Early this year, the Indian arm of Pfizer decided to discontinue the manufacture and sale of Corex cough syrup, the crown jewel in its domestic portfolio. Corex was its biggest revenue generator and among the country's top five drug brands. What made the decision more surprising was that Pfizer had fought a legal battle against a March 2016 Central government ban on sale of this fixed dose combination, or FDC, medicine, along with 333 others, and won. The decision to discontinue the syrup came a month after the court ruling. The government had banned these FDC drugs in March 2016 after a committee of experts found that they were likely to pose a risk to patients and safer alternatives were available. An FDC drug includes two or more active pharmaceutical ingredients combined in a single dosage form.
Pfizer says the decision was based on a review of "respiratory offerings" that happened independent of the legal issues. "We decided to discontinue the manufacture of the erstwhile Corex cough syrup. At the same time, we decided to launch a series of line extensions of the Corex brand that will address specific sub-therapeutic areas under the broad respiratory segment," says a Pfizer spokesperson.
Perhaps, that was not the only reason. By winning the case, Pfizer proved its argument that there was no legal basis for banning Corex (a combination of chlorpheniramine maleate, codeine phosphate and some colorants). At the same time, the decision to discontinue the sale of the specific FDC drug made a bigger point - that Pfizer was not opposing the spirit behind the government decision, which was to stop the sale of 'irrational' and 'unapproved' FDC drugs. An FDC is called 'irrational' when there is no scientific rationale for combining two or more individual drugs in a particular combination.
Pfizer is not alone. In spite of the court staying the ban just a few days after it was imposed, the share of FDC drugs in total sales has been going down (see The Lost Cause). One reason could be the uncertainty about the final court verdict and government policy. The other could be pharmaceutical companies, too, being alive to the safety concerns around some of these drugs.
For instance, Pfizer, in response to queries from BT, said while it welcomed the high court order that allowed the company to continue the manufacture and sale of Corex, it is also "fully supportive of any process that is aimed at weeding out medicines that are irrational or not duly approved by the central and state regulators".
Market research firm AIOCD-AWACS has estimated that the market of all these FDC drugs, at the time of the ban, was worth `4,000 crore or about 4 per cent of the Indian pharmaceutical market. Early estimates by AWACS put Pfizer's potential loss at 12 per cent of revenues. Abbott, affected the most, was staring at a potential 15 per cent revenue loss, it said.
India has been battling the problem of unapproved and irrational FDCs for two decades. While FDCs account for a small percentage of new drugs approved globally, in India, almost every second medicine that gets marketing approval is a combination drug. The combination of two or more medicines is not a problem in itself. It is, in fact, preferred for several conditions such as HIV-AIDS and diabetes that are lifelong or life threatening, as fewer drugs means lower cost and better patient compliance. However, the presence of hundreds of drug combinations with untested efficacy/safety was an India-specific problem that the government had no option but to sort out.
What is worse is that India's regulatory system was indirectly contributing to the mess till 2002. The companies were, until then, exploiting the ambiguity over the powers of state drug regulatory authorities and the central drug regulator, the Drugs Controller General of India or DCGI. This allowed them to launch FDC drugs after state regulators' approval, though laws (clarified again in 2002) stipulated that all new drugs, including new combinations of approved medicines, could be approved only by the central regulator. By 2007, the DCGI had identified 294 unapproved FDC drugs and asked state drug authorities to ban these. The decision was not implemented due to a Madras High Court stay order. The matter is still sub judice.
The second move to weed out irrational drug combinations came in 2012, when the Parliamentary Standing Committee on Health came out with startling revelations about unapproved and FDC drugs. The committee called for a transparent policy for approving FDC drugs based on scientific principles. As a result, in 2013, the DCGI asked drug manufacturers for proof of safety and efficacy of medicines that had only "state approval". In the next 18 months, it got 6,300 applications. An expert committee scrutinised these and recommended ban on 344 FDC drugs. It was government action on this recommendation that was challenged by companies such as Pfizer in the Delhi High Court, which quashed it on December 1, 2016. Since all 454 petitioners, including Pfizer, had anyways got a stay on the order immediately after it was notified in March 2016, the companies were free to sell these medicines.
Almost every major player Business Today contacted either refused to comment or stood by the FDCs it was selling. "No comments," said a spokesperson for Sun Pharmaceuticals, India's biggest drug company. The India arm of US major Abbott, the most impacted, said the "judgment provides thousands of patients continued access to Abbott's doctor-prescribed products, which have the necessary regulatory approvals for manufacture, distribution and sale in India". Abbott's FDC drugs in question were mostly from Piramal Healthcare, whose formulations business it had acquired years ago.
The drugs controller, G.N. Singh, was on an official visit to Washington when the ban was notified. Among the visitors, immediately after the news about the ban spread, were some senior executives of Pfizer. "They met me there. I made it clear that we expected companies to be fair. They shouldn't go by the technicalities of approvals when their medicines are creating a public health issue. If people are getting addicted by your medicine, and if the government decides to ban the drug in public interest, there is no point in saying you have the approval," Singh recalls his message to the Pfizer team.
The problem with Corex and similar syrups was not whether they had all the approvals or whether the combinations were 'rational' or not. The issue was misuse. Codeine, its key ingredient, was a derivative of opium, and addictive. Singh, too, was referring to the alleged rampant misuse, which was the key reason for its inclusion among other 'irrational' and 'unapproved' FDC drugs.
Singh recalls that the executives of the global drug major assured to look into the 'ethics' of the problem. That perhaps explains the voluntary recall after the favourable court ruling.
Was Pfizer's response an exception? Not likely. Numbers suggest it has not been business-as-usual in the FDC segment ever since the ban order. Despite the high court stay on the ban, sale of FDCs, growing steadily before the ban, started falling. The fall has been severe in categories that most banned FDCs belonged to - respiratory, pain, anti-diabetic, dermatology and gastro-intestinal. AIOCD-AWACS data say the sale of FDC drugs fell 34.9 per cent in February 2017, when the overall domestic market grew7.1 per cent. In the preceding 12 months, the average fall in revenues was 22.3 per cent. The drugs controller says there has been a fall in the number of new FDC applications too. "Unfortunately, whenever there is confusion, the sentiment of manufacturers is hit. It will also impact development of FDC drugs. I hope the trend goes away," says Singh.
"The future (of FDCs in trouble) is doubtful. So, companies are not pushing such products. Not much brand building is happening. This is a short-term impact," says D.G. Shah, Secretary General of the Indian Pharmaceutical Alliance, which represents leading 20 drug makers that together account for 46 per cent domestic drug market.
While sales do indicate broad trends, they do not capture the complete reality of the market, served by close to 10,000 - majority of them tiny - pharmaceutical formulation manufacturing and marketing companies. While sales data tracked by market intelligence agencies capture the traditional wholesale and stockist channels, a big chunk of drugs, including FDCs approved by states, is marketed directly through medical practitioners, especially in rural markets. There are hundreds of companies that focus on these small pockets. The problem will end when one can ensure that even the smallest of such entities also stop making unethical and 'irrational' FDC drugs.
Unfortunately, the DCGI office has no database to track approvals given by state authorities on a real-time basis. Even past data are not fully available. One can only hope that state regulators are approving only those combinations that have undergone clinical trials as per the central protocol and received approval from the central regulator. "I don't think they will be giving fresh licences, as we have already informed them that these drugs are 'irrational' and that they should not clear FDC drugs that we have not approved. Since there is status quo, the companies that have old approvals from states continue to market these drugs but not the new ones," says Singh.
The irrationality of drugs approved by the central authority was also questioned by a parliamentary panel in 2013. The DCGI says it has since then set up 25 expert committees within the central drug administration to track medicines that may become 'irrational' on the basis of latest scientific developments. "We are making extra efforts. Our inspections are now meaningful as we are handholding state administrations. We are strengthening our surveillance systems so that no wrong-doer can get away. The WHO has declared us a stringent regulatory authority and we are in the same league as the US FDA and the UK's MHRA. We need to sustain that. The message is clear. Wrong-doers will be thrown out," says Singh.
Incidentally, over 40 per cent FDCs that were scrutinised by the expert committee were given a clean chit. The road ahead for irrational FDCs might be difficult but that might not be the case with rational combinations. ~