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

Abstract

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.

Abstract

Patricia McGettigan and colleagues investigated approval for and availability of oral fixed-dose-combination drugs from four therapeutic areas in India.

Editors' Summary

Background

Patients who are prescribed several different tablets to treat a single condition or multiple coexisting conditions often find it hard to take all their drugs correctly. For some conditions, clinicians can improve medication compliance by prescribing a fixed dose combination (FDC) product, a drug formulation containing two or more active drugs combined in a fixed ratio of doses that are usually available only in a single dosage form. FDCs, which are sometimes called “polypills,” are particularly useful in situations where both the drug combination and the doses needed to treat patients are standardized and stable, such as in the management of HIV/AIDS. FDCs can also be cheaper to manufacture and easier to distribute than single drug formulations, but they nevertheless have some disadvantages over such formulations. For example, the risks of adverse effects can be compounded by including multiple drugs from the same therapeutic group in a single FDC. Thus, to prevent patients being given unsafe or dangerous formulations, many countries regulate the development and marketing of FDCs.

Why Was This Study Done?

Concerns have been expressed internationally about the regulation of medicinal drugs in India, where thousands of FDCs are available. In response to these concerns, in 2011, an Indian parliamentary standing committee closely examined the Indian national drug regulator—the Central Drugs Standard Control Organization (CDSCO). The committee’s report, released in 2012, highlighted multiple deficiencies in the approval processes of the CDSCO, including a failure to test the efficacy and safety of many of the FDCs available in India, but provided no systematic evidence to support its concerns about FDCs. Here, the researchers undertake a time-trend analysis of the sales volumes of oral FDCs for pain relief (analgesia; formulations of non-steroidal anti-inflammatory drugs, NSAIDs), diabetes (metformin formulations), depression/anxiety (anti-depressant/benzodiazepine formulations), and psychosis (anti-psychotic formulations) in India between 2007 and 2012. In addition, they undertake a cross-sectional examination of data from 2011–2012 to determine the contributions to FDC product numbers and sales volumes of formulations with a known record of CDSCO approval (referred to as “approved”) and those for which such a record could not be found (referred to as “unapproved”).

What Did the Researchers Do and Find?

The researchers obtained information on FDC formulations approved between 1961 and 2013 in each therapeutic area from the CDSCO, and FDC sales data from 2007 to 2012 from PharmaTrac, a database of drug sales in India. Of the 175 FDC formulations marketed in India in the therapeutic areas studied, only 60 (34%) were approved. Although 80% of 25 marketed metformin FDC formulations were approved, only 27% of 124 NSAID FDC formulations, 19% of 16 anti-depressant/benzodiazepine FDC formulations, and 30% of ten anti-psychotic FDC formulations were approved. Over the five years included in the time-trend analysis, FDCs accounted for an increasing proportion of total sales volumes. By 2011–2012, FDCs accounted for more than half of all NSAID and oral anti-diabetic drug sales, and one-third and one-fifth of anti-psychotic and anti-depressant/benzodiazepine sales, respectively. Moreover, in 2011–2012, the proportion of FDC sales volumes arising from unapproved formulations was 43% for anti-psychotics, 69% for anti-depressants/benzodiazapines, 28% for NSAIDs, and 0.4% for metformin; formulations including drugs of which use is banned or restricted internationally accounted for 13.6% and 53% of NSAID and anti-psychotic FDC sales, respectively. While “ambiguity” in the rules prior to 2002 was advanced as a reason for some FDCs having been marketed without a record of central approval, the researchers identified no ambiguity, and in fact, following an amendment to the rules in May 2002 that extended the requirements on approval applicants, new FDCs continued to be marketed without a record of central approval.

What Do These Findings Mean?

Although the accuracy of these findings is likely to be limited by the use of publicly available records of drug approvals and by the use of commercial sales records, the study’s results support concerns about the marketing and use of FDCs in India. They indicate that large numbers of unapproved formulations are available for three of the four therapeutic areas examined, and that sales volumes of these unapproved FDCs (including FDCs that included internationally banned or restricted drugs) are high. The researchers make several recommendations to remedy this situation, which in their view risks harming patients. Sale and manufacture of unapproved FDC formulations, they suggest, should be banned immediately. Withdrawal from the market should be staged, with priority given to removing those formulations containing drugs that are banned or restricted internationally. Manufacturers who wish to retain specific FDCs on the market should be required to submit approval applications to the CDSCO. If this recommendation is implemented, the researchers note, clinicians will need to review the needs of patients taking unapproved FDCs and provide appropriate alternatives. To ensure in the long-term the safety and effectiveness of new medicines marketed in India, as well as transparency of the approval process, the researchers call for amendments in India’s regulatory processes and drug laws. They also suggest that a review should be undertaken of the safety and effectiveness of FDCs currently available in India.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001826.

• Wikipedia provides information about fixed dose combination products (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

• The US Food and Drug Administration regulates all medical drugs and devices in the US and provides information about combination products, including FDCs

• The World Health Organization provides a brief introduction to FDCs and draft guidance for the registration of FDCs

• Information about the CDSCO, the Indian national drug regulatory body, is available; the CDSCO website includes the approved FDC list; the Indian parliamentary standing committee report on the CDSCO is available

• The Medicines and Healthcare Products Regulatory Agency provides information on medicines regulation in the UK

• The European Medicines Agency provides information on medicines regulation in Europe