The Unbanned Drug Story: The Centre banned the sale of Deanxit, a contentious mental medication that was approved without any clinical evidence. However, other businesses are still selling it after ten years.

 A 2009 Monthly Index of Medical Specialities article brought attention to a Danish-made mental medication that was being marketed in India.

The journal’s editor, Dr. Chandra Gulhati, noted in the report that the drug Deanxit’s sale should never have been authorized by India’s drug regulatory bodies for the straightforward reason that the medication was not allowed to be sold in Denmark.

The Drugs and Cosmetics Act, of 1940, in India, states that a drug may only be imported if it has been authorized for sale in the nation of origin. This was broken.

The Union Health Ministry banned the sale of Deanxit in 2013. It was a fixed dosage form of melitracen and flupenthixol.

Despite suing to overturn the ruling, the Danish firm Lundbeck ultimately ceased operations and departed India in 2021. However, at least ten additional Indian businesses are still selling the flupenthixol and melitracen combination under different brand names ten years after the prohibition was implemented. This is the tale of how legal obstacles and weaknesses in India’s drug regulatory framework made it challenging for drug regulators to take contentious medicine off the Indian market.

Clinical trials were not conducted.

Two or more medications are combined in a fixed dose combination, or FDC, to treat a specific condition. Every medication in a fixed dose combination has a specific function in the course of treatment. Melitracen is used in Deanxit to regulate mood and lessen depression, while flupenthixol functions as an anti-psychotic medication to alleviate anxiety.

Dr. Soumitra Pathare, a psychiatrist, claims he is not persuaded by melitracen’s efficacy as an antidepressant. Melitracen has not been licenced for usage in India, whereas flupenthixol has. He questioned, “If melitracen is the less effective of the two, why will I still prescribe it to my patients?”

A new drug cannot be approved in India under the Drugs and Cosmetics Act, 1940, unless it has completed several phases of clinical studies to determine its effectiveness on the Indian populace.

Since melitracen had not previously received individual approval, any fixed medicine combination containing it would be deemed novel and require clinical trial testing, according to a 2012 report by a legislative standing committee.

The health ministry gave a blank response when the parliamentary committee questioned it about this. The 59th Parliamentary Committee stated in its report that “the Ministry failed to provide any documents and information on the regulatory process that led to its [Deanxit’s] approval, except for giving file number (12-62.95- DC) and the date of approval (28-10-1998).”

Attorney Prashant Reddy claimed that the procedure used to approve Deanxit for sale on the Indian market was dubious in and of itself, based on insufficient data. Clinical trial research lends legitimacy to a medication. However, a high-caliber trial is still lacking for this fixed-dose combination, according to Reddy.

Primarily, studies in humans were required to determine whether the fixed medication combination worked for each indication that it was intended to be used for.

As two parliamentary committee reports made clear, neither the company nor the drugs controller general of India, who is in charge of the Central Drugs Standard Control Organisation, looked into the trial data that was marketed for psychogenic depression, depressive neuroses, masked depression, or psychosomatic affections.

Rejected in the majority of nations.

A critical assessment of the operations of the Central Drugs Standard Control Organisation was presented by the 59th Parliamentary Standing Committee in May 2012.

One of the most prominent inconsistencies on the list was the approval of Deanxit. The committee vehemently denounced the drug authorities for permitting the sale of Deanxit in India. It listed numerous reasons, the absence of clinical trial data being just one of them.

The Drugs and Cosmetics Act, 1940, rule 30B states that any substance that is illegal in its country of origin cannot be imported or marketed in India. Despite this clause, the study discovered that Deanxit was being imported and sold.

The committee also took note of Gulati’s observation that just 23 nations, all of which had subpar drug laws, had approved Deanxit. Gulati informed to Scroll that “countries like the USA, Canada, and those in the European Union had not approved it.”

Furthermore, the committee expressed its disbelief at the manufacturer’s focus on small markets in developing nations with lax regulations or no regulation at all, such as Aruba, Bangladesh, Cyprus, Jordan, Kenya, Myanmar, Pakistan, and Trinidad, rather than nations with significantly higher patient and financial numbers.

A study conducted in Lebanon on 125 patients who were using Deanxit revealed that 36 percent of them had developed a drug addiction due to the Deanxit use problem. According to the study, the majority of patients in Lebanon “were prescribed Deanxit by their physicians, but they reported not knowing enough about its potential for abuse and side effects.”

Although no such studies have been conducted in India, physicians who prescribe it claim no negative side effects from their patients.

An inquiry and an official declaration.

On the advice of the parliamentary committee, the Indian Drug Controller General established an expert committee in March 2013 to look at the drug clearance procedure.

However, the investigation seemed to encounter unforeseen obstacles after a month. There were no infractions of its clearance, according to a statement released by the health ministry. It referenced information from a study that indicated melitracen and flupenthixol to be beneficial for treating depressive disorders. The psychiatrist, Dr. Udayan Kasthigar, of Lady Hardinge Medical College in Delhi, presented the data. The size of the patient sample and the control group were not specified. In fact, this was not a clinical trial.

The government claimed that the results of this study were the foundation for its approval. The Drug Controller General of India promptly approved Deanxit two months after the trial data was presented in August 1998.

Ironically, the drug controller’s expert group reviewed the permission that Lundbeck, the Danish company that makes Deanxit, submit a request to carry out Phase IV clinical trials to prove the medicine’s effectiveness and safety. At that point, it made no recommendations for action and disregarded the Phase I, II, and III studies conducted in India.

However, the health ministry was examining the approval procedure even as it formally defended its decision to approve the fixed-dose combination internally.

In March 2013, the CDSCO’s New Drug Advisory Committee, which guides novel medications and clinical studies, convened to deliberate on the topics of flupenthixol and melitracen. It was noted that flupenthixol had “potentially serious neurologic side effects” and that melitracen was “not efficacious as a single agent in depression.”

The committee asked whether it was still necessary to market the product in India. The 66th Report on Health and Family Welfare, a second study by a parliamentary committee, said in April 2013 that the Deanxit case “conveys a strong whiff of collusion and cover-up.” This report, which was released a year after the 59th parliamentary report, concluded that the government had done nothing in response to “an open and shut case that needs immediate action.”

Although the DCGI established an expert group to suggest actions in the event of a Deanxit, the parliamentary committee stated that no action was ever suggested and the ministry never followed up.

Similar to the preceding study, this one also voiced concerns about the dearth of clinical studies. It stated that phase-wise clinical studies involving at least three to four sites and one hundred patients should have been conducted for melitracen. The report noted, “Such trials were not conducted.”

The report described it as “strange” that the drug controller had approved the medicine based on ambiguous research conducted by Lady Hardinge’s psychiatrist.

The parliamentary committee suggested that the CDSCO officials who approved the drug be held accountable and that Lundbeck’s permission to market and sell the medication in India be revoked.

After a month, the CDSCO Drugs Technical Advisory Board finally suggested banning the medication. The action sparked a protracted legal dispute.

The government, according to the Danish manufacturer Lundbeck, denied it the opportunity to submit Phase IV trial results, and the company filed a case with the Karnataka High Court. Phase IV trials are only conducted following a drug’s national marketing and sale. The court referred to the restriction as a “knee-jerk reaction” and noted that 63 lakh prescriptions for melitracen and flupenthixol had been written each year. The court overturned the first ban three months after it was implemented.

The government was also asked by the court to permit Phase IV trials. Throughout the course of the following year, the DCGI discovered numerous flaws in Lundbeck’s Phase IV trial proposal and requested revisions.

The authorities once more declared that melitracen and flupenthixol were prohibited in 2014. Reversing the prohibition took three years this time. The Karnataka High Court overturned the drug controller’s ruling in December 2017 and let Mankind, a pharmaceutical company that had started producing the fixed-dose combination, and Lundbeck to resume production based on a combined petition.

Due to safety concerns, activist Dinesh Thakur petitioned the Delhi High Court in 2018 to have this medication and two other medications banned.

A subcommittee to investigate flupenthixol and melitracen was established in 2019 by the Drugs Technical Advisory Board, a division of CDSCO that provided technical guidance to the government on the Drugs and Cosmetics Act. Requesting to remain anonymous, a committee member informed to Scroll that the approval of the fixed-dose combination did not adhere to the required protocol and that “ideally it should not be marketed until all clinical trials had been done.”

“The court order has tied even our hands,” the participant remarked. In June 2021, the DCGI finally approved Mankind to conduct Phase IV clinical trials on the FDC, following an eight-year wait for study approval. This occurred despite the government-appointed panels’ recommendations for a drug ban.

The issue with Fixed Dose Combinations

India’s broader inability to control fixed-dose combinations is exemplified by the flupenthixol and melitracen instance. Health advocate Dinesh Thakur and attorney Prashant Reddy claim in an article that India has banned 444 medications under Section 26A of the Medications and Cosmetics Act since 1983, the majority of which were fixed-dose combinations like Deanxit. In the public interest, the government may outlaw drugs under this clause.

However, a lot of these orders are still mired in legal disputes, such as the ones involving melitracen and flupenthixol. Their sale is still going on in the interim.

The combination may not always be more effective in some situations, experts note, but many pharmaceutical companies adopt fixed-dose combinations to price their product more than accessible solo drugs.

To stop this practice, the Indian government passed a law in 1982 that forbade the use of such fixed-dose combinations in cases where they were ineffective or had no therapeutic value.

Reddy stated, “The issue is that the government approach is wholly incorrect when it comes to fixed-dose combinations.” He claimed that whenever a high court or municipal court overturned the government’s decision prohibiting a specific fixed-dose combination, the government hardly ever filed an appeal.

During his tenure, KL Sharma, a former joint secretary in the Union health ministry from 2014 to 2017, said that a specially established committee studied fixed-dose combinations and proposed banning 349 of them. According to Sharma, “We found that they were being marketed illegally and that no proper clinical trials were conducted in the majority of cases.”

In March 2016, the government outlawed all 349 fixed-dose combinations, sparking numerous legal disputes throughout India throughout his administration. Sharma stated, “The Supreme Court took all of these cases and ordered the government to review the ban.” “The government once more outlawed the FDCs after three years. The businesses appeared in court once more.

The courts are not “competent to look into the technical and scientific nature of such cases,” according to Sharma. “And in these cases, the government ought to have filed an appeal, but it chose not to,” he continued. The government did not file an appeal against the Karnataka High Court’s ruling in the Deanxit case either.

SOURCE:https://scroll.in/article/1061277/the-story-of-a-drug-that-india-has-failed-to-ban