No Evidence to Back Up India's Best-Selling Diabetes Drugs

Liam Davenport

March 09, 2018

Fixed-dose combinations (FDCs) of diabetes drugs are being widely used in India to treat millions of patients with type 2 diabetes but have little or no clinical data to back their safety and efficacy, say researchers.

In the first study of its kind, researchers applied internationally recognized criteria to the available data for the five top-selling metformin FDCs in India and found no evidence to back up their approval by India's drug regulator.

Moreover, the results, which were published March 6 in BMJ Global Health, reveal that only a small minority of the clinical trials for the drug combinations had been conducted in India and the vast majority were sponsored, or led by, pharmaceutical companies.

"The lack of good trial evidence for these five top-selling metformin combination medicines for the treatment of type 2 diabetes is of deep concern," noted senior author Allyson M Pollock, MD, Institute of Health and Society, Newcastle University, UK, in a press release by the University of Massachusetts Amherst.

And lead author Valerie Evans, MPH, School of Public Health and Health Sciences, University of Massachusetts Amherst, added that pharmaceutical companies in India are worldwide distributors, "so if there's a problem it can go everywhere."

"You hope that the regulatory systems in the consumer countries can filter out problems, but that's not always the case. We feel that people really need to know about this."

"We want the medicines that doctors prescribe for their patients to be safe and effective, and for that to be supported by sound evidence and properly conducted, transparent clinical trials," she stressed.

India: Diabetes Capital of the World

More than 60 million people are diagnosed with type 2 diabetes in India, which has been described as the diabetes capital of the world.

India approves more than 100 medicines a year but does not publish data on submitted applications or summaries of approved drugs, and concerns have been raised about the safety and efficacy around medicine approvals in the absence of appropriate clinical trials, according to background information in the article.

The country's drugs regulator, the Central Drugs Standard Control Organization (CDSCO), has approved 52 FDCs that include metformin for type 2 diabetes, resulting in more than 500 marketed metformin FDC brands.

In contrast, very few metformin FDCs are approved for use in the United States and other western countries.

Despite suggestions that such FDCs improve adherence because of greater convenience, they are not currently recommended by any national or international diabetes guidelines because glucose levels fluctuate and treatment adjustments are often needed, which are particularly difficult with FDCs because doses are fixed.

FDCs should only be considered when the patient has been stable on a regimen of concomitant single-drug formulations for an extended time, say researchers, noting that "convenience...should not trump efficacy."

Scrutinizing the Data On the Top Five Metformin FDCs in India

For the current study, Evans and colleagues used PharmaTRAC, a commercial drug sales database, which showed that the five top-selling metformin FDCs in India, covering 80% of the market between 2011 and 2012, were glimepiride/metformin, glimepiride/pioglitazone/metformin, glipizide/metformin, glibenclamide/metformin, and gliclazide/metformin.

Although these five FDCs were approved by the CDSCO, three were launched prior to approval: glimepiride/metformin, glimepiride/pioglitazone/metformin, and gliclazide/metformin.

 In March 2016, the government of India banned 344 unapproved FDCs that lacked clinical support or were found to be potentially harmful. The ban included different doses of three of the five top-selling metformin FDCs.

The ban was overturned by the state-level Delhi High Court in December 2016, and the government later appealed to the Supreme Court. In December 2017, the latter gave the country's Drugs Technical Advisory Board 6 months to consider the banned drugs.

"This work is relevant to an active case in the courts in India. We are in the 6-month review window ordered by India's Supreme Court right now," Evans observed.

To determine the efficacy and safety of the five metformin FDCs, researchers searched the PubMed, Embase, and Cochrane Library databases for relevant trials in patients with type 2 diabetes published between 1980 and 2016.

In addition, they looked at clinical registries and published and unpublished trial websites, yielding 25 publications eligible for inclusion.

Only one trial, which involved 40 patients and lasted 2 weeks, compared an FDC with the individual component drugs. Just three trials were conducted in India, involving a total of 129 patients.

Applying the World Health Organization (WHO) 2005 Technical Report, Guidelines for Registration of Fixed-Dose Combination Medicinal Products, the team found that none of the 25 trials met all four WHO criteria for FDCs in terms of study size, design, duration, and side effects.

"Overall, no trials provided enough evidence of safety and efficacy to justify the use of the FDC over concomitant treatments of the same active ingredients," Evans and colleagues write.

Moreover, 18 of the trials were sponsored by multinational companies.

"Our examination exposes serious deficiencies in the evidence base for metformin FDCs for type 2 diabetes. The poor quality of available published trials and their funding sources raise concerns about the motivation for conducting these trials and whether the sponsors are using them for seeding or marketing purposes to gain a foothold in country markets," the researchers said.

"To justify metformin FDC approvals and provide confidence in their efficacy and safety, CDSCO should make public the evidence it used in approving the metformin FDCs examined in this review," they write.

"If that evidence does not extend beyond the trials reviewed here, those FDCs should be banned immediately."

"If that evidence includes the results of trials not reviewed in this paper, which do not meet the four WHO standards used for evaluation, those FDCs should be banned."

The research was funded by the European Union Seventh Framework Program. The authors have reported no relevant financial relationships.

BMJ Glob Health. 2018;3:e000263. Article

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