Risk factors

Regulator criticised for inaction on strontium safety concerns

The European Medicines Agency took a decade too long to act on concerns about the cardiovascular safety of strontium ranelate and placed patients with osteoporosis at unnecessary risk, a recent review has claimed.

Associate Professors Mark Bolland and Andrew Grey, from the University of Auckland, said documentation from 2006-07 showed that strontium ranelate increased the risk of myocardial infarction and congestive heart failure.

“The EMA did not act on these data at the time or make them publicly known until 2013, indicating regulatory failure,” they wrote in the BMJ.

“The risks of strontium ranelate outweigh the benefits, and it should not be prescribed for fracture prevention.”

Bolland and Grey outlined the sequence of events since the findings of the phase 3 TROPOS study were used to support approval of the drug in 2004 for postmenopausal osteoporosis. It was not until 2013 that the EMA reported it increased the risk of myocardial infarction.

They obtained clinical safety reports and safety assessments conducted by EMA in 2006-07, after successfully appealing against a decision that the information should be withheld because of commercial sensitivity.

The documentation confirmed that EMA identified cardiac safety concerns in 2007 but did not report them.

A further review was initiated in 2013, leading an EMA committee to recommend – with some dissenters – that the benefits of strontium did not outweigh the risks and its registration should be suspended.

A superior EMA committee overruled the finding – again with dissenters – allowing strontium to remain on the market with restrictive prescribing conditions for patients with no other treatment options.

Bolland and Grey criticised elements of the regulatory and review processes, including their transparency and reliance on the drug’s manufacturer to provide and interpret new data.

They said the initial reporting of adverse events in clinical trials was also flawed, for example because of multiple terms used to describe heart failure.

“Ten years after strontium was introduced to clinical practice, its risks and benefits can be independently evaluated,” they said. Among about 6,700 patients enrolled in two pivotal phase 3 studies, there would be 55 fewer non-vertebral fractures and five fewer hip

fractures as a result of strontium treatment. However, there would be 25 more cases of myocardial infarction, 27 more cases of venous thromboembolism (including 11 more cases of pulmonary embolism) and 19 more cases of heart failure.

In Australia a warning on cardiovascular risk was added to the prescribing information for Protos in 2014. The drug was withdrawn from the PBS in August 2016 after a failure to reach agreement on the price following its restricted listing.

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