In 2009, an article in Monthly Index of Medical Specialities drew attention to a psychiatric drug from Denmark being sold in the Indian market.

In the article, the editor of the journal, Dr Chandra Gulhati, pointed out that India’s drug regulatory authorities should never have approved the sale of the drug, Deanxit, for a simple reason – the medicine was prohibited for sale in Denmark itself.

This was a violation of India’s Drugs and Cosmetics Act, 1940, which says that a drug can only be imported in India if it has been approved for sale in the home country.

In 2013, the Union health ministry banned the sale of Deanxit, which was a fixed dose combination of flupenthixol and melitracen.

Though the Danish manufacturer, Lundbeck, moved court against the order, it eventually wound up its operations and left India in 2021.

But 10 years after the ban, the combination of flupenthixol and melitracen continues to be sold by at least 10 other companies in India under various brand names. This is the story of how gaps in India’s drug regulatory system and legal hurdles made it difficult for drug regulators to remove a contested drug from the Indian market.

No clinical trials done

A fixed dose combination, or FDC, combines two or more drugs to treat a particular ailment. Each of the drugs in a fixed dose combination have a certain role to play in treatment. In the case of Deanxit, flupenthixol acts as an anti-psychotic drug and is used to reduce anxiety while melitracen is used to regulate the mood and reduce depression.

Psychiatrist Dr Soumitra Pathare says he is not convinced of melitracen’s ability to work as an anti-depressant. While flupenthixol has been approved for use in India, melitracen has not. “If out of the two, melitracen is not really effective, why will I prescribe it to my patients?” he asked.

Under the Drugs and Cosmetics Act, 1940, a new drug can be approved in India only after it has undergone stages of clinical trials to check its efficacy on the Indian population.

As a report of a parliamentary standing committee noted in 2012, since melitracen had not been individually approved earlier, any fixed drug combination in which it is used would be considered a new drug and needed to be tested in clinical trials.

Did that happen in the case of Deanxit?

When the parliamentary committee asked the health ministry about this, it drew a blank. In its report, the 59th parliamentary committee noted, “Except for giving file number (12-62.95- DC) and the date of approval (28-10-1998), the Ministry failed to provide any documents and information on the regulatory process that led to its [Deanxit’s] approval.”

Lawyer Prashant Reddy said the process by which Deanxit was approved for sale on the Indian market was itself suspect and based on incomplete information. “Clinical trial studies give credibility to a drug. But a high quality study remains missing for this fixed dose combination,” Reddy said.

More importantly, clinical trials needed to be conducted to find out if the fixed drug combination was effective for each indication it would be prescribed for.

Deanxit was marketed for psychogenic depression, depressive neuroses, masked depression and psychosomatic affections, but neither did the drugs controller general of India, who heads the Central Drugs Standard Control Organisation, look into such trial data nor did the company submit it, as two parliamentary committee reports pointed out.

Dr Chandra Gulhati.

Denied approval in most countries

In May 2012, the 59th parliamentary standing committee submitted a scathing report on the function of the Central Drugs Standard Control Organisation.

The approval for Deanxit figured high on the list of the irregularities.

The committee strongly criticised the drug authority for allowing Deanxit to be sold in India. The lack of clinical trial data was just one of the many reasons it cited.

Under rule 30B of the Drugs and Cosmetics Act, 1940, the import and marketing of any drug that is prohibited in its country of origin is banned in India. The report found that Deanxit was being imported and marketed despite this provision.

The committee also flagged what Gulati had pointed out – that Deanxit was approved only in 23 countries, all with poor drug regulatory systems. “Countries like the USA, Canada, those in the European Union had not approved it,” Gulati told Scroll.

The committee also said that it was “strange that the manufacturer is concentrating on tiny markets in unregulated or poorly regulated developing countries like Aruba, Bangladesh, Cyprus, Jordan, Kenya, Myanmar, Pakistan, and Trinidad instead of countries with far more patients and profits”.

In Lebanon, a study of 125 patients using Deanxit found that 36% suffered from Deanxit-use disorder, that is, they became addicted to the drug. The study observed that most patients in Lebanon “were prescribed Deanxit by their physicians but reported inadequate knowledge of its side-effects and risk of abuse”.

In India, no such studies have been undertaken, though doctors who prescribe it say their patients have not reported any adverse events.

Screenshot of the portion from the 59th parliamentary standing committee on Deanxit.

An investigation, and a statement

In March 2013, following the parliamentary committee’s recommendation, the Drug Controller General of India formed an expert committee to investigate the approval process of the drug.

But a month later, the inquiry appeared to hit unexpected roadblocks.

The health ministry issued a statement stating that there were no violations in its approval. It quoted data submitted by a psychiatrist named Dr Udayan Kasthigar from Lady Hardinge Medical College in Delhi from a study that found flupenthixol and melitracen effective on depressive disorders. No data on the patient sample size or control group was provided. This was not even a clinical trial.

The government said it had based its approval on the findings of this study. The study data was submitted in August of 1998, and the Drug Controller General of India approved Deanxit quickly two months later.

Surprisingly, the expert committee appointed by drug controller to investigate the approval advised Lundbeck, the Danish manufacturer of Deanxit, to submit a proposal to conduct Phase IV clinical trials to establish the safety and efficacy of the drug. It did not recommend any action at that point and also ignored the omission of Phase I, II and III trials within India.

‘A strong whiff of collusion’

But while the health ministry officially defended its stand of approving the fixed dose combination internally it was reviewing the process of its approval.

The New Drug Advisory Committee, an arm under the CDSCO that advises the body on new drugs and clinical trials, held a meeting in March 2013 to discuss flupenthixol and melitracen. It pointed out that melitracen was “not efficacious as a single agent in depression” and flupenthixol had “potentially serious neurologic side-effects”.

The committee questioned the need to continue its marketing in India.

In April 2013, a second report by a parliamentary committee (called the 66th report on Health and Family Welfare) observed that the “case of Deanxit conveys a strong whiff of collusion and cover up”. This report came a year after the 59th parliamentary report and found that despite “an open and shut case that needs immediate action”, the government failed to take any action.

The parliamentary committee said that while the DCGI set up an expert committee to recommend action in case of Deanxit, no action was ever recommended and the ministry never followed up.

Like the previous report, this too raised red flags over the lack of clinical trials. It said that melitracen should have undergone phase-wise clinical trials in at least three to four sites and covered 100 patients. “Such trials were not conducted,” the report said.

The report said it was “strange” that drug controller approved the drug based on a vague study by a psychiatrist of Lady Hardinge.

The parliamentary committee recommended action against CDSCO officials who approved the drug and to reverse the approval given to Lundbeck to market and sell the drug in India.

Representative image, created using Canva.

Bans and stay orders

Finally, a month later, the Drugs Technical Advisory Board of CDSCO recommended a ban on the drug. The move led to a long-drawn legal battle.

The Danish manufacturer, Lundbeck, approached Karnataka High Court and argued that the government had not given it a chance to present Phase IV trial data. Phase IV trials are carried out only after a drug has been marketed and sold in the country. The court observed that annually 63 lakh prescriptions had been made for flupenthixol and melitracen and called the ban a “knee jerk reaction”. Three months after the first ban, the court struck it down.

The court also asked the government to allow Phase IV trials. Over the next one year, the DCGI found multiple gaps in the Phase IV trial proposal submitted by Lundbeck and asked for changes.

In 2014, the government again announced a ban on flupenthixol and melitracen. This time it took three years to get the ban revoked. In December 2017, based on a joint petition by Mankind, a pharmaceutical company that had also begun to manufacture the fixed dose combination, and Lundbeck, the Karnataka High Court set aside the drug controller’s order and allowed the companies to restart manufacturing.

In 2018, activist Dinesh Thakur filed a petition in the Delhi High Court seeking a ban on this drug and two other drugs over safety concerns.

In 2019, the drugs technical advisory board, an arm of CDSCO that gave technical advice to the government on Drugs and Cosmetics Act, formed a sub-committee to examine flupenthixol and melitracen. A member of this committee, requesting anonymity, told Scroll that the fixed dose combination’s approval did not follow the necessary protocol and “ideally it should not be marketed until all clinical trials had been done”.

“Even our hands are tied because of the court order,” the member said.

Finally, after delaying the approval for a trial for eight years, in June 2021, the DCGI granted Mankind the permission to conduct Phase IV clinical trials on the FDC. This happened despite several committees constituted by the government recommending a ban on the drug.

The Fixed Dose Combination problem

The case of the flupenthixol and melitracen combination is emblematic of India’s larger failure to regulate fixed dose combinations.

In an article, health activist Dinesh Thakur and lawyer Prashant Reddy state that since 1983, India has issued 444 orders under Section 26A of Drugs and Cosmetics Act to ban drugs, most of them fixed dose combinations like Deanxit. This section allows the government to ban a drug in public interest.

But many of these orders, like in the case of flupenthixol and melitracen, remain entangled in litigation. Meanwhile, their sale continues.

Experts point out that several pharmaceutical companies introduce fixed dose combinations to price their product higher than available individual drugs, but the combination may not necessarily have better efficacy in certain cases.

To counter this practice, in 1982 the Indian government introduced a provision to prohibit such fixed dose combinations if they lack therapeutic value or efficacy in treatment.

“The problem is that the government strategy is completely wrong when it comes to fixed dose combinations,” said Reddy. He said that the government hardly went into an appeal if a local court or high court set aside their order to ban a particular fixed dose combination.

KL Sharma, former joint secretary in the Union health ministry between 2014 and 2017, said in his tenure fixed dose combinations were reviewed by a specially formed committee that recommended a ban on 349 of them. “In most cases, we found that no proper clinical trials were conducted and they were being marketed illegally,” Sharma said.

The government banned all 349 fixed dose combinations in March 2016, which led to over hundreds of court cases across India during his tenure. “All these cases were transferred to the Supreme Court which asked the government to reexamine the ban,” Sharma said. “After three years, the government again banned the FDCs. The companies again went to court.”

Sharma claimed that the courts lack the “competency to look into the technical and scientific nature of such cases”. “And the government should have gone into an appeal [in these cases] which it did not,” he added. In case of Deanxit, too, the government made no appeal against Karnataka High Court’s order.

Scroll sent questions on the approval process of Deanxit and the continued sale of the flupenthixol and melitracen combination in India to the Union ministry of health and the Central Drugs Standard Control Organisation. The story will be updated if they respond.

This reporting was supported by a grant from the Thakur Family Foundation. Thakur Family Foundation has not exercised any editorial control over the contents of this article.