Regulatory Challenges in Clinical Trials: Strategies to Overcome Commonly Observed Deficiencies

140-148Apart from the regular clinical trials, bioavailability/bioequivalence studies are conducted to assess the safety and efficacy of generic drugs, comparing it with a reference listed drug. Clinical trial data is mandatory for further approval of the drug, for it to enter the market. These investigations are strictly regulated by various global and national regulatory authorities. The global clinical trials market is expected to register a Compound Annual Growth Rate (CAGR) of nearly 4.5% during the forecast period, 2018 to 2023. A major challenge for them to achieve the forecasted growth is meeting the increased level of compliance to the regulations. In recent times the research Organizations have been issued an increased number of warning letters with stringent procedures and even subsequent closure of the organizations. This case study conducted by the review of warning letters and other observations pointed out by two major global regulatory authorities, the FDA and EMA and the critical areas were identified. Recommendations were made for the major areas which were critical and repetitive. It was concluded that consistent methods are required to improve the quality of studies to effectively eliminate the challenges in mere future and contribute for the betterment of the drugs’ market

NEATTILL: A simplified procedure for nucleic acid extraction from arrayed tissue for TILLING and other high-throughput reverse genetic applications

<p>Abstract</p> <p>Background</p> <p>TILLING (Targeting Induced Local Lesions in Genomes) is a reverse genetics procedure for identifying point mutations in selected gene(s) amplified from a mutagenized population using high-throughput detection platforms such as slab gel electrophoresis, capillary electrophoresis or dHPLC. One essential pre-requisite for TILLING is genomic DNA isolation from a large population for PCR amplification of selected target genes. It also requires multiplexing of genomic DNA isolated from different individuals (pooling) in typically 8-fold pools, for mutation scanning, and to minimize the number of PCR amplifications, which is a strenuous and long-drawn-out work. We describe here a simplified procedure of multiplexing, NEATTILL (Nucleic acid Extraction from Arrayed Tissue for TILLING), which is rapid and equally efficient in assisting mutation detection.</p> <p>Results</p> <p>The NEATTILL procedure was evaluated for the tomato TILLING platform and was found to be simpler and more efficient than previously available methods. The procedure consisted of pooling tissue samples, instead of nucleic acid, from individual plants in 96-well plates, followed by DNA isolation from the arrayed samples by a novel protocol. The three variants of the NEATTILL procedure (<it>vast, in-depth </it>and <it>intermediate</it>) can be applied across various genomes depending upon the population size of the TILLING platform. The 2-D pooling ensures the precise confirmation of the coordinates of the positive mutant line while scanning complementary plates. Choice of tissue for arraying and nucleic acid isolation is discussed in detail with reference to tomato.</p> <p>Conclusion</p> <p>NEATTILL is a convenient procedure that can be applied to all organisms, the genomes of which have been mutagenized and are being scanned for multiple alleles of various genes by TILLING for understanding gene-to-phenotype relationships. It is a time-saving, less labour intensive and reasonably cost-effective method. Tissue arraying can cut costs by up to 90% and minimizes the risk of exposing the DNA to nucleases. Before arraying, different tissues should be evaluated for DNA quality, as the case study in tomato showed that cotyledons rather than leaves are better suited for DNA isolation. The protocol described here for nucleic acid isolation can be generally adapted for large-scale projects such as insertional mutagenesis, transgenic confirmation, mapping and fingerprinting which require isolation of DNA from large populations.</p

Facile and scalable preparation of bovine serum albumin stabilized cobalt sulfide nanostructures with various morphologies

We present a protein-assisted method for the facile and scalable synthesis of Cobalt sulfide (CoS) nanostructures with various morphologies using bovine serum albumin (BSA) as a stabilizing agent. The CoS samples prepared from 10:1 volume ratio of Cobalt (Co):Sulfur (S) and 1:10 volume ratio of Co:S at 0.01% w/v amount of BSA shows 3D flowers with an average diameter of 510 nm and hollow spheres about 900 nm in average diameter, respectively. The CoS samples prepared from 0.01, 0.1 and 0.5% w/v amounts of BSA at 1:1 volume ratio of Co:S shows nanosheet based porous clusters, nanosheet based partially porous clusters and aggregated spheres, respectively. Fourier transform infrared spectroscopy study confirms that the obtained BSA stabilized CoS nanostructures are stabilized by hydroxyl and amine groups present in the BSA molecules. © 2021 Elsevier B.V.1

Management of Multi Drug Resistance Tuberculosis in the Field: Tuberculosis Research Centre Experience

Setting: Multi-drug TB resistant (resistant to isoniazid and rifampicin) patients identified from a rural and urban area. Objective: To study the feasibility of managing MDR TB patients under field conditions where DOTS programme has been implemented Methods: MDR TB Patients identified among patients treated under DOTS in the rural area and from cases referred by the NGO when MDR TB was suspected form the study population. Culture and drug susceptibility testing were done at Tuberculosis Research Centre (TRC). Treatment regimen was decided on individual basis. After a period of initial hospitalization, treatment was continued in the respective peripheral health facility or with the NGO after identifying a DOT provider in the field. Patients attended TRC at monthly intervals for clinical, sociological and bacteriological evaluations. Drugs for the month were pre-packed and handed over to the respective center. Results: A total of 66 MDR TB patients (46 from the rural and 20 from the NGO) started on treatment form the study population and among them 20 (30%) were resistant to one or more second line drugs (Eto, Ofx, Km) including a case of “XDR TB”. Less than half the patients stayed in the hospital for more than 10 days. The treatment was provided partially under supervision. Providing injection was identified to be a major problem. Response to treatment could be correctly predicted based on the 6-month smear results in 40 of 42 regular patients. Successful treatment outcome was observed only in 37% of cases with a high default of 24%. Adverse reactions necessitating modification of treatment was required only for three patients. Implications Despite having reliable DST and drug logistics, the main challenge was to maintain patients on such prolonged treatment by identifying a provider closer to the patient who can also give injection, have social skills and manage of minor adverse reactions

Biological Seed Coating Innovations for Sustainable Healthy Crop Growth in Tomato

Biological seed coating (BSC) is the fastest-growing segment under the seed treatment approaches in the global seed market. It refers to the application of certain beneficial microbes to the seed prior to sowing in order to suppress, control, or repel pathogens, insects, and other pests that attack seeds, seedlings, or plants. Beneficial bioagents along with the compatible adjuvants can safely be delivered through coatings onto the seed surface. The polymer acts as a protective cover for bioagents and helps in improving the shelf life and dust-free seed. It is an efficient mechanism for placement of microbial inoculum into soil where they colonize the seedling roots and protect against soil-borne pathogens. It is also used to increase the speed and uniformity of germination, along with protection against soil-borne pathogens in nursery and improves final stand. Some induces systemic resistance in plants against biotic agents. It is a low-cost, alternative viable technology to chemical-based plant protection and nutrition. Thus, the demand for biological seed treatment solutions is increasing in view of consumer acceptance for chemical-free food. They give protection to seedlings in the nursery against damping-off fungi like Fusarium spp. or Rhizoctonia spp. and improve crop growth and yield in the main field

Patients' Costs and Cost-Effectiveness of Tuberculosis Treatment in DOTS and Non-DOTS Facilities in Rio de Janeiro, Brazil

Costs of tuberculosis diagnosis and treatment may represent a significant burden for the poor and for the health system in resource-poor countries.The aim of this study was to analyze patients' costs of tuberculosis care and to estimate the incremental cost-effectiveness ratio (ICER) of the directly observed treatment (DOT) strategy per completed treatment in Rio de Janeiro, Brazil.We interviewed 218 adult patients with bacteriologically confirmed pulmonary tuberculosis. Information on direct (out-of-pocket expenses) and indirect (hours lost) costs, loss in income and costs with extra help were gathered through a questionnaire. Healthcare system additional costs due to supervision of pill-intake were calculated considering staff salaries. Effectiveness was measured by treatment completion rate. The ICER of DOT compared to self-administered therapy (SAT) was calculated.DOT increased costs during the treatment phase, while SAT increased costs in the pre-diagnostic phase, for both the patient and the health system. Treatment completion rates were 71% in SAT facilities and 79% in DOT facilities. Costs per completed treatment were US$194 for patients and U$ 189 for the health system in SAT facilities, compared to US$336 and US$ 726 in DOT facilities. The ICER was US$ 6,616 per completed DOT treatment compared to SAT.Costs incurred by TB patients are high in Rio de Janeiro, especially for those under DOT. The DOT strategy doubles patients' costs and increases by fourfold the health system costs per completed treatment. The additional costs for DOT may be one of the contributing factors to the completion rates below the targeted 85% recommended by WHO

Dove or Hawk? Characterizing monetary policy regime switches in India

The past two decades have witnessed a worldwide move by emerging markets to adopt explicit or implicit inflation targeting regimes. A notable and often discussed exception to this trend, of course, is China which follows a pegged exchange rate regime supported by capital controls. Another major exception is India. It is not clear how to characterize the monetary regime or identify the nominal monetary anchor in India. Is central bank policy in India following a predictable rule that is heavily influenced by a quasi inflation target? And how has the monetary regime been affected by the gradual process of financial liberalization in India? To address these points, we investigate monetary policy regime change in India using a Markov switching model to estimate a time-varying Taylor-type rule for the Reserve Bank of India. We find that the conduct of monetary policy over the last two decades can be characterized by two regimes, which we term 'Hawk' and 'Dove.' In the first of these two regimes, the central bank reveals a greater relative (though not absolute) weight on controlling inflation vis-à-vis narrowing the output gap. The central bank however was found to be in the "Dove" regime about half of our sample period, focusing more on the output gap and exchange rate targets to stimulate exports, rather than moderating inflation. India thus seems to be following its own direction in the conduct of monetary policy, seemingly not overly influenced by the emphasis on quasi-inflation targeting seen in many emerging markets. © 2013 Elsevier B.V

The road to tuberculosis treatment in rural Nepal: A qualitative assessment of 26 journeys

BACKGROUND: The fact that tuberculosis can be treated with the DOTS strategy (Directly Observed Treatment, Short-course) is not enough to control the disease. Patients have to find their way to tuberculosis treatment first. To better understand the route to tuberculosis treatment in rural Nepal we interviewed twenty-six patients under treatment. METHODS: In semi-structured interviews patients shared their disease history and health seeking behaviour. The analysis focused on the encounters with the health care system before enrolment in the tuberculosis treatment program. RESULTS: Patient routes often started in the medical shop and led via intricate routes with multiple providers to facilities with higher qualified and more competent staff where tuberculosis was diagnosed. Several factors influenced the route to tuberculosis treatment. Besides known patients factors (such as severity of complaints, the ability to pay for services, availability of services and peer support for choosing a provider) specific health services factors were also identified. These included the perceived quality, costs and service level of a provider, and lack of provider initiated referral. Self referral because of waned trust in the provider was very common. In contrast, once tuberculosis was considered a possible diagnosis, referral to diagnostic testing and tuberculosis treatment was prompt. CONCLUSION: Patient routes towards tuberculosis treatment are characterised by self referral and include both private and public health care providers. Once tuberculosis is suspected referral for diagnosis and treatment is prompt. Given the importance of the private practitioners in the patient routes, quality improvement initiatives need to address not only the public sector but the private health care sector as well