Introduction
Clinical trials are a crucial step in the development of new medicines. They are required by national drug regulatory agencies to ensure medicines are safe and effective for use in a human population. Every country is responsible for maintaining a stringent approval system to control the entry and distribution of medicines within their borders. Typically, this requires the successful completion and adequate presentation of results from phase I through phase III clinical trials, from preliminary safety data to the analysis of safety and efficacy results from extensive human trials. The US Food and Drug Administration (FDA) approves approximately 40 new medicines for the US market each year through this process.1 Drug approval packages for new drugs, which include a full review of submitted materials for approved drugs, are available through the FDA’s website. India approves more than 100 new medicines a year but does not publish data on submitted applications or summaries of approved medicines, and concerns have been raised about the safety and efficacy around medicine approvals in the absence of appropriate clinical trials.2–5
Over 60 million people have been diagnosed with type 2 diabetes mellitus in India, which has been described as ‘the diabetes capital of the world’.6 Given the constant monitoring and rapid adjustment of treatment regimens required to maintain adequate glycaemic control, metformin fixed-dose combinations (FDCs) are not recommended by national or international treatment guidelines. Nevertheless, the Central Drugs Standard Control Organization (CDSCO), India’s drug regulator, has given approval for 52 FDC formulations for type 2 diabetes, which in turn has given rise to more than 500 marketed brands of metformin FDCs. In contrast, only two metformin FDCs are approved in the USA, one in Australia, and none in either the UK or Canada (figure 1).3 4 Twenty-seven metformin FDCs were included in the Indian government’s ban of 344 unapproved FDCs in March 2016 as having ‘no therapeutic justification’ following consideration of nearly 6000 unapproved FDCs by an expert committee (see online supplementary table 1).2 The ban was lifted in December 2016 by the Delhi High Court and was upheld by the Supreme Court in December 2017.7 8 The Supreme Court required the Drugs Technical Advisory Board to consider the banned drugs (except those approved before 1988) and to submit a report within 6 months.
One of the primary arguments for prescribing FDCs for treatment of type 2 diabetes is improved adherence to treatment due to convenience.9 10 While some studies suggest FDCs are associated with better adherence than concomitant single-drug formulations (SDFs), they should only be considered when the patient has been stable on a regimen of concomitant SDFs for an extended period of time.11–14 Glucose levels fluctuate and treatment adjustments are often needed, but such adjustments are particularly difficult when using FDCs because doses are fixed. Regardless, the convenience of FDCs should not trump efficacy.
The availability of irrational or inadequately tested medicines puts the safety of the public at risk. It is important to ensure that those medicines that are available on the market have been approved after examination for safety and efficacy through the implementation of appropriately designed and analysed clinical trials. This work is an evaluation of the clinical evidence on the safety and efficacy of the most common metformin FDCs sold for treating type 2 diabetes in India.