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.
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.
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