How serious a threat are combination drugs?

Gurgaon: The news that India's Apex drug regulator is seeking companies to withdraw scores of combination drugs from the market must have frightened many.

The obvious question that arises is if these drugs are irrational (the regulator's euphemism for being unsafe or useless) as the Drug Controller General of India (DCGI) seems to suggest, then how did they find the way to the market and to the bodies of the patient-consumers. Most of these drugs have been in the market for many years now.

A top official of a leading Indian drug company, known for its unparalleled skills in process chemistry and for that reason, in generic drugs, sought to belittle the issue.

"FDCs are the flavour of the world. The doctors should have the discretion (to decide if a new fixed dose combination drug is safe and efficacious or not)," he said, on condition of not being quoted. But that is obviously a flimsy argument. Everybody knows that with their sales promotion skills, drug companies would easily influence most doctors.

And every doctor can't be expected to be an instant judge of the safety or usefulness of a new FDC. Won't the drugs in FDCs interact with each other with adverse results for the patient, even a casual observer would ask. An FDC in the terminology of medicine regulators is as good (or bad) as a new drug.

Wikipedia says these are formulations of two or more active ingredients (the substances that give the formulation the therapeutic/curative potency). FDCs are sold either as a single product (tablet/capsule/syrup) containing two or more active ingredients, all contributing to the product's efficacy or as co-packaged products—two or more products (drugs) in their final dosage form packaged together for ease of use or distribution. The current debate in India is over the raison d'être of a few hundred FDCs of the former category in the domestic market.

Why FDCs? Because they reduce the pill burden of patients and pinch pockets much less. Though first-time FDCs are akin to new drugs from a strict regulatory perspective, there is a comparative laxity in practice among regulators worldwide when it comes to examining FDCs and giving approvals. This is because the active ingredients in FDCs are already approved (if not established) drugs in their individual capacities and so a much reduced threat to safety is perceived in their combinations.

Why a "sudden action" on FDCs by India's regulator—the DCGI? No, the move is not sudden or dramatic. Conventionally, India has been a combination market. We have more FDCs in the market than abroad. Proliferation of FDCs in India can be partly attributed to Indian drug companies' adroitness in concocting such combinations.

But an equally important reason for the large prevalence of FDCs is the fact that the state drug authorities used to license these products sans proper technical scrutiny and compunction. Once any state licenses manufacturing and marketing of an FDC, it bestows the licencee a pan-Indian marketing right.

For the last many years, the Apex regulator has been telling the state-level authorities to desist from issuing licences for new FDCs on their own. In doing so, the DCGI was influenced by the opinion of the Drugs Technical Advisory Board (DTAB), the country's highest statutory authority to decide on technical matters of medicines.

The DTAB had repeatedly warned that scores of FDC drugs available in the Indian market might have had no rationality whatsoever, while many might be unsafe for consumption. When it appeared to the DCGI that moral suasion would not do, the regulator had made its displeasure with the state regulators' indulgence public and issued a directive saying that a no-objection certificate from it would be mandatory for licensing of FDCs. But even this did not have the desired effect on many state drug authorities.

As Pfizer India managing director, Kewal Handa says, "FDCs are not bad per se." They can have many benefits such as improving the treatment compliance and reduced cost. Co-packaged products are virtually the treatment norm now for not only infectious diseases such HIV/AIDS, TB etc, but also for cardiovascular ailments, diabetes etc. Such regimens are even authenticated by the World Health Organisation and other reputed bodies with technical competence.

Even in the case of one-product-many-drugs FDCs, there is a strong case of defence. Take the case of Pfizer's Caduet, a prescription drug that combines two medicines, Norvasc (amlodipine besylate) and Lipitor (atorvastatin calcium). While Norvasc is used to treat high blood pressure, angina and coronary artery diseases, Lipitor is used along with diet and exercise to lower cholesterol and reduce the risk of heart attack and stroke.

Caduet is found to be particularly effective in addressing certain body profiles and disease conditions. Separately, the individual drugs in the FDC would not have done so better in such cases. But besides the obvious issue of likely interactions of the chemicals that could harm the patient, combination drugs have certain other drawbacks, too.

FDCs offer less flexibility to make available the most appropriate (dose) strength for the patient. Also, since there are more than one drug in a product, it would be that much more difficult to identify the ingredient causing the reaction.

No doubt, the anxiety of drug companies worldwide to promote FDCs is not due to singular motive of providing better therapeutic benefit to the patients. FDCs are sometimes used by patent-holders as an instrument to prolong patents with doubtful claims of the extra or new curative potency of the product.

In an almost 100% generic market such as India, the companies' incentive for introducing FDCs is to sell them as comparatively low cast alternatives for treating multiple ailments. True, some firms may also be guilty of deliberately misleading the patient, in connivance with the state-level regulators.

Have the regulator an answer? DCGI, M Venkateswarlu says, "We have firmed up a common programme with the states. As per this, we have classified the FDCs 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 Apex 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 Drugs and Cosmetics (Amendment) Bill, 2007 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.

Source: Economic Times
31st October 2007

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