India has been called the pharmacy of the world. Many generic drugs are made there and much of its drug production is exported internationally. Thousands of fixed dose combination (FDC) drugs—where two or more drugs are combined according to set ratios in a single dosage form, usually a tablet or capsule—are formulated, made, and sold within India.
Many FDCs are safe and effective. They are used in situations where both the drug combination and the doses needed are standardized and stable. For example, FDCs are used in the treatment of HIV, for Parkinson’s disease, and in contraceptive pills.
However, in a study investigating these drugs in India, we found thousands of FDCs on the market made up of formulations never approved for marketing by the national regulator, the Central Drugs Standard Control Organization, and that these were likely to be more harmful than beneficial to patients.
As two pharmacologists in India, writing in response to our study put it:
“One can find any crazy drug combination which could give nightmares to any doctor who has some understanding of the concept of the rational use of medicine. It is simply beyond comprehension of any rationalist. Even antimicrobials are being combined weirdly, which is a grave challenge for crusaders against antimicrobial resistance.”
FDCs in India
Considered an innovation of India’s national pharmaceutical industry, FDCs are promoted extensively and used in huge numbers within the country. These drugs are mostly available through wholesalers, pharmacies (not necessarily with a prescription), and dispensing doctors, but some are used in hospitals too.
For years though, there has been disquiet. In 2007, the national regulator banned 294 of the drugs because they had never been approved for marketing but had been given manufacturing licenses by authorities. FDC manufacturers disputed the ban and the matter remains unresolved in the courts. In 2012, an Indian government committee investigating the standards and capacity of the regulator issued a report highlighting multiple problems, including that of FDC approvals.
The committee found that state authorities were issuing manufacturing licenses for new formulations that were never approved. It said: “The end result is that many FDCs in the market have not been tested for efficacy and safety. This can put patients at risk.” Many formulations were also medically unnecessary.
The report noted that, prior to an amendment to existing legislation in May 2002, “ambiguities” in the rules on new drugs might have encouraged the marketing of FDCs without approval. However, we identified no ambiguities in the drug rules and found that just as many unapproved, new FDCs appeared on the market after the amendment as before.
The Scale of the Issue
The committee’s report included no investigation of the size of the problem or potential risks to patients, so we used drug approval records from 1961–2013 and commercial sales data from 2007–2012 to identify approved and unapproved FDCs on the market and calculate the quantities being sold of each.
We examined four categories of drugs: pain-relief, diabetes, anxiety/depression, and psychosis. We chose these because the drugs that fall under them are commonly used and many, even when used alone, have serious side effects.
In the four categories, we found 175 FDC formulations on the market, out of which 115, or 66 percent, had no record of approval. Metformin drugs for diabetes had the best approval compliance, while antipsychotic drugs had the worst.
FDC formulations have given rise to many branded products made by different pharmaceutical companies. These companies promote their own products in crowded marketplaces. Among anti-inflammatory drugs, there were almost 3,000 branded products, with more than 1,000 of them made from unapproved formulations. Vast volumes of these FDC products are sold in India.
Banned or Restricted in Other Countries
Among the products on the market, we found numerous combinations containing drugs that are banned or restricted in other countries. Some of these were formulations actually approved by the regulator, while others were unapproved. For example, combinations were found to contain melitracen, an antidepressant widely banned owing to central nervous system toxicity. In India, the top-selling combination of melitracen with flupentixol, an antipsychotic, was banned in 2013, re-approved, and then banned again 2014. Another banned drug found in combinations was nimesulide, an analgesic also widely banned due to its association with liver toxicity and put under sales restrictions in 2007 by the European Medicines Agency.
Several anti-inflammatory drugs included a muscle relaxant drug banned because of damage to dividing cells in the body while yet others contained a mix of two types of anti-inflammatory drugs, giving no advantages for treating pain but increasing the risk of serious side effects like bleeding in the stomach and a heart attack.
Some combinations were potentially lethal. For example, one antipsychotic contained two drugs from the same class, both individually associated with major toxicity and also sudden death. Dozens of antidepressants and benzodiazepines included combinations of sedatives shown individually to increase the risk of falls and accidents.
Response and Remedy
Following the committee report in 2012, the Indian government made attempts to improve FDC regulation. But there was little enforcement. In fact, manufacturers lobbied against regulatory change, making “an earnest appeal” to government to “maintain status quo”, both approved and unapproved. And that is exactly what has happened.
It is clear from our research that drug regulation in India, a key international exporter of medicines, needs a major overhaul. Unapproved FDCs should be banned and patients should be given appropriate single drugs. Public health, not manufacturers’ commercial concerns, should inform the regulation of India’s drugs.
But all too often, as we have found, business comes first and citizens are the losers. Alongside Indian medical and legal colleagues, we are now working to see unapproved FDCs banned once and for all and to draft a new drugs act for India. With strong and clear legislation, a most important step will be taken to ensure that in the long term the people of India have safe and effective drugs made in their country.
Patricia McGettigan is a senior lecturer in clinical pharmacology at Queen Mary University of London. She worked with colleagues funded through the Accessing Medicines in Africa and South Asia (AMASA) project supported by the European Union Seventh Framework Programme Theme: Health. This article was previously published on TheConversation.com
