After decades of fighting a legal battle, the government finally banned Fixed Dose Combination drugs—many of which are dangerous. But it may do little to stem the tide of illegal FDCs that flood the Indian market.
Researched by: Rachel John & Aarthi Ramnath
I have no clue what an FDC is…
The ingredients: Any medicine is made up of two components. One is the active pharmaceutical ingredient (API) which helps treat the disease. The other is the excipient—an inactive ingredient that helps deliver the API inside your body. So paracetamol is the active ingredient in Crocin—and acetaminophen in Tylenol.
The formulation: A medicine with a single active ingredient is called a single dose formulation (SDF). When it has two or more APIs, then it’s called a Fixed Dose Combination or FDC. There are four kinds of FDCs that require approval for sale in the Indian market when:
- One or more of the APIs is a new drug.
- Two approved APIs are being combined for the very first time.
- The ratio of two or more APIs is changed.
- The manufacturer combines two widely used APIs for convenience—which is common in cold medicines.
The need for FDCs: Combining active ingredients is considered ‘rational’ when a disease requires a patient to take a combination of different meds every day—and at a specific dosage. For example, HIV, tuberculosis or malaria. So it makes sense to put some of them in a single tablet so the patient does not miss any of her medicines–which is critical in these treatments. Also: she doesn’t develop resistance because she is inconsistent in taking the meds. And in some cases, the active ingredients actually work better when delivered in combination.
A good example: HIV and TB often attack the same patient—especially in sub-Saharan Africa. The HIV virus severely compromises the immune system—making them vulnerable to a TB infection—which progresses rapidly in people living with HIV. FYI: more than 75% of TB patients in the world have HIV. Therefore, an FDC that combines treatment for both diseases is necessary.
Ok, now tell me what’s the problem in India…
The ‘irrational’ FDC: To state the obvious, active ingredients cannot be combined at whim. The ‘what’ matters as does the ‘how much’—as in dosage. Combining the wrong APIs can make one or both ineffective—or the combination can pose a serious health risk. Such combo drugs are called ‘irrational FDCs’.
A plague of Indian FDCs: A 2015 study found 175 FDC formulations that were widely sold on the market—of these 115 (66%) had no record of approval. Each of these formulations is then sold by different companies under different brands—which makes matters even worse: “Among anti-inflammatories, there were almost 3,000 branded products, with more than 1,000 of them made from unapproved formulations.” Responding to the study, Indian pharmacologists said:
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.
A number of the combinations in these drugs were banned in other countries. One example:
Several anti-inflammatories included a muscle relaxant drug banned because of damage to dividing cells in the body while yet others contained two types of anti-inflammatory together, giving no advantage for pain but increasing the risk of serious side effects including bleeding in the stomach and heart attack.
And this wild, wild West of FDCs can also be lethal:
Some combinations were potentially lethal, for example, an anti-psychotic containing two drugs from the same class, both individually associated with major toxicity including sudden death. Dozens of antidepressants and benzodiazepines included combinations of sedating drugs shown individually to increase the risk of falls and accidents.
Point to note: India is the #1 consumer of antimicrobial FDCs—which leads to antimicrobial resistance—i.e antibacterial and antifungal medicines become ineffective.
Why isn’t the government doing anything?
Ah, the government has done its best to get rid of these FDCs—but has been stymied by a long legal process. But first let’s look at how these dangerous drugs get into the market.
The great ‘state’ loophole: Since 1988, any medicine—FDC or not—must receive approval from the Drugs Controller General of India (DCGI). Then the state governments can hand out licences for the manufacture and sale of these medicines. That’s where the problems start. A company has to get approval for a new active ingredient or API from the DCGI. However, once this drug has been on the market for four years, it can directly approach the state government for a licence:
The states read this to mean that if each of the constituent drugs of an FDC had been approved by the DCGI, their combination was not "new". As a result, a plethora of FDCs, unsupported by sufficient evidence but licensed by states, flooded the Indian market. By the time the DCGI took note, the problem had gotten out of hand. When it tried reining the states in, it was initially rebuffed. Its demand for data found little traction.
A data point to note: Between 1961 and mid-2018, the federal drug authorities approved only 1,292 FDCs—yet there were at least 6,000 sold in the Indian market—including those approved by state regulators. If you add in the large number of brands hawking these FDCS, the total number runs into “tens of thousands.”
The legal battle: For decades, state governments—backed by powerful pharmaceutical companies—stymied all efforts to pull ‘irrational’ FDCs from the market: “[E]ven those that were being called into question in the scientific community and by the central regulator continued to be sold in India. Repeated calls for data to let them stay on market fell on deaf ears.” This tug-of-war has turned into a long and arduous legal battle:
- In 2007, the union government ordered state regulators to remove 294 FDCs from the market—which did not have DCGI approval.
- The pharma companies managed to get a stay from the Madras High Court.
- In 2016, a special expert committee set up by the union government found that 15% of all FDCs were completely irrational—and 30% required further investigation.
- The government banned the 344 that were confirmed to be irrational.
- The pharma industry went back to the courts—and secured a stay from the Delhi High Court.
- The government went to the Supreme Court—which in its infinite wisdom referred the matter to another expert body—Drugs Technical Advisory Board.
- The union government was finally able to ban 329 FDCs in 2018.
- And the remaining 14 were banned over this weekend.
The Saridon exception: in 2019, the Supreme Court granted an exemption to the popular headache tablet Saridon—which was among the 300-plus banned by the government. Saridon has three active ingredients—paracetamol, caffeine and propyphenazone. Of these, propyphenazone has been linked to “serious side-effects”—and is not recommended by the WHO—and is on a UN list of banned products. What’s interesting: it is not on the latest list of 14 banned FDCs either.
The bottomline: The bans are no guarantee of safety—since pharma companies find creative ways to work around them. But it’s a start.
The Conversation piece by the lead author of the 2015 study is a must read—as is this excellent Moneycontrol column laying out why the regulatory process is so messed up. The ORFOnline take on FDC regulation is good but filled with jargon. Mint has the full list of the 14 FDCs banned recently. We did two Big Stories on lethal Indian cough syrups sold in Gambia and Uzbekistan—which also throw light on the regulatory mess.