Recently, Indian federal drug regulator, Drug Controller General of India (DCGI), instructed scores of combination drugs to be withdrawn form the market. This is a rare notice for such drugs, more so when it came from the Indian regulator.
Fixed dose combination drugs are not totally uncommon. In Singapore, some of the examples are like co-trimoxazole (trimethoprim-sulfamethoxazole). Augmentin (amoxicillin-clavulanate), Fansidar (sulfadoxine-pyrimethamine), Niften (nifedipine-atenolol), Actifed Compound Linctus (triprolidine HCl-pseudoephedrine HCl-dextromethorphan) etc. are some common examples pharmacists deal with regularly & frequently. The basic issue is how rational it is to combine drugs in a fixed dose formulation to the point that it becomes more a “commercial” decision to limit the proportion of each drug. There are sound reason why it should be done for efficacy reason, but then came the issue of safety issue. That throws the challenge back to healthcare professionals & the drug regulators.
The doctors and pharmacists should have the discretion (to decide if a new fixed dose combination drug is safe and efficacious or not), but they can’t be expected to be an instant judge of the safety or usefulness of a fixed dose combination drug. If one of the combination drug is nehrotoxic but not the others. It would be impossible to make adjustment of the nephrotoxic compoment in the fixed dose formula for patient with renal insufficiency, vs. when the drugs are available as individual dosages that are amenable to titration.
Fixed drug combination do have a distinct advantages too. For one, it reduces chance of polyphamacy, may reduce cost of buying multiple drugs, and some combinations are therapeutically optimized instead of being designed purely for convenience per se. Additionally, the individual active ingredients in fixed dose combination drugs are already approved (if not established) drugs, thereby according the new dosage form with the perceived “safety” profile.
Why a “sudden action” on such fixed dose combination drugs by the DCGI? No, the move is not sudden or dramatic. Conventionally, India has been a combination market which could partly be attributed to Indian drug industry’s adroitness in concocting various combinations. No doubt, the anxiety of drug companies worldwide to promote fixed dose combination drugs is not due to singular motive of providing better therapeutic benefit to the patients, they are sometimes used by patent-holders as an instrument to prolong patents. The Director General of DCGI, M Venkateswarlu says, “We have firmed up a common programme with the states. As per this, we have classified the FDCs (fixed dose combiniation drugs) in the market broadly into four categories - absurd, rejected and to-be-examined. The banned products, needless to say, will not be there in the market, lest those concerned will face legal action.
Besides, the manufacturers will have to withdraw over 140 products which are dubbed either absurd or rejected within specified periods of time. Another 150-odd formulations are put under the scanner on which decisions will be taken on a case- by-case basis after necessary pharmacological experimentation.” The US-FDA normally insist on clinical trials before giving approval for a new FDC. The objective is find the efficacy and safety profile of the drug in human body. This is in addition to the stability (availability of the drug in human blood) and bio-equivalence (BE) tests.
In India, even the DCGI has rarely mandated clinical trials for new FDCs. Mr Venkateswarlu says clinical trials might not be necessary in all cases. “It will depend on the character of the (drug) molecule whether to perform clinical trials or not. In some cases, all the three tests - clinical trials, stability and bioequivalence - would be needed; in some BE and stability tests would suffice,” he says.
Strict regulatory action on FDCs in India comes belatedly. The cleansing exercise the federal regulator has now initiated is entirely in order. The DCGI would do well to establish a foolproof system to evaluate FDCs. The Parliament is now considering the central drug authority (CDA) bill which proposes to vest the drug licensing powers solely with the centre. To stride, the CDA ought to get the required infrastructure support and technical competence.
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