Extension of Indication for Authorised Oncology Products in the European Union: A Joint Effort of Multiple Stakeholders

After marketing authorisation, the development of a medicinal product often continues with studies investigating new therapeutic indications. Positive results can potentially lead to changes to the terms of the marketing authorisation, such as an extension of therapeutic indication(s). These studies can be initiated and sponsored by the marketing authorisation holder (MAH) or by others. When results from an investigator-initiated trial suggest that an authorised medicinal product is safe and effective for a new therapeutic indication, physicians may want to treat their patients with this medicinal product. In such a situation, it is desirable to extend the therapeutic indication(s) via the regulatory approval process, as this can facilitate patient access within the European Union. There may however be challenges when the MAH did not conduct the study and might not have access to the data. In this perspective, we focus on the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product based on results from investigator-initiated trials. We address: (1) the advantages of an extension of indication; (2) the regulatory requirements for a variation application; (3) investigator-initiated trials as a basis for regulatory approval; (4) the role of the MAH in extending the indication. With this article, we want to emphasize the importance of a collaborative approach and dialogue between stakeholders with the aim to facilitate access to effective medicinal products.

Drug Repurposing and Polypharmacology to Fight SARS-CoV-2 Through Inhibition of the Main Protease

The outbreak of a new coronavirus (SARS-CoV-2), which is responsible for the COVID-19 disease and is spreading rapidly around the world, urgently requires effective therapeutic treatments. In this context, drug repurposing represents a valuable strategy, as it enables accelerating the identification of drug candidates with already known safety profiles, possibly aiding in the late stages of clinical evaluation. Moreover, therapeutic treatments based on drugs with beneficial multi-target activities (polypharmacology) may show an increased antiviral activity or help to counteract severe complications concurrently affecting COVID-19 patients. In this study, we present the results of a computational drug repurposing campaign that aimed at identifying potential inhibitors of the main protease (Mpro) of the SARS-CoV-2. The performedin silicoscreening allowed the identification of 22 candidates with putative SARS-CoV-2 Mproinhibitory activity. Interestingly, some of the identified compounds have recently entered clinical trials for COVID-19 treatment, albeit not being assayed for their SARS-CoV-2 antiviral activity. Some candidates present a polypharmacology profile that may be beneficial for COVID-19 treatment and, to the best of our knowledge, have never been considered in clinical trials. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.

Drug repurposing and polypharmacology to fight SARS-CoV-2 through the inhibition of the main protease

Therapeutic options are urgently needed to fight the outbreak of a novel coronavirus (SARS-CoV-2), which causes the COVID-19 disease and is spreading rapidly around the world. Drug repurposing can significantly accelerate the identification of drug candidates suitable for clinical evaluation. Moreover, polypharmacological effects may increase antiviral activity and/or counteract severe complications concurrently affecting COVID-19 patients. Herein, we present the results of a computational drug repurposing campaign in search of potential inhibitors of the main protease of SARS-CoV-2. The screening allowed the selection of 22 promising drugs. Some of them have already entered clinical trials, but the vast majority of the identified compounds are new and have never been considered before. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.

PHARMACEUTICAL STANDARDIZATION OF “HINGULADRASA SINDOORA” PREPARED BY ELECTRIC MUFFLE FURNACE

Kupipakwa Rasayana bears a unique place in Rasa Shastra treatises because of its mercurial preparation with quicker action and synergistic effects in the body at very low dose. Rasa Sindoora is one of the Kupipakwa Rasayana a most potent medicine of Ayurveda. Acharaya Sadanand Sharma mentioned in his text Rasatarangini that Hinguladrasa Sindoora has equal property, dose, therapeutic indication, Anupan (Adjuvant) and Pathya (Wholesome) etc. same as Rasa Sindoora. Hinguladrasa Sindoora was prepared with same proportion of Shodhita Hingula (Purified Cinnabar) and Shodhita Gandhaka (Purified Sulphur) as per the reference of Rasa Tarangini. Aim-To standardize manufacturing procedure of Hinguladrasa Sindoora. Material and Method- Purified Hingula and Purified Gandhaka both grounds properly and made into the Shlakshana Churna (Smooth Powder). Three batches were prepared to standardize the procedure by using electric muffle furnace (EMF). Results and Conclusion - Average melting temperature of Shlakshana Churna, Average flame appearing temperature and Average corking temperature were 1850C, 4830C and 7030C respectively. Average yield in three consecutive batches was 85 gm and the average time was 15.41 hrs. Three batches of Hinguladrasa Sindoora preparation concluded that for 200 gm of Shlakshana Churna by following intermittent heating pattern that was mild heat (100-2500C) for 4 hrs., Moderate heat (250-4500C) for 4 hrs. and strong heat (450-7500C) for 7-8 hrs.

Utilitarian redundancy in local medical systems - theoretical and methodological contributions

The utilitarian redundancy model (URM) is one of the recent contributions to ethnobiology. We argue that URM can be applied to access use-pressure on plant species, the resilience of socioecological systems (e.g., local medical systems), cultural keystone species, and the role of exotic species in social-ecological systems. Based on previous URM studies, we also emphasize the need to differ practical (considering plants and uses that are currently employed) and theoretical (considering both currently employed and potentially employed plants and uses) redundancy. Based on the main applications of the URM, we propose a new index to access redundancy of a therapeutic indication: the Uredit, so that Uredit = NSp + CR, were Uredit is the Utilitarian Redundancy Index for the therapeutic indication; NSp is the total number of species mentioned for the indication, and CR is the species’ contribution to redundancy (in terms of knowledge sharing). The maximum value that the Uredit could reach is twice the number of species employed for the therapeutic indication. We believe that this theoretical and methodological improvement in the model can improve comparisons of redundancy in different social-ecological systems. We also highlight some limitations of the URM (and our Uredit), and we believe that conscious reasons behind people’s decisions should be incorporated into future studies on the subject.

Risks associated with vortioxetine in the established therapeutic indication

Background: Vortioxetine is approved for the treatment of Major Depressive Disorder (MDD). However, the safety of this drug in a large group of populations is still unclear. Thus, we have tried to analyze the risk profile of vortioxetine. Material and Methods: The data related to the risk profile of vortioxetine has been extracted from Pub-Med from January 2014 to May 2019. The adverse drug reactions (ADRs) have been categorized into a listed and unlisted categories as per Summary of product characteristics (SmPC) of the innovator. Further, unlisted ADRs have been analyzed as per Naranjo Scale. Results: The galactorrhea, hyperprolactinemia, glycolimia, exacerbation of anxiety, weight gain, edema, excessive itching, petechiae, and ecchymoses have been observed with the use of vortioxetine and falls under the unlisted category. Further, the causality assessment results have shown probable relation between vortioxetine and galactorrhea, hyperprolactinemia, edema, excessive itching, ecchymoses, and petechiae. The weight gain, glycolimia and exacerbation of anxiety have a possible relationship with vortioxetine. The common ADRs observed with the use of vortioxetine are nausea, diarrhea, constipation, vomiting, pruritus including pruritus generalized, abnormal dreams, and dizziness. Conclusion: In conclusion, more data is required to establish the strong relationship between vortioxetine and reported unlisted ADRs.