The Newcastle University and University of Massachusetts study, published in BMJ Global Health, finds the requisite trial data falling well short of the international standards set by the World Health Organization.

It shows so poor are the data that, not only could the health of patients with type 2 diabetes be potentially put at risk, but they also call into question the role of the multinational corporations behind the manufacture of these drug combos.

Diabetes capital of the world

India is often referred to as ‘the diabetes capital of the world’, with 60 million of its population affected by type 2 diabetes. Two thirds of all diabetes drugs sold in India are what is known as fixed dose combinations, or FDCs for short, often containing metformin and one other drug.

The widespread use of FDCs runs counter to national and international guidelines which don’t recommend their use for treating type 2 diabetes, because of the need for constant monitoring and adjustment of drug doses to maintain adequate blood glucose control.

Amid mounting national and international concerns about the drug regulatory system in India, where more than 100 new medicines are approved each year by the Central Drugs Standard Control Organization (CDSCO), the UK and US research team set out to scrutinise the clinical trial data for the top five best-selling FDCs.

They combined data on these FDCs from 25 published and unpublished trials with information from a commercial drugs sales database (PharmaTrac) for the 12 months from November 2011 to October 2012.

The trial data were reviewed in the context of the four WHO standards set for FDC approvals in 2005. India has its own regulations for FDCs, but the WHO guidelines are more comprehensive and rigorous, say the researchers.

They comprise minimum requirements for the conduct of FDC clinical trials on size (several hundred to several thousand participants); duration (at least six months); design (whether the combination is better than the individual drugs); and side-effects (the pros have to outweigh the cons).

None of the 25 trials met all four WHO criteria.

Trial data falls short

For example, only two trials had more than 500 participants; only 10 lasted at least six months; only one had been designed to show whether the combination was better than the individual drugs alone; no study assessed the balance between the pros and cons. And only three trials had been conducted in India.

The five top sellers accounted for 80% of all metformin FDC sales by value and volume. While all five had been given the green light by CDSCO,  three had already been sold and marketed before they were submitted for regulatory approval.

What’s more, scrutiny of the clinical trial data for these five FDCs revealed that not one provided any evidence of safety or effectiveness for the treatment of type 2 diabetes.

In fact, four out the five were on the list of FDCs banned by the Ministry of Health and Family Welfare in March 2016--a ban that was subsequently overturned by the Delhi High Court, a decision upheld by the Supreme Court in 2017, following extensive lobbying by the multinationals behind the manufacture of FDCs.

Eighteen of the 25 trials were sponsored by multinational corporations or conducted by pharmaceutical companies, prompting the researchers to question the independence of the approvals process.

Co-author Professor Allyson Pollock, Director of the Institute of Health and Society at Newcastle University, said: “The lack of good clinical trial evidence for these five top-selling metformin combination medicines for treatment of type 2 diabetes is of deep concern for patients and the public – without it prescribers and patients do not know that the drugs that are being prescribed and consumed are safe and effective.”

Concerns raised

Professor Pollock and her fellow researchers write, “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.” 

They go on to say that the CDSCO should go public on the data it used to approve these drugs, given the ostensible lack of evidence on their safety and effectiveness.

“If that evidence does not extend beyond the trials reviewed here, those FDCs should be banned immediately,” they urge in the research paper, adding that “legislation setting out clinical trial requirements for new drugs should be revised to prevent irrational FDCs from entering the market.”

Professor Pollock added: “In the interests of public health and patient safety , the Government’s 2016 ban on FDCs should be reinstated and a review of FDCs mandated by the Indian Parliament, and the regulations strengthened.”

Reference: Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India. BMJ Global Health. DOI: 10.1136/bmjgh-2016-000263

 (Press release adapted with thanks to BMJ)