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
Patricia McGettigan , Peter Roderick, Rushikesh Mahajan, Abhay Kadam, Allyson M. Pollock
Abstract
Background
In 2012, a committee in the Indian parliament revealed that state authorities had issued manufacturing licenses for numerous fixed dose combination (FDC) drugs without prior approval from the Central Drugs Standard Control Organization (CDSCO). This was a violation of rules, and it was believed that some confusion about the powers of the states prior to May 1, 2002, may have contributed to the situation. However, no systematic investigation had been conducted to determine if there was evidence to support these findings. Therefore, our study aimed to investigate the CDSCO approvals 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
Our research followed an ecologic study design, including a time-trend analysis of FDC sales volumes from 2007 to 2012, as well as a cross-sectional examination of data from 2011 to 2012 to establish the number of formulations on the market with and without CDSCO approval (referred to as "approved" and "unapproved" respectively), along with their branded products and sales volumes. We compared the data on approved FDC formulations from CDSCO with sales data from PharmaTrac, a national drug sales database. We analyzed the proportions of FDC sales volumes from 2011 to 2012 that came from centrally approved and unapproved formulations, as well as from formulations containing drugs that were internationally banned or restricted. We also compared the proportions of centrally approved and unapproved formulations marketed before and after May 1, 2002, when amendments were made to the drug rules. Finally, we compared FDC approvals in India, the United Kingdom (UK), and the United States of America (US).
For NSAID FDCs, a total of 124 formulations were marketed, with 34 (27%) being centrally approved and 90 (73%) unapproved. In the case of metformin, there were 25 formulations, with 20 (80%) approved and five (20%) unapproved. For anti-depressants/benzodiazepines, there were 16 formulations, with three (19%) approved and 13 (81%) unapproved. Lastly, for anti-psychotics, there were ten formulations, with three (30%) approved and seven (70%) unapproved. After May 1, 2002, the proportions of approved FDC formulations increased for NSAIDs (from 26% to 28%) and anti-psychotics (from 0% to 38%), while they decreased for metformin (from 100% to 75%) and anti-depressants/benzodiazepines (from 20% to 18%). Overall, the proportion of approved FDC formulations remained similar before and after that date.
FDC formulations led to the creation of 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 originating from unapproved formulations were as follows: anti-depressants/benzodiazepines (69%), anti-psychotics (43%), NSAIDs (28%), and metformin (0.4%). Formulations that included drugs banned or restricted internationally accounted for over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. In the four therapeutic areas examined, the UK had approved 14 FDC formulations, while the US had approved 22.
In conclusion, our findings provided evidence supporting concerns about FDCs in India. With the exception of met
Citation: McGettigan P, Roderick P, Mahajan R, Kadam A, Pollock AM (2015) 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. PLoS Med 12(5): e1001826. doi:10.1371/journal.pmed.1001826
Academic Editor: Aaron S. Kesselheim, Harvard University, Brigham and Women's Hospital, UNITED STATES
Received: August 8, 2014; Accepted: April 3, 2015; Published: May 12, 2015
Copyright: © 2015 McGettigan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: EU FP7 Health-2009-4.3.2-2 (Grant 242262). This paper results from research funded by the European Union Seventh Framework Programme Theme: Health-2009-4.3.2-2 (Grant no. 242262) under the title 'Access to Medicines in Africa and South Asia [AMASA]'. The project team includes partners at the University of Edinburgh (UK), Foundation for Research in Community Health (India), University of Ghent (Belgium), Mbarara University of Science and Technology (Uganda), Makerere University (Uganda), Queen Mary University of London (UK), Swiss Tropical and Public Health Institute at the University of Basel (Switzerland) and the University of the Western Cape (South Africa). Details are located at: http://ec.europa.eu/research/health/public-health/public-health-and-health-systems/projects/amasa_en.html and at http://www.amasa-project.eu/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Abbreviations: CDSCO, Central Drugs Standard Control Organization (in this paper, the term CDSCO encompasses both the Central Licence Approving Authority and the Drugs Controller General [India]; the Central Licence Approving Authority is defined in the national rules as the Drugs Controller, India); CNS, central nervous system; DCG(I), Drugs Controller General (India) (the officer who heads up the CDSCO; DCG(I) is the non-statutory term for “Drugs Controller, India”, the statutory term used in the legislation); FDA, Food and Drug Administration; FDC, fixed dose combination; MHRA, Medicines and Healthcare Products Regulatory Agency; MIMS, Medical Index of Medical Specialties; NSAID, non-steroidal anti-inflammatory drug; SDF, single drug formulation; UK, United Kingdom; US, United States of America
