New Delhi: Over 60 percent fixed-dose combination (FDC) drugs consumed for mental health disorders in India are “unapproved” and lack therapeutic benefit, an analysis has found amid a major crackdown on FDC drugs by the country’s apex drug regulator.
In the study published in the Journal of Pharmaceutical Policy and Practice this month, researchers from UK, India and Qatar found that unapproved FDCs accounted for 60.3 percent psychotropic FDC sales in 2020, slightly lower from 69.3 percent in 2008 but still too high.
FDCs contain two or more drugs in a single pharmaceutical form, such as a capsule. Many FDC drugs available in India lack approval from the central regulator, the Central Drugs Standard Control Organisation (CDSCO), and are approved for manufacturing by states without showing proof of safety and efficacy.
“Psychotropic FDCs are widely marketed in India despite their absence from Indian clinical guidelines, limited evidence of therapeutic benefit, concerns about potential harm, and limited use in other markets,” the study has noted.
Unapproved FDC drugs continue to account for most psychotropic FDC sales, potentially putting the public at risk because their safety and efficacy have not been evaluated, the researchers also noted.
Ashna Mehta, a health economist and co-author of the study, told ThePrint that India’s FDC problem was well-known, and despite several efforts by the regulator to weed them out, unapproved FDCs continued to be on the market.
“There is no doubt that regulatory enforcement must be strengthened,” Mehta, who is associated with the Public Health Foundation of India and has been researching FDC drug use in the country over the past decade, stressed.
The team’s previous work which was published last year in the same journal had shown that nearly 70 percent of antibiotic fixed-dose combination drugs sold in India were either unapproved or banned.
In response to a query by ThePrint on the latest findings, Rajeev Singh Raghuvanshi, Drugs Controller General of India who heads the CDSCO, said he was yet to come across the details presented in the analysis.
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Multiple red flags
As part of the study, the researchers analysed sales data of FDC drugs, provided by PharmaTrac, a commercial database of Indian pharmaceutical sales, for mental health disorders.
For the purposes of the study, FDCs were regarded as psychotropic if they contained at least one psychotropic drug and were clearly marketed for psychiatric indications.
There were 35 psychotropic FDCs listed on PharmaTrac that had measurable sales volumes for at least one year between 2008 and 2020.
Of the 35 FDCs, 30 had fully specified drug name data, and of these 30 FDCs, 13 were antipsychotics, 11 were antidepressants and six were benzodiazepine or sedatives.
One FDC comprised four drugs, three comprised three drugs, and 26 comprised two drugs. Of the 30 FDCs, there was evidence of regulatory approval for six in India, two in the US, one in the European Union, and none in the UK.
The analysis showed that the number and formulations of psychotropic FDC drugs marketed in the country significantly increased between 2008 and 2020.
The share of the overall psychotropic drug market accounted for by FDCs increased from 18.4 percent to 20.1 percent over the same period, driven by increasing sales of antidepressant and benzodiazepine or sedative FDCs.
The analysis also showed that the proportion of overall psychotropic FDC sales accounted for by unapproved formulations fluctuated, increasing from 69.3 percent in 2008 to 75.5 percent in 2014, and then decreasing to 60.3 percent in 2020.
The proportion of antipsychotic FDC sales accounted for by unapproved formulations increased from 49.7 percent in 2008 to 57.7 percent in 2020.
“Nearly all benzodiazepine or sedative FDC sales were for unapproved formulations across the study period,” the paper has underlined.
It has highlighted that the use of unapproved or banned psychotropic FDCs could potentially cause significant harm to patients, from both adverse effects and lack of efficacy.
There are specific risks associated with the FDCs listed on PharmaTrac, for instance, many contained combinations of psychotropic drugs, and psychotropic polypharmacy may lead to significant adverse effects such as liver injury and falls, says the study.
Also, most of the FDCs contained benzodiazepines or related sedatives, which are associated with misuse and addiction, and some FDCs contained thioridazine, which was withdrawn worldwide in 2005 due to the risk of severe cardiac arrhythmias.
In addition, some of the FDCs contained combinations of antipsychotics that are not evidence-based, the study has found.
“These risks are compounded by an under-resourced pharmacovigilance system, meaning that there is minimal opportunity to identify harms arising from the use of such FDCs,” the researchers noted.
‘Regulatory measures not enough’
The analysis also said the Indian government launched two initiatives to regulate the sale of unapproved FDCs.
The first was a 2007 directive to state regulators to cancel manufacturing licences for 294 FDCs.
It is not known why these particular FDCs were selected from the many unapproved FDCs that were marketed at the time, says the paper.
The second was a 2013 request by the CDSCO to state regulators to ask pharmaceutical companies to “prove the safety and efficacy” of FDC formulations— specific strength and pharmaceutical form—which had been licensed by states without the CDSCO’s prior approval. This led to a spiral of events—and subsequent formation of two committees which recommended banning 344 FDCs citing them as “irrational”.
Deeper scrutiny, however, showed that overall, three FDCs for mental illnesses were banned as a result of the second initiative and no FDCs for these conditions were banned as a result of the first.
Based on the findings, the researchers noted that unapproved FDCs should be withdrawn from the market and the CDSCO and state regulators should ensure that unapproved and banned FDCs are no longer manufactured.
Also, the apex drug regulator should publish the evidence used to justify approvals, no-objection certificates, and bans in full, while also undertaking regular audits and market surveillance to identify unapproved FDCs and intervene, the researchers have said.
(Edited by Nida Fatima Siddiqui)
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