New Delhi / Mumbai: India’s drug regulator is set to ask state drug control departments to withdraw approvals for 3,000 brands of so-called “combination drugs", which generate nearly Rs4,000 crore in annual revenues for dozens of drug companies but whose efficacy and safety are in question.

The move comes after years of discussions and deliberations over the pending proposal. The drugs in question are manufactured and marketed by almost all of India’s leading drug makers.


The move to pull the drugs from the market is on the ground that they were not approved by the central authority, because of which no regulatory formalities to prove their safety and efficacy were conducted, as is the requirement for all new drug approvals.

The Central Drugs Standard Control Organisation, the central authority that approves new drugs for marketing in the country, will soon send notices to all state drug control departments asking them to withdraw licences for manufacturing these combination drugs.

The office of the Drug Controller General of India (DGCI) has prepared a list of 282 such drug combinations, known in the industry as fixed-dose combinations. These combinations, made by combining one key drug with one or more other drugs, are available throughout the country in hundreds of drug brands.

The fixed-dose combinations are made under the pretext of combining different drugs, which are already approved in India individually, into a single pill or capsule for treating multiple indications (diseases) in patients.

“Though these drugs are individually approved here, a combined formulation has to be treated as a new drug and the safety and efficacy tests have to be conducted again to clear them for marketing. This is not done when the licences are sought from the state departments," M. Venkateswarlu, DGCI, told Mint.

“We have already sensitized the issue in the Drug Consultative Committee, an advisory board to the central drug department that comprises of senior regulatory officials, drug experts and the state drug controllers," he said. “A list of these drug combinations has also been circulated to the state drug commissioners for their immediate attention."

According to a senior member in the drug consultative committee who did not want to be identified, the list circulated to the states by the central department includes 37 brands sold by Cipla Ltd and Alkem Laboratories Ltd, 36 brands of Nicholas Piramal India Ltd, 21 of the antibiotics leader Lupin Ltd, 12 brands of the Mumbai-based Sun Pharmaceuticals Industries Ltd and Wockardt Ltd, 15 brands of the country’s largest drug maker Ranbaxy Laboratories Ltd and 30 brands of Ahmedabad-based Cadila Healthcare Ltd.

Other drug makers included in the list are Emcure Pharmaceuticals Ltd (30 brands), Ind-Swift Laboratories Ltd (40 brands), Mankind Pharmaceuticals Ltd (45 brands), Intas Pharmaceutical Ltd (30 brands), Blue Cross Laboratories Ltd (15 brands), Elder Pharmaceuticals Ltd (15 brands) and Cadila Pharmaceuticals Ltd (28 brands).

“All these brands have been manufactured and marketed with licences obtained from state drug controllers in the last few years. If these states do not come out with an immediate action to review the licences, the central department will be forced to stop circulation of these drugs by using its judiciary provisions," said the drug controller general.

Said Gujarat’s commissioner, food and drug control administration, Subodh P. Adeshara: “We have not received any specific instruction from the central department to withdraw the licences so far. We are awaiting certain direction in this regard as states do not have powers to ban products, which are licenced from other states."

According to Adeshara, Gujarat has never issued licences to any such first-time combinations.

“At the same time, such products are already available in the state, which are licenced by other states. So, denial of licences to such products to the manufacturers in Gujarat will be an injustice. Hence, we have issued licences and had also immediately alerted the central department about the same," Adeshara said.

Industry experts said companies use fixed-dose combinations for two reasons, the most important being to override the Drug Price Control Order by adding one or two drugs with a drug on which the National Pharmaceutical Pricing Authority (NPPA) fixes a price ceiling.

The second reason is higher margins as drug makers can charge more for the combination even as the packaging and distribution cost typically remain that of a single drug.

Swati Piramal, director, strategic alliances, Nicholas Piramal, maintains that Indian companies have developed combinations in response to the needs of the medical community. “Doctors have often complained that patient compliance is a huge issue," she said. “We have to understand the realities of treating chronic illnesses where patients have to take too many pills and usually end up not taking some of them, causing more harm."

According to her, Indian companies can lead the way in proving to the world that in some cases combinations work well and could provide an alternative to some of the compliance issues that plague medical management today.

Most of the drug makers who are active in this market segment and contacted by Mint declined to comment on the regulator’s move.

As per current drug regulatory system in India, any new drug to be launched in the country has to be approved by DGCI. At the time of new drug approval, the central department requires detailed safety and efficacy data submitted by the drug maker after completing the mandatory clinical trials, bio-equivalence and bioavailability studies. Following this, the state drug control departments issue manufacturing licences for those drugs.

However, the states can issue manufacturing licences to any drug after four years of its first approval in the country without a mandatory clearance from the drug controller no matter where such drugs are sold. Since the state drug controllers are appointed by respective state governments, the drug controller has no direct power to take penal actions against the state departments for any alleged wrongdoing.

“This is the key reason for introducing a single licensing body for drugs in the country by setting up the proposed Central Drug Authority," says Venkateswarlu.

Says Chandra Gulhati, editor of MIMS India, a drug reference index for physicians: “The fixed-dose combination problem finds its genesis in the government’s move to promote the small-scale industry in the 1970s. While it was fine to promote the growth of small-scale industries for other sectors, extending those benefits to the pharmaceutical industry has been disastrous," says Dr Gulhati, who has been spearheading the cause of banning these drugs saying that no other country has these drugs.

“If DCGI is serious and implements this, it will wipe out many of the small sector companies that survived purely on marketing these drugs."

Sampada Patvardhan, director of drug information centre, Maharashtra State Pharmacy Council, believes it is possible for fixed-dose combinations to be created in such a way that it will not be harmful and may be even more beneficial than the individual drugs.

“The Indian drug industry is quite advanced in its formulation technology," says Dr Patvardhan. “It can develop combinations using certain coatings to enable them to be different entities within a single formulation."

“Many irrational fixed-dose combinations have been around in the Indian market for a while now," adds Urmila Thatte, head, department of clinical pharmacology at BYL Nair Hospital and Research Centre in Mumbai. “In principle, most drugs should not be put in combinations because this could create more problems than they could solve. The drugs may interact with each other, or may interact with food. They may even cause adverse reactions and a physician may find it impossible to identify which drug has caused it."

“Implementation of rules targeting irrational fixed-dose combinations may be a little tricky now as health is a state subject," adds Dr Thatte. “The authorities at the Centre will have to ensure that all states agree to tackle the issue and also actually implement the rules. Also, it is not fair to tar all combinations with the same brush. In some cases, combinations may not be harmful and may even be desirable—such as anti-TB drugs, where patient compliance is improved, or oral contraceptives, where a combination works better than a single drug."