Two significant sets of measures have been taken by the government and CDSCO under separate initiatives which began in 2007 and 2013 (see Table 1).

In June 2007, the statutory Drugs Consultative Committee was briefed by the DCG(I) on a reference from the Prime Minister’s Office (PMO) concerning irrational and unapproved FDCs, which was described as a “perennial problem” requiring a solution [32].

In November 2007, the central government directed state drug regulators to cancel licences they had issued for the manufacture of 294 FDCs including 52 unique systemic antibiotic FDCs which had not had central approval [11]. This action followed complaints from Consumer Associations [33] and a DCG(I) examination [32], and a presumably unsuccessful prior request by the DCG(I) to states to withdraw the licences [32]. It is unknown how the list of 294 was drawn up.

Immediate legal challenges by the industry persuaded the Madras High Court to stay the effect of these directions, enabling the FDCs to remain on the market. A sub-committee of the statutory Drugs Technical Advisory Board (DTAB) was set up, apparently in 2008, to examine these FDCs ‘on a fast tract (sic) basis’ [34]. Seven years later, in February 2015, a summary of the assessment report of that sub-committee, chaired by Professor Y.K. Gupta, was published [18].

Following publication of a highly critical parliamentary report in May 2012 [35], a separate initiative was begun in January 2013. The DCG(I) wrote letters to state authorities asking them to request manufacturers within 18 months to prove the safety and efficacy of FDCs which fell within the definition of a ‘new drug’ and which the state authorities had licensed before 1st October 2012 without permission of the central regulator [36]. Prosecutions of companies which continued to manufacture such FDCs were not systematically instituted and they remained on the market.

By November 2013, over 5000 ‘applications’ had been submitted by manufacturers [37]. Ten Expert Committees were set up to consider the submitted FDCs [38]. The DTAB set up a sub-committee chaired by Dr. B. Suresh, President of the Pharmacy Council of India to prepare guidelines for the Expert Committees to follow [39].

This route, however, was subsequently aborted following concerns expressed by manufacturers. In July 2014, the President of the Indian Drugs Manufacturers’ Association wrote to the MoHFW stating that “India is the world leader in FDCs” and suggesting that the Expert Committees were “strongly biased against advocating combinations” [40]. In September 2014, a committee chaired by Professor C.K. Kokate was established by the Ministry, replacing the Suresh and Expert Committees [14].

Over 6000 FDC formulations were eventually submitted to the Kokate committee. It published four reports between January 2015 and May 2016 (Table 1). In July 2015, CDSCO began a process for issuing ‘No Objection Certificates’ (NOCs) for formulations of FDCs which the committee had assessed as ‘rational’. It appears that manufacturers were entitled to apply for NOCs which, when issued, would amount to a de facto or effective approval of the formulations outside the statutory regime and without a formal CDSCO approval. A total of 68 systemic antibiotic FDC formulations were allowed NOCs in 2015–2017 and 2020 (Additional file 1: Table A1). However, how many manufacturers have applied for NOCs remains unknown.

The third Kokate committee report in February 2016 set out its then final evaluation of formulations which it considered irrational, referring to the “serious concern in the country” of antibiotic resistance from “injudicious use”. In March 2016 the government prohibited the manufacture, sale and distribution of 344 FDCs and formulations including 35 systemic antibiotic (Additional file 1: Table A2). Immediate legal challenges again by the industry led to a temporary stay of the bans in the Delhi High Court. The stay was confirmed by the court in December 2016 on the basis that the DTAB should have been consulted. An appeal was made to the Supreme Court.

In December 2017, the Supreme Court held that it was not necessary for the DTAB to have been consulted and set aside the judgment of the Delhi High Court. However, the court ordered 334 FDCs and formulations to be examined by the DTAB. These consisted of the 344 banned in 2016, excluding 15 licensed before 21 September 1988, plus five which had been banned in 2017. The court set aside the banning orders for the 15 FDCs. The five banned in 2017 included an additional dosage form of an antibiotic banned in 2016 and one additional antibiotic FDC. The Supreme Court also accepted the assessment report on the FDCs that had been evaluated by the Gupta committee.

The examination ordered by the Supreme Court was conducted by a DTAB sub-committee chaired by Dr. Nilima Kshirsagar. This committee reported in July 2018, and the government issued fresh bans and restrictions for 334 FDCs and formulations in September 2018.

These included 33 of the 35 antibiotics prohibited in March 2016, plus a restriction on one formulation (amoxycillin + potassium clavulanate), which had been banned in 2016 and 2017 (Additional file 1: Table A2). Amoxycillin + bromhexine FDC was not banned in 2018 as its manufacture had been licensed before 21 September 1988, although the Kshirsagar committee recommended its prohibition.

In January 2019, a further 80 FDCs including 11 systemic antibiotics were banned, following the recommendations of the Gupta committee (Additional file 1: Table A2).

In April 2019, a fifth report from the Kokate committee, was put before the DTAB [41]. This report confirmed findings of irrationality for over 400 formulations which the committee had evaluated as irrational in its fourth report in May 2016. The DTAB set up another sub-committee, again chaired by Dr. Kshirsagar, to evaluate those formulations. Neither the fifth report of the Kokate committee, nor of the sub-committee, have been published. The process of issuing NOCs continued beyond the study period [42].

(1) Antibiotic FDCs and single drugs in India, 2008–2020

Total sales of antibiotics increased by volume between 2008 and 2015 and then declined (Table 2). However, FDC volumes in 2020 were 23.3% higher than in 2008, accounting for a larger proportion of the market in 2020 (37.3%) than in 2008 (32.9%), whilst single drug volumes grew by 1.5% over the same period. 114 FDCs were marketed in 2008 increasing to 123 in 2014 and decreasing to 112 in 2020.

(2) Antibiotic FDCs

Between 2008 and 2020, there were 143 different antibiotic FDCs (Additional file 1: Table A3) on the market of which 79 (55.2%) were dual antimicrobials. The 143 FDCs were marketed in 817 different formulations, with the highest number of FDC formulations marketed in 2011 at 646 and the lowest number in 2020 at 395 (Table 3).

(i) FDC formulations with formal CDSCO approval

Among the 817 FDC formulations marketed during 2008–2020, 129 (15.8%) had a record of prior formal approval. The number of formally approved formulations on the market decreased between 2013 and 2020 while the total number of FDC formulations decreased more markedly (Table 3). As a result, the proportion of formally approved formulations increased from 18.9% (113/599) in 2013 to 23.8% (94/395) in 2020. Overall, the market share of formally approved formulations increased from 32.0% to 55.3% between 2008 and 2020, respectively.

(ii) FDC formulations permitted NOCs

In 2015, 16 FDC formulations on the market had NOCs rising to 23 in 2020. Their market share by volume increased from 8.0% to 10.6% in the same period (Table 3). There were 28 formulations with NOCs for which no sales were recorded (Additional file 1: Table A1). Effective approval of FDC formulations using NOCs, brought the overall proportion of approved FDC formulations on the market to 29.6% (117/395) in 2020 from 15.0% (86/574) in 2008 (Table 3). All approved formulations accounted for 32.0% and 65.9% of sales volume in 2008 and 2020, respectively (Table 3).

(iii) Banned FDCs

In 2008–2012 there were traces on the market of FDCs banned before 2008, although their market volume was small (Table 3). 48 different systemic antibiotic FDC were banned and restricted in use in 2016–2019, with more than half being dual antimicrobials (Additional file 1: Table A2).

First initiative in 2007

The first initiative to control proliferation of FDCs resulted in 11 FDCs being banned over 11 years later in January 2019 (Additional file 1: Table A2). Six of the 11 FDCs banned in 2019 were not marketed in the study period. Five banned combinations were marketed in nine formulations in 2019, with four combinations in eight formulations remaining on the market in 2020 (Table 4). Their market share by volume, although very small, increased until 2018 and declined only after the 2019 ban.

Second initiative in 2013

The second initiative resulted in 35 FDCs being banned in 2016, and an additional two FDCs being banned in 2017. In 2018, 34 of these 36 FDCs were banned again, the use of one was restricted, and one was neither banned again nor restricted (Additional file 1: Table A2). 60 marketed formulations were banned in 2016 accounting for about 5% of the systemic antibiotic FDC market by volume (Table 5). That share had begun to decline two years before the ban, and continued to decline in 2017 despite the ban having been immediately stayed. The 2017 ban accounted for less than 1% of the total systemic antibiotic FDC market by volume (three marketed formulations). About 4% of the market volume was banned in 2018 (47 marketed formulations), falling to 0.1% by 2020.

For 17/34 (50.0%) combinations banned in 2018 no sales were recorded during the study period (Additional file 1: Table A2). However, 16 of the 17 FDCs with market data remained on the market in at least 31 formulations in 2020 (Additional file 1: Table A4), although with a decreasing sales volume and market share (Table 5).

(iv) Unapproved (and not banned) FDC formulations

From 2008 to 2020 the unapproved formulations decreased in number from 488 to 239 (Additional file 1: Table A5) and their market share by volume decreased from 63.3% to 15.7% (Table 3). Nevertheless, in every year of the study period the majority of marketed FDC formulations were unapproved (Fig. 1a).

Systemic antibiotic FDC formulations marketed in India by approval and ban status, 2008–2020

(v) NLEM-listed FDC formulations

Of the 817 marketed FDC formulations, 20 (2.4%) were listed on NLEM2011, NLEM2015, or both. 13/20 (65.0%) had a record of formal CDSCO approval and NOCs were permitted for two additional formulations in 2015 (Additional file 1: Table A6). The number of NLEM-listed FDC formulations on the market increased from 2% (10/574) to 4% (14/395) between 2008 and 2020 (Additional file 1: Table A7). Their overall market share rose from 21.2% to 26.7% by volume during 2008–2020.