Regulatory enforcement of the marketing of fixed-dose combinations in India: a case study of systemic antibiotics

\ua9 2023, The Author(s).Background: In India, states have licensed the manufacture of large numbers of fixed-dose combination (FDC) drugs without the required prior approval of the central regulator. This paper describes two major regulatory initiatives to address the problem, which began in 2007 and 2013, and examines whether they have been sufficient to remove centrally unapproved systemic antibiotic FDCs from the market. Methods: Information was extracted from documents published by the central regulator and the ministry of health, including the National List of Essential Medicines (NLEM), and court judgments, and analysed alongside sales volume data for 2008–2020 using PharmaTrac market dataset. Results: The regulatory initiatives permitted 68 formulations to be given de facto approvals (‘No Objection Certificates’) outside the statutory regime, banned 46 FDCs and restricted one FDC. Market data show that FDCs as a proportion of total antibiotic sales increased from 32.9 in 2008 to 37.3% in 2020. The total number of antibiotic FDC formulations on the market fell from 574 (2008) to 395 (2020). Formulations with a record of prior central approval increased from 86 (2008) to 94 (2020) and their share of the antibiotic FDC sales increased from 32.0 to 55.3%. In 2020, an additional 23 formulations had been permitted de facto approval, accounting for 10.6% of the antibiotic FDC sales. Even in 2020, most marketed formulations (70.4%, 278/395) were unapproved or banned, and comprised a 15.9% share of the antibiotic FDC sales. The share of NLEM-listed antibiotic FDC sales increased from 21.2 (2008) to 26.7% (2020). Conclusion: The initiatives had limited impact. Regulatory enforcement has been slow and weak, with many unapproved, and even banned, FDCs remaining on the market

The impact of stringent prescription-only antimicrobial sale regulation (Schedule H1) in India: an interrupted time series analysis, 2008–18

To assess the impact of Schedule H1 regulation notified and implemented in 2014 under the amended rules of the Drugs and Cosmetics Act (DCA), 1940 on the sale of antimicrobials in the private sector in India.The dataset was obtained from the Indian pharmaceutical sales database, PharmaTrac. The outcome measure was the sales volume of antimicrobials in standard units (SUs). A quasi-experimental research design—interrupted time series analysis—was used to detect the impact of the intervention.We observed a substantial rise in antimicrobial consumption during 2008–18 in the private sector in India, both for antimicrobials regulated under Schedule H1 as well as outside the regulation. Key results suggested that post-intervention there was an immediate reduction (level change) in use of Schedule H1 antimicrobials by 10% (P = 0.007), followed by a sustained decline (trend change) in utilization by 9% (P > 0.000) compared with the pre-intervention trend. Segregated analysis on different antimicrobial classes suggests a sharp drop (level changes) and sustained decline (trend changes) in utilization post-intervention compared with the pre-intervention trend. Our findings remained robust on carrying out sensitivity analysis with the oral anti-diabetics market as a control. Post-intervention, the average monthly difference between antimicrobials under Schedule H1 and the control group witnessed an immediate increase of 16.3% (P = 0.10) followed by a sustained reduction of 0.5% (P = 0.13) compared with the pre-intervention scenario.Though the regulation had a positive impact in terms of reducing sales of antimicrobials notified under the regulation, optimizing the effectiveness of such stand-alone policies will be limited unless accompanied by a broader set of interventions

Antibiotic prescriptions for Oral Diseases in India: Pattern and Practices

Introduction: The key objective of this research was to describe the prescription rate of various antibiotics for dental problems in India and to study the relevance of the prescriptions by analysing antibiotic type associated with different dental diagnoses, using a large scale nationally representative dataset. Methods: We used a 12-month period (May 2015 to April 2016) medical audit dataset from IQVIA (formerly IMS Health). We coded the dental diagnosis provided in the medical audit data to International Statistical Classification of Diseases and Related Health Problems (ICD-11) and the prescribed antibiotics for the diagnosis to Anatomic Therapeutic Chemical (ATC) -2020 classification of World Health Organization. The primary outcome measure was the medicine prescription rate per 1,000 persons per year (PRPY1000). Results: Our main findings were -- 403 prescriptions per 1,000 persons per year in the year 2015 -2016 for all dental ailments. Across all ATC level 1 classification, ‘Diseases of hard tissues’ made up the majority of the prescriptions. ‘Beta-lactam’, ‘Penicillin,’ and ‘Cephalosporins’ were the most commonly prescribed antibiotics for dental diagnoses followed by ‘Macrolides’ and ‘Quinolones’. ‘Dental caries’ , ‘Discoloration of tooth’, and ‘Toothache’ were the most common reasons for ‘Beta-Lactams’ and ‘Penicillin’ prescriptions. Conclusion: To conclude our study reports first ever country (India) level estimates of antibiotic prescription by antibiotic classes, age groups, and ICD-11 classification for dental ailments

Acute health effects of the Tasman Spirit oil spill on residents of Karachi, Pakistan

BACKGROUND: On July 27 2003, a ship carrying crude oil run aground near Karachi and after two weeks released 37,000 tons of its cargo into the sea. Oil on the coastal areas and fumes in air raised health concerns among people. We assessed the immediate health impact of oil spill from the tanker Tasman Spirit on residents of the affected coastline in Karachi, Pakistan. METHODS: We conducted a study consisting of an exposed group including adults living in houses on the affected shoreline and two control groups (A and B) who lived at the distance of 2 km and 20 km away from the sea, respectively. We selected households through systematic sampling and interviewed an adult male and female in each household about symptoms relating to eyes, respiratory tract, skin and nervous system, smoking, allergies, beliefs about the effect on their health and anxiety about the health effects. We used logistic regression procedures to model each symptom as an outcome and the exposure status as an independent variable while adjusting for confounders. We also used linear regression procedure to assess the relationship exposure status with symptoms score; calculated by summation of all symptoms. RESULTS: Overall 400 subjects were interviewed (exposed, n = 216; group A, n = 83; and group B, n = 101). The exposed group reported a higher occurrence of one or more symptoms compared to either of the control groups (exposed, 96% vs. group A, 70%, group B 85%; P < 0.001). Mean summary symptom scores were higher among the exposed group (14.5) than control group A (4.5) and control group B (3.8, P < 0.001). Logistic regression models indicated that there were statistically significant, moderate-to-strong associations (Prevalence ORs (POR) ranging from 2.3 to 37.0) between the exposed group and the symptoms. There was a trend of decreasing symptom-specific PORs with increase in distance from the spill site. Multiple linear regression model revealed strong relationship of exposure status with the symptoms score (β = 8.24, 95% CI: 6.37 – 10.12). CONCLUSION: Results suggest that the occurrence of increased symptoms among the exposed group is more likely to be due to exposure to the crude oil spill

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference