A review of use errors reported in human factor validation studies of biological combination products.

Drug-device combination products should be safe and effective for intended uses by intended users under intended use environment during human factor (HF) studies. All known use errors and use-related problems should be considered during design of device and use-related risk analysis. Availability of such information in a compiled manner is scarce. This review compiles information of use errors reported during HF validation studies of biological combination products (drug + device) approved by USFDA's Centre for Drug Evaluation and Research between 21 June 2011 and 31 December 2019. Information regarding product, indication, type of devices, use errors, root causes and mitigation strategies were collected from published documents. Total 280 use errors were reported during HF validation studies of 39 devices across 5 categories. Overall approach and methodology for use error data collection during HF validation studies was in line with the US FDA recommendations. Performance of participants for critical and essential tasks was evaluated during HF validation studies via simulated use assessment, knowledge task assessment and interview. The root causes for use errors reported during HF validation studies were identified and use errors were mitigated by suitable corrective measures. Instructions for use clarification/improvement and labelling improvement were the most common mitigation strategies implemented across devices.

Prevention of acute graft-versus-host-disease by Withaferin a via suppression of AKT/mTOR pathway.

Acute Graft versus Host Disease (aGVHD) is a frequent and serious complication in patients receiving allogeneic bone marrow transplantation (allo-BMT) and often requires rigorous prophylaxis. The current treatment regimens for aGVHD are associated with several side effects which necessitates the development of novel interventions that prevent aGVHD without precluding graft-versus-tumor effects. In the present study, we show that treatment of donor graft with plant steroidal lactone Withaferin A (WA) prior to transplantation markedly reduced aGVHD mediated damage in target organs without compromising the graft-versus.-tumor activity of the transplanted lymphocytes. WA abrogated post-transplant cytokine storm associated with allo-activation of donor lymphocytes. This was attributed to the ability of WA to inhibit early signaling events in T-cell activation including lymphoblast formation and activation of AKT/mTOR pathway. Mortality and morbidity related to allo-transplantation was significantly reduced in recipients of WA treated donor splenocytes compared to recipient of vehicle treated donor splenocytes. Further, WA treatment did not have any effect on reconstitution of lymphoid and myeloid lineages in recipients, resulting in stable and complete donor chimerism. In agreement with previous reports showing the effectiveness of WA in a mouse model of partial chimerism, our data further establishes that WA is able to attenuate aGVHD in an MHC-mismatched high dose chemo-conditioned murine model without compromising engraftment. This study provides compelling scientific basis for possible application of WA for prevention and treatment of aGVHD in patients receiving allo-BMT.

Insights into human factor studies conducted for US FDA-approved biological combination products.

Introduction: With increasing use of biological products and devices, importance of human factor (HF) studies is increasing. The HF study ensures safe and effective use of the device by intended users, for intended uses, under intended use environments.Areas covered: This review compiles information of HF studies conducted for biological combination products (biological products plus device) approved by US FDA's Center for Drug Evaluation and Research between 21 June 2011 and 31 December 2018. Information regarding product, indication, device type, administration frequency, and various aspects related to HF studies was collected from published documents.Expert opinion: Learnings from HF studies and known use-related problems of similar devices should be incorporated in the design of the device and the HF validation study. User profile, group, subgroup, and sample size are important aspects of the HF validation study. Early engagement with US FDA can be helpful to integrate the HF program with the overall device development program. It may not be possible to eliminate all use errors or risks for the device. Any residual risk after an HF validation study should be evaluated, and benefits of the device use should outweigh the residual risk.Abbreviations: BCP: biological combination product; BLA: Biological License Application; CDER: Center of Drug Evaluation and Research; FDA: Food and Drug Administration; FDC: Food Drug and Cosmetic; HCP: healthcare professional; HF: human factor; IFU: instructions for use; NDA: New Drug Application; PFS: pre-filled syringe; PHS: Public Health Service; PI: prescribing information; US: United States.

An update on the animal studies conducted for biosimilar approvals - Regulatory requirement vs actual scenario.

Nonclinical animal studies are considered as an integral part of biosimilar development program to demonstrate similarity and safety. We have compiled, reviewed and summarized animal studies conducted for European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) submission from 2006 till December 2018. The commonest animal studies conducted included repeat-dose toxicity study along with toxicokinetic, local tolerance and immunogenicity assessments, while the least common included primary pharmacodynamic, pharmacokinetic, safety pharmacology and single-dose toxicity studies. Animal studies were designed based on pharmacology of the drug, disease condition and innovator studies. Studies mostly used EU-sourced reference products as a comparator. For biosimilars approved both in the US and European Union (EU), similar data packages were submitted to these regions. Despite the regulatory guidelines allowing waiver of animal studies based on analytical data, animal studies have been conducted for almost all the approved biosimilars in the US and EU. There is an increasing need to re-assess the relevance of animal studies to support regulatory approval of biosimilars. Stepwise assessment for biosimilarity and conducting animal studies only if required at the right instance based on residual uncertainties may assist in optimizing animal study requirement for biosimilar development.

Surface-Modified Liposomal Formulation of Amphotericin B: In vitro Evaluation of Potential Against Visceral Leishmaniasis.

Surface modification of liposomes with targeting ligands is known to improve the efficacy with reduced untoward effects in treating infective diseases like visceral leishmaniasis (VL). In the present study, modified ligand (ML), designed by modifying polysaccharide with a long chain lipid was incorporated in liposomes with the objective to target amphotericin B (Amp B) to reticuloendothelial system and macrophages. Conventional liposomes (CL) and surface modified liposomes (SML) were characterized for size, shape, and entrapment efficiency (E.E.). Amp B SML with 3% w/w of ML retained the vesicular nature with particle size of ∼205 nm, E.E. of ∼95% and good stability. SML showed increased cellular uptake in RAW 264.7 cells which could be attributed to receptor-mediated endocytosis. Compared to Amp B solution, Amp B liposomes exhibited tenfold increased safety in vitro in RAW 264.7 and J774A.1 cell lines. Pharmacokinetics and biodistribution studies revealed high t 1/2, area under the curve (AUC)0-24, reduced clearance and prolonged retention in liver and spleen with Amp B SML compared to other formulations. In promastigote and amastigote models, Amp B SML showed enhanced performance with low 50% inhibitory concentration (IC50) compared to Amp B solution and Amp B CL. Thus, due to the targeting ability of ML, SML has the potential to achieve enhanced efficacy in treating VL.

Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: preparation, characterization and antitumor activity.

Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209 nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53 m(2)/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group.

Medium chain triglyceride (MCT) rich, paclitaxel loaded self nanoemulsifying preconcentrate (PSNP): a safe and efficacious alternative to Taxol.

The current work was aimed to develop Medium Chain Triglyceride (MCT) rich self nanoemulsifying preconcentrate of paclitaxel (PTX) for parenteral delivery. Very high concentrations of Cremophor EL and ethanol in Taxol have rendered patients to severe side effects. Years of extensive research on development of cost effective and safer vehicle for PTX, have failed to provide a promising replacement for Taxol. MCT was selected as oil owing to its parenteral acceptability, high solubilization capacity and multiple therapeutic benefits in cancer cachexia. PTX precipitation kinetics and reported toxicity profile of Kolliphor HS15 has favored its selection for PTX Self Nanoemulsifying Preconcentrate (PSNP). Presence of 30% free PEG in Kolliphor HS15 (PEG-15-hydroxystearate) restricts its miscibility with MCT, imposing significant challenge in development of MCT rich self nanoemulsifying preconcentrate. Removal of PEG layer from oil-surfactant mixture facilitated the formulation of PSNP with 51% w/w MCT. PSNP exhibited better precipitation kinetic profile, higher PTX loading with negligible hemolysis and histamine release compared to Taxol. PSNP was bioequivalent to Taxol, though V(d) and MRT was significantly higher than Taxol. PSNP showed distinctly better profile in inhibiting tumor growth and maintaining body weight with significantly higher % survival. Thus, PSNP can be a safer vehicle with potential clinical benefits.

A clinical comparative study of the management of chronic renal failure with Punarnavadi compound.

India like any other country is facing a silent epidemic of chronic renal failure (CRF)- a facet of the health transition associated with industrialization partly fuelled by increase in sedentary lifestyle, low birth weight and malnutrition. Increasing figures by many folds seen is posing a difficult situation to overcome with respect to economy and health of the working and earning population of the nation. There is an urgent need to explore, highlight new interventions and modify modifiable risk factors as a basis for treatment strategies to prevent the development and progression of CRF. The present study was taken up to evaluate the role of trial formulation tab. Punarnavadi compound in the management of chronic renal failure. This was an open clinical comparative study in controlled circumstances wherein 67 patients were studied for two months in three groups- Group A (allopathic control), Group B (ayurvedic control) and Group C (ayurvedic test). It was a multi-centric study; patients were registered from Anandababa charitable dialysis centre, Jamnagar, Kayachikitsa O.P.D. of I.P.G.T. and R.A. Jamnagar and P. D. Patel Ayurveda hospital, Nadiad. Results were assessed on 15 parameters using Students (paired) 't' test. Group A patients showed comparatively better results in eight parameters- weight, platelet count, serum urea, serum uric acid, serum sodium, potassium, chloride and total proteins. Parameter Hemoglobin% showed better results in Group B patients and in Group C patients comparatively better results in six parameters viz.- quality of life (breathlessness, weakness, general functional capacity), total count, serum creatinine and serum calcium - were observed. Throughout the study, trial drug tab. Punarnavadi compound did not show any adverse drug reaction. The results of this study will help in developing a cheap and safe treatment for the management of CRF.