD: A narrative review of the literature has been conducted to delve into ISRIB's chemistry, mechanisms of action, disease-specific considerations, and long-term safety implications. RESULTS: While ISRIB has shown promising results in preclinical studies, more research is needed to determine its safety and effectiveness in human patients. Clinical trials are required to validate its therapeutic potential for various conditions. Despite having been proposed a decade ago, news of its clinical trials has been circulated only recently, without any published information yet and with rumors that its efficacy vs. safety profile may be compromised by side effects. CONCLUSION: While ISRIB offers exciting prospects for a range of biomedical applications, addressing challenges related to specificity, disease-specific considerations, and importantly long-term safety, is crucial for realizing its full potential.
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Liver disease is a serious public health problem worldwide, affecting human health. However, there are still many unmet needs for the treatment of liver disease, especially with new therapeutic drugs. At present, there is no treatment method to eradicate the hepatitis B virus, nor are there therapeutic drugs for liver fibrosis, liver failure, and others. Chemotherapy and targeted immunotherapy are still unsatisfactory for liver cancer. This article provides an overview of the current status and challenges that arise in new drug research and development for liver diseases.
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Drug Development , Liver Diseases , Humans , Liver Diseases/drug therapy , Liver Neoplasms/drug therapy , Liver Cirrhosis/drug therapyABSTRACT
Liver fibrosis is a key step in the developmental process of various chronic liver diseases, including cirrhosis. Therefore, the focus and difficulty of liver disease research have always been on how to reverse liver fibrosis. However, due to complex mechanisms, difficulties in endpoint evaluation, a lack of non-invasive diagnostic methods, and other factors, the research and development of new drugs are hindered and lengthy. Currently, some new drugs are being researched and developed, which signifies the prospect is optimistic.
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Liver Cirrhosis , Liver Cirrhosis/drug therapy , Humans , Drug DevelopmentABSTRACT
Drugs have structural homology across similar biological targets. Small molecule drugs have the efficacy to target specific molecular targets within the cancer cells with enhanced cell membrane permeability, oral administration, selectivity, and specific affinity. The objective of this review is to highlight the clinical importance and synthetic routes of new small molecule oncology drugs approved by the FDA during the period 2021-2022. These marketed drugs are listed based on the month and year of approval in chronological order. We believed that an in-depth insight into the synthetic approaches for the construction of these chemical entities would enhance the ability to develop new drugs more efficiently.
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Antineoplastic Agents , Drug Approval , Small Molecule Libraries , Humans , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Neoplasms/drug therapy , Molecular Structure , United States , United States Food and Drug AdministrationABSTRACT
Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by an increased risk of vascular complications and a tendency to progress to myelofibrosis and acute leukaemia. ET patients have traditionally been stratified into two thrombosis risk categories based on age older than 60 years and a history of thrombosis. More recently, the revised IPSET-thrombosis scoring system, which accounts for the increased risk linked to the JAK2 mutation, has been incorporated into most expert recommendations. However, there is increasing evidence that the term ET encompasses different genomic entities, each with a distinct clinical course and prognosis. Moreover, the effectiveness and toxicity of cytoreductive and anti-platelet treatments differ depending on the molecular genotype. While anti-platelets and conventional cytoreductive agents, mainly hydroxycarbamide (hydroxyurea), anagrelide and pegylated interferon, remain the cornerstone of treatment, recent research has shed light on the effectiveness of novel therapies that may help improve outcomes. This comprehensive review focuses on the evolving landscape of treatment strategies in ET, with an emphasis on the role of molecular profiling in guiding therapeutic decisions. Besides evidence-based management according to revised IPSET-thrombosis stratification, we also provide specific observations for those patients with CALR-, MPL-mutated and triple-negative ET, as well as cases with high-risk mutations.
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Thrombocythemia, Essential , Humans , Thrombocythemia, Essential/drug therapy , Thrombocythemia, Essential/genetics , Janus Kinase 2/genetics , Janus Kinase 2/antagonists & inhibitors , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Mutation , Receptors, Thrombopoietin/agonists , Receptors, Thrombopoietin/genetics , CalreticulinABSTRACT
INTRODUCTION: Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED: We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION: Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.
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Chenodeoxycholic Acid , Liver Cirrhosis, Biliary , Receptors, Cytoplasmic and Nuclear , Animals , Humans , Bile Acids and Salts/metabolism , Chenodeoxycholic Acid/pharmacology , Chenodeoxycholic Acid/analogs & derivatives , Chenodeoxycholic Acid/therapeutic use , Cholagogues and Choleretics/pharmacology , Dose-Response Relationship, Drug , Drug Development , Drugs, Investigational/pharmacology , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/physiopathology , Pruritus/drug therapy , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/metabolism , Ursodeoxycholic Acid/pharmacologyABSTRACT
Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.
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Drug Repositioning , Liver Diseases , Drug Repositioning/methods , Humans , Liver Diseases/drug therapy , Computational Biology/methods , Drug Discovery/methodsABSTRACT
Background The role of academia in clinical research has given rise to the concept of academic clinical trials (ACTs), which are vital in generating evidence. Through the implementation of the New Drugs and Clinical Trials Rules-2019 (NDCTR-2019) rules, the Institutional Ethics Committee (IEC) has obtained a quasi-regulatory role. The study aims to assess the challenges the IEC faced when processing, approving, and monitoring ACTs. The other objectives included the number of ACTs submitted to the IEC, as well as administrative, scientific, and ethical issues stated by the IEC and the Drug Controller General of India (DCGI) authorities. We also aimed to provide some insight into the type of decision made by IEC and DCGI - the delay or inconsistency between the queries. Methods This retrospective study was conducted in the IEC of a tertiary care hospital, Mumbai, Maharashtra, India. A comprehensive search of the IEC database was carried out by the study team, and only those protocols of ACTs submitted to IEC between January 2015 and December 2021 were included. The studies submitted between January 2015 and February 2019, i.e., before the release of NDCTR-2019, were classified as the "Before" category. All subsequently submitted protocols were grouped together as the "After" group. Descriptive statistics were used to represent the data, while comparison between the two timeframes were made using the Mann-Whitney U test with a level of significance at 5%. Results This six-year study showed that merely 1.4% (34/2400) trials fulfilled the criteria of an ACT. An increase in the ACT protocol submission was noted in the "After" group (20 vs. 14). Most ACTs were drug trials, with 67.6% (23/34) trials conducted majorly in the Department of Anesthesiology. There was a statistical increase in time query reply by the principal investigator to IEC and the time between submission and approval in the "After" group (p<0.05). IEC sent out 94 administrative, 565 scientific, and 216 ethical queries. On IEC monitoring, protocol deviations were noted; nonetheless, no ACTs reported protocol deviations or serious adverse events. Conclusions Since the implementation of NDCTR-2019, IEC has taken on a quasi-regulatory function, and there has been an increase in the caliber of IEC monitoring and adherence to ethical norms.
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Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disease characterized by intravascular hemolysis due to the targeting of affected red blood cells by the complement system. Eculizumab and ravulizumab are two monoclonal antibodies that inhibit the complement system's components and have been shown to significantly improve survival and quality of life. This review describes the role of these monoclonal antibodies in the treatment of PNH with an emphasis on their safety profile. The challenges in the use of these drugs and new drugs in various stages of drug development are also described, which may be helpful in addressing some of these challenges.
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Antibodies, Monoclonal , Hemoglobinuria, Paroxysmal , Humans , Antibodies, Monoclonal/adverse effects , Hemoglobinuria, Paroxysmal/drug therapy , Quality of Life , Erythrocytes , Complement System ProteinsABSTRACT
Natural products (NPs) have consistently played a pivotal role in pharmaceutical research, exerting profound impacts on the treatment of human diseases. A significant proportion of approved molecular entity drugs are either directly derived from NPs or indirectly through modifications of NPs. This review presents an overview of NP drugs recently approved in China, the United States, and other countries, spanning various disease categories, including cancers, cardiovascular and cerebrovascular diseases, central nervous system disorders, and infectious diseases. The article provides a succinct introduction to the origin, activity, development process, approval details, and mechanism of action of these NP drugs.