NEW DELHI – India has banned 344 fixed-dose combination (FDC) drugs, including several antibiotics and painkillers and syrups with codeine, stating that they "involve risk to humans," they have safer alternatives available or they have no therapeutic justification.

Under India's federal structure, the Drugs Controller General of India (DGCI) is responsible for approving new and imported drugs, while the Central Drugs Standards Control Organisation (CDSCO) lays down standards. The state regulators deal with local manufacture, sale and distribution. But, given the often acute shortage of money, staff and technical expertise in several state drug regulatory agencies, companies sometimes seek approval for marketing from those agencies that often fail to check whether the drugs have been approved for use by the CDSCO.

In 2007, the DGCI ordered all states to stop making and marketing 294 FDCs on the grounds that they were "banned, absurd, rejected, or under investigation." Additionally, in 2012, the Ministry of Health and Family Welfare prohibited the manufacture and sale of 91 drugs, of which 45 are FDCs.

In 2012, an Indian Parliamentary Committee report indicted the CDSCO for its "skewed priorities" by according importance to the drug industry rather than public health. It highlighted how new drug approvals were granted in the absence of evidence of efficacy and clinical trials. In response to the parliamentary committee's report, the CDSCO appointed an expert committee headed by Ranjit Roychowdhury, a former professor at the National Institute of Immunology and campaigner against irrational use of drugs, to investigate and submit a report on drug regulation in India. Roychowdhury had also headed a program by the Indian government and the World Health Organization (WHO) on the rational use of drugs.

The Roychowdhury committee's report, submitted in 2013, called for an urgent review of the scientific basis for approval of many drug formulations in India and for an overhaul of the regulatory system. It pointed out, among its findings, that there was no progress in withdrawing current approvals for oral FDCs that were banned in 2007.

The problem of FDCs in the Indian market was also addressed in two recent reports in medical journals – The Lancet in 2016 and PLoS Medicine in 2015. The Lancet review said metformin-based drugs, including FDCs used to treat type 2 diabetes in India, which affects an estimated 60 million Indians and is on the rise, "show the scale of the problem." The CDSCO has approved 41 FDC formulations for type 2 diabetes that, in turn, have given rise to more than 500 marketed brands. In some cases, drugs were launched prior to the CDSCO giving approval, it said.

The problem is that in ongoing monitoring and changes to treatment regimens to maintain glycemic control, metformin FDCs are not included in recommended national or international guidelines.

Similarly there are a number of FDCs available in India used as painkillers (nonsteroidal anti-inflammatory drugs, or NSAIDs), diabetes drugs, anti-anxiety and antidepressant drugs, and anti-psychotic drugs that are not available in the U.S. or U.K.

Estimates by Indian pharma industry representatives and analysts of the impact of the March notification on the industry vary, but there is general agreement that, in the long run, it will serve the Indian life sciences and pharma industry through stricter regulation.

LOSSES NOW, BETTER COMPLIANCE LATER

Subir Basak, president of Bangalore-based Jubilant Biosys Ltd., a company that offers drug discovery services, estimates that the impact of the Indian government's ruling will add up to losses of about $450 million (INR30 billion) annually.

While Pushpa Vijayaraghavan, vice president of Hyderabad-based Sathguru Management Consultants, which, along with the Associated Chambers of Commerce and Industry in India, released in March a report of the Indian pharma industry's performance, expects the ban to have a much larger impact on the industry of between $1 billion and $1.5 billion (INR70 billion to INR100 billion).

"The pharmacy rationale of combining drugs for patient convenience might be an appealing hypothesis, and in many cases might offer the potential for clinical and safety benefit as well. However, this hypothesis needs to be backed by data," Basak told BioWorld Today. Some Indian pharma companies have provided such data and obtained DCGI approval, said Basak. For those that have not, an FDC "carries the risk of showing no incremental benefit and, in fact, might cause drug-drug interactions which need to be studied carefully to avoid any serious adverse events. Data need to be demonstrated as per global and India regulatory norms." Despite the initial losses, "the bigger impact is the incredible opportunity for the pharmaceutical industry to engage with the regulatory bodies for increased compliance and also submit the medical rationale to justify their specific FDCs in question," he added.

Vijayaraghavan also pointed out that it is important to address and balance the multiple concerns of industry, consumers or patients, and clinicians. "Foremost, if the drugs were actually approved by the state regulators without CDSCO approval, it is significant regulatory loophole that needs be addressed as a priority. But it would be unfair to place a heavy burden of compliance on industry if such regulatory gaps exist," she said.

Vijayaraghavan said the banned FDCs fall into the three main groups of anti-infectives, anti-diabetics and analgesics.

There might be merit in easing out unjustified antibiotic combinations as they "significantly compound the antimicrobial resistance problem that we are already struggling to deal with."

But parts of the government decision are "very debatable." Among the more popular drugs banned such as Vicks Action 500 Extra include combinations that are sold in over-the-counter products in the U.S. and U.K., and are generally considered safe by the FDA and MHRA for sale without a prescription.

"The abruptness of action justifies industry calling it a knee-jerk reaction. The FDCs in the notification are not so harmful that an overnight ban was warranted," said Vijayaraghavan.