FDC drug rationality back in focus as DCGI asks manufacturers of 49 formulations to submit data to justify therapeutic claims

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The irrationality of many fixed dose combination (FDC) drugs in the Indian market would be back in the spotlight as the Drugs Controller General of India (DCGI) has asked manufacturers of 49 combination medications to submit clinical trial protocol or post marketing surveillance (PMS) data to justify therapeutic claims.

The regulator’s move is based on recommendations of the Drug Technical Advisory Board (DTAB). A sub-committee constituted by the board to examine these FDCs, drugs containing two or more active pharmaceutical ingredients in a fixed dosage ratio, has observed that additional data regarding safety and efficacy is required in the said cases.

The 49 FDC medicines on the list include aceclofenac+ paracetamol+ chlorzoxazone, alprazolam+ melatonin, aceclofenac+ paracetamol+ tramadol, calcium dobesilate+ lignocaine+ hydrocortisone and amoxycillin+ lactic acid bacillus.

The combination drugs are part of a list of 294 FDCs that were banned by the regulator way back in 2008. The ban was later stayed by the Madras High Court on a petition filed by the manufacturers. The matter was deliberated at the DTAB meeting and the sub-committee was formed to examine it.

In a circular issued last week, the DCGI has asked drug controllers of all states and Union Territories to obtain the required information “so that final action can be taken on these FDCs”. In case of non-submission, the directorate would make its decision on the basis of information available before it in light of the Supreme Court judgment on FDCs, the circular reads. The top court had accepted the recommendations of the DTAB last year.

Regarding the FDC drug aceclofenac+ paracetamol+ chlorzoxazone, the expert panel observes that there is no published data on its safety and efficacy. Further, muscle relaxant like chlorzoxazone is generally given for short term use while paracetamol and diclofenac are administered for longer time period in case of arthritis patients. Although clinicians opined in favour of the FDC, the panel concluded that documented evidence to support the claims were necessary. Moreover, statistically powered clinical trials comparing the three-drug FDC with the two-drug combination of chlorzoxazone + paracetamol are required to be conducted within one year from the date of final decision on its marketing.

The committee has observed that alprazolam + melatonin FDC drug, used for treating chronic insomnia, has no rationality. Since scientific evidence is not available to support it, a clinical trial should be carried out to prove its efficacy. Experts have opined that the combination is not rational for treatment of insomnia or sleep disorders as alprazolam is an anxiolytic or anxiety-reducing medication.

In the case of amoxycillin+ lactic acid bacillus, the regulator is seeking PMS data on prevention of diarrhea and opportunistic infections. However, manufacturers can submit published data if available in this regard, and if not, phase IV trial should be conducted.

The national regulator’s stern action on FDCs with dubious rationality is crucial for patient safety. A recent report in the British Journal of Clinical Pharmacology has revealed that, of the 118 FDC antibiotic formulations sold in India between 2007 and 2012, around 64 per cent were not approved by the Central Drugs Standard Control Organisation. Only 4 per cent of these drugs were cleared in the US or Britain. Last year, an expert panel reviewing a health ministry ban on 349 FDCs also recommended that 343 of them should be “prohibited” and the remaining six to be “restricted or regulated”.

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