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

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.

Systemic antibiotic sales and WHO recommendations, India.

Objective: To analyse sales of fixed-dose combination and single antibiotics in India in relation to World Health Organization (WHO) recommendations and national regulatory efforts to control antibiotic sales. Methods: We extracted data on sales volumes of systemic antibiotics in India from a market research company sales database. We compared the market share of antibiotic sales in 2020 by WHO AWaRe (Access, Watch and Reserve) category and for those under additional national regulatory controls. We also analysed sales of fixed-dose combinations that were: formally approved for marketing or had a no-objection certificate; on the national essential medicines list; and on the WHO list of not-recommended antibiotics. Findings: There were 78 single and 112 fixed-dose combination antibiotics marketed in India, accounting for 7.6 and 4.5 billion standard units of total sales, respectively. Access, Watch and Reserve antibiotics comprised 5.8, 5.6 and 0.1 billion standard units of total market sales, respectively. All additionally controlled antibiotics were Watch and Reserve antibiotics (23.6%; 2.9 billion standard units of total sales). Fixed-dose combinations on the WHO not-recommended list were marketed in 229 formulations, with 114 formulations (49.8%) having no record of formal approval or no-objection certificate. While there were no not-recommended fixed-dose combinations on the national list of essential medicines, 13 of the top-20 selling antibiotic fixed-dose combinations were WHO not-recommended. Conclusion: The sale of Watch group drugs, and antibiotics banned or not approved, needs active investigation and enforcement in India. The evidence base underpinning formal approvals and no-objection certificates for not-recommended fixed-dose combinations should be audited.

Dismantling the National Health Service in England.

The National Health Service was established in the United Kingdom in 1948 as a universal, comprehensive service free at the point of delivery, which is publicly provided, funded, and accountable. Market incrementalism in England has eroded this system over three decades. The recently enacted Health and Care Act will erode it further. This article first explains briefly how legislation and policy initiatives in 1990, 2003, and 2012 furthered development of the market and private provision of health services, and then describes the main structural changes in the new Act and their implications. England is now moving decisively toward a marketized, two-tier, mixed-funding system with several similarities to the United States.

Going upstream - an umbrella review of the macroeconomic determinants of health and health inequalities.

BACKGROUND: The social determinants of health have been widely recognised yet there remains a lack of clarity regarding what constitute the macro-economic determinants of health and what can be done to address them. An umbrella review of systematic reviews was conducted to identify the evidence for the health and health inequalities impact of population level macroeconomic factors, strategies, policies and interventions. METHODS: Nine databases were searched for systematic reviews meeting the Database of Abstracts of Reviews of Effects (DARE) criteria using a novel conceptual framework. Studies were assessed for quality using a standardised instrument and a narrative overview of the findings is presented. RESULTS: The review found a large (n = 62) but low quality systematic review-level evidence base. The results indicated that action to promote employment and improve working conditions can help improve health and reduce gender-based health inequalities. Evidence suggests that market regulation of tobacco, alcohol and food is likely to be effective at improving health and reducing inequalities in health including strong taxation, or restriction of advertising and availability. Privatisation of utilities and alcohol sectors, income inequality, and economic crises are likely to increase health inequalities. Left of centre governments and welfare state generosity may have a positive health impact, but evidence on specific welfare interventions is mixed. Trade and trade policies were found to have a mixed effect. There were no systematic reviews of the health impact of monetary policy or of large economic institutions such as central banks and regulatory organisations. CONCLUSIONS: The results of this study provide a simple yet comprehensive framework to support policy-makers and practitioners in addressing the macroeconomic determinants of health. Further research is needed in low and middle income countries and further reviews are needed to summarise evidence in key gaps identified by this review. TRIAL REGISTRATION: Protocol for umbrella review prospectively registered with PROSPERO CRD42017068357.

The global prevalence of tobacco use in type 2 diabetes mellitus patients: A systematic review and meta-analysis.

BACKGROUND: A multi-layered association between tobacco use and type 2 diabetes mellitus (T2DM) is well established. However, global epidemiological patterns of tobacco use among T2DM patients are not well documented; this review thus aims to estimate the overall global burden of tobacco use in T2DM. METHODS: A systematic review of studies published from Jan 1, 1990 to October 5, 2017 was undertaken, comprising: a comprehensive literature search on multiple electronic databases; quality assessment of studies; data extraction for the primary (prevalence of tobacco use in T2DM patients) and secondary outcomes (patterns of tobacco use in T2DM patients); and a meta-analysis. The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. A protocol for this review is available on PROSPERO (CRD42016038793). FINDINGS: 74 studies were included in the review, reporting data from 3.2 million participants across 33 countries. Global mean prevalence of tobacco use in T2DM was 20·81% (95% CI 18·93-22·76), and was higher in the WHO East Asia and Pacific and South Asia regions, compared to the Americas, Middle East and North Africa, Europe and Central Asia. In studies which compared prevalence of tobacco use in patients to non-patients, patients with T2DM were 26% less likely to use tobacco (pooled OR = 0·74 (CI 0·61-0·88). INTERPRETATION: Tobacco is used by one in five T2DM patients globally, but usage is less likely in patients than in non-patients. Global patterns of use demonstrated by this review have implications for both prevention and The understanding of diabetes burden, and the success of tobacco cessation strategies.

Threats to global antimicrobial resistance control: Centrally approved and unapproved antibiotic formulations sold in India.

AIMS: Rising antimicrobial resistance (AMR) is a global health crisis. India has among the highest resistance rates and antibiotic consumption internationally. Extensive use of fixed-dose combination (FDC) antibiotics and of unapproved formulations are claimed contributory factors but there has been no systematic examination of formulations or volumes sold. The aim of the present study was to investigate the regulatory approval status and sales volumes of systemic antibiotics marketed in India. METHODS: This was an ecological study using regulatory records in India, the UK and the US to determine the approval status in each country of systemic antibiotic FDCs and single-drug formulations (SDFs) sold in India. Pharmatrac® sales data were used to determine the formulations and volumes sold (2007-2012), branded-product numbers and manufacturers. RESULTS: Of 118 systemic antibiotic FDC formulations sold in India, 43 (36%) were approved but 75 (64%) had no record of regulatory approval; four (3%) formulations were approved in the UK and/or US. Almost half of formulations (58/118; 49%) comprised dual antimicrobials, most unapproved in India (43/58; 74%), and many were pharmacologically problematic. In contrast, 80/86 (93%) SDFs were approved in India and over two-thirds in the UK and/or US. Total antibiotic sales increased by 26%, from 2056 million units (2007-08) to 2583 million units (2011-12). FDC sales rose by 38% vs. 20% for SDFs. By 2011-12, FDCs comprised one-third of sales (872 million units). Over one-third of FDCs sold (300.26 million units; 34.5%) were of unapproved formulations. Multinational companies manufactured unapproved formulations and accounted for 19% of all FDC and SDF sales annually. CONCLUSIONS: Sales in India of antibiotic FDCs, including unapproved formulations, are rising. In the context of increasing AMR rates nationally and globally, unapproved antibiotic FDCs undermine India's national AMR strategy and should be banned from sale.

Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India.

There is growing national and international concern about the drug regulatory system in India. Parliamentary reports have highlighted the presence of high numbers of unapproved medicines and irrational combinations of both approved and unapproved drugs in the Indian market-place. Fixed-dose combinations (FDCs) are a peculiar feature of the Indian pharmaceutical landscape. Although metformin is a first-line treatment, FDCs for diabetes in India account for two-thirds of all diabetes medicine sales, and some have not been approved by the Central Drugs Standard Control Organization (CDSCO). This study examines the basis of efficacy and safety of top-selling metformin FDCs in India against four WHO criteria from clinical trials guidelines for the approval of FDCs. Data from a commercial drug sales database (PharmaTrac) were combined with searches through published literature, clinical trial registries, and published and unpublished trial websites of metformin FDCs in adults with type 2 diabetes mellitus. Five metformin FDCs in India from November 2011 to October 2012 accounted for 80% of all metformin FDC sales by value and volume. Although all five had obtained CDSCO approval, three had been sold and marketed prior to receiving this approval. Evaluation of published and unpublished clinical trials of these five FDCs found none provided robust evidence of safety and efficacy for the treatment of type 2 diabetes. Recommendations are made for publishing evidence that underpins drug approvals, marketing bans, greater transparency through updated clinical trials databases and legislative reform in order to prevent irrational FDCs from entering the market.

Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs.

BACKGROUND: In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states' powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). METHODS AND FINDINGS: This was an ecologic study with a time-trend analysis of FDC sales volumes (2007-2012) and a cross-sectional examination of 2011-2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval ("approved" and "unapproved"), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011-2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved; anti-psychotics: ten formulations, three (30%) approved, seven (70%) unapproved. After 1 May 2002, the proportions of approved FDC formulations increased for NSAIDs (26%/28%) and anti-psychotics (0%/38%) and decreased for metformin (100%/75%) and anti-depressants/benzodiazepines (20%/18%), and the overall proportion approved remained similar before and after that date. FDC formulations gave rise to multiple branded products, ranging from 211 anti-psychotic FDC products from ten formulations to 2,739 NSAID FDC products from 124 formulations. The proportions of FDC sales volumes arising from unapproved formulations were as follows: anti-depressants/benzodiazepines, 69%; anti-psychotics, 43%; NSAIDs, 28%; and metformin, 0.4%. Formulations including drugs banned/restricted internationally comprised over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. Across the four therapeutic areas, 14 FDC formulations were approved in the UK and 22 in the US. CONCLUSIONS: There was evidence supporting concerns about FDCs. Metformin excepted, substantial numbers of centrally unapproved formulations for NSAID, anti-depressant/benzodiazepine, and anti-psychotic FDCs were marketed; sales volumes were high. The legal need for central approval of new drugs before manufacture has been in place continuously since 1961, including for FDCs meeting the applicable legal test. Proportions of centrally unapproved formulations after 1 May 2002 did not decrease overall, and no ambiguity was found about states' licensing powers. Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally and undertaking a review of benefits and risks for patients in ceasing or switching to other medicines. Drug laws need to be amended to ensure the safety and effectiveness of medicines marketed in India.